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  • 1.
    Abadpour, Shadab
    et al.
    Oslo University Hospital, Oslo, Norway.
    Halvorsen, Bente
    Oslo University Hospital, Oslo, Norway.
    Sahraoui, Afaf
    University of Oslo, Oslo, Norway.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Aukrust, Pål
    Oslo University Hospital, Oslo, Norway.
    Scholz, Hanne
    Oslo University Hospital, Oslo, Norway.
    Interleukin-22 reverses human islet dysfunction and apoptosis triggered by hyperglycemia and LIGHT2018In: Journal of Molecular Endocrinology, ISSN 0952-5041, E-ISSN 1479-6813, Vol. 60, no 3, p. 171-183Article in journal (Refereed)
    Abstract [en]

    Interleukin (IL)-22 has recently been suggested as an anti-inflammatory cytokine that could protect the islet cells from inflammation- and glucose-induced toxicity. We have previously shown that the tumor necrosis factor family member, LIGHT can impair human islet function at least partly via pro-apoptotic effects. Herein, we aimed to investigate the protective role of IL-22 on human islets exposed to the combination of hyperglycemia and LIGHT. First, we found up-regulation of LIGHT receptors (LTβR and HVEM) in engrafted human islets exposed to hyperglycemia (>11 mM) for 17 days post transplantation by using a double islet transplantation mouse model as well as in human islets cultured with high glucose (HG) (20mM glucose) + LIGHT in vitro and this latter effect was attenuated by IL-22. The effect of HG + LIGHT impairing glucose stimulated insulin secretion was reversed by IL-22. The harmful effect of HG + LIGHT on human islet function seemed to involve enhanced endoplasmic reticulum stress evidenced by up-regulation of p-IRE1α and BiP, elevated secretion of pro-inflammatory cytokines (IL-6, IL-8, IP-10 and MCP-1) and the pro-coagulant mediator tissue factor (TF) release and apoptosis in human islets, whereas all these effects were at least partly reversed by IL-22. Our findings suggest that IL-22 could counteract the harmful effects of LIGHT/hyperglycemia on human islet cells and potentially support the strong protective effect of IL-22 on impaired islet function and survival.

  • 2.
    Abadpour, Shadab
    et al.
    Oslo Univ Hosp, Dept Transplant Med, Sognsvannsveien 20, Oslo 0027, Norway.;Oslo Univ Hosp, Inst Surg Res, Sognsvannsveien 20, Oslo 0027, Norway.;Univ Oslo, Inst Basic Med Sci, Ctr Excellence, Hybrid Technol Hub, Oslo, Norway..
    Tyrberg, Bjorn
    AstraZeneca, BioPharmaceut R&D, Res & Early Dev Cardiovasc Renal & Metab, Peppredsleden 1, Gothenburg 43183, Sweden..
    Schive, Simen W.
    Oslo Univ Hosp, Dept Transplant Med, Sognsvannsveien 20, Oslo 0027, Norway.;Oslo Univ Hosp, Inst Surg Res, Sognsvannsveien 20, Oslo 0027, Norway..
    Huldt, Charlotte Wennberg
    AstraZeneca, BioPharmaceut R&D, Res & Early Dev Cardiovasc Renal & Metab, Peppredsleden 1, Gothenburg 43183, Sweden..
    Gennemark, Peter
    AstraZeneca, BioPharmaceut R&D, Res & Early Dev Cardiovasc Renal & Metab, Peppredsleden 1, Gothenburg 43183, Sweden.;Univ Linköping, Dept Biomed Engn, Linköping, Sweden..
    Ryberg, Erik
    AstraZeneca, BioPharmaceut R&D, Res & Early Dev Cardiovasc Renal & Metab, Peppredsleden 1, Gothenburg 43183, Sweden..
    Ryden-Bergsten, Tina
    AstraZeneca, BioPharmaceut R&D, Res & Early Dev Cardiovasc Renal & Metab, Peppredsleden 1, Gothenburg 43183, Sweden..
    Smith, David M.
    AstraZeneca, BioPharmaceut R&D, Res & Early Dev Cardiovasc Renal & Metab, Peppredsleden 1, Gothenburg 43183, Sweden.;AstraZeneca, BioPharmaceut R&D, Discovery Sci, Hit Discovery, Cambridge, England..
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Skrtic, Stanko
    AstraZeneca, BioPharmaceut R&D, Res & Early Dev Cardiovasc Renal & Metab, Peppredsleden 1, Gothenburg 43183, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Inst Med, Gothenburg, Sweden..
    Scholz, Hanne
    Oslo Univ Hosp, Dept Transplant Med, Sognsvannsveien 20, Oslo 0027, Norway.;Oslo Univ Hosp, Inst Surg Res, Sognsvannsveien 20, Oslo 0027, Norway.;Univ Oslo, Inst Basic Med Sci, Ctr Excellence, Hybrid Technol Hub, Oslo, Norway..
    Winzell, Maria Sorhede
    AstraZeneca, BioPharmaceut R&D, Res & Early Dev Cardiovasc Renal & Metab, Peppredsleden 1, Gothenburg 43183, Sweden..
    Inhibition of the prostaglandin D2-GPR44/DP2 axis improves human islet survival and function2020In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 63, no 7, p. 1355-1367Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis Inflammatory signals and increased prostaglandin synthesis play a role during the development of diabetes. The prostaglandin D-2 (PGD(2)) receptor, GPR44/DP2, is highly expressed in human islets and activation of the pathway results in impaired insulin secretion. The role of GPR44 activation on islet function and survival rate during chronic hyperglycaemic conditions is not known. In this study, we investigate GPR44 inhibition by using a selective GPR44 antagonist (AZ8154) in human islets both in vitro and in vivo in diabetic mice transplanted with human islets. Methods Human islets were exposed to PGD(2) or proinflammatory cytokines in vitro to investigate the effect of GPR44 inhibition on islet survival rate. In addition, the molecular mechanisms of GPR44 inhibition were investigated in human islets exposed to high concentrations of glucose (HG) and to IL-1 beta. For the in vivo part of the study, human islets were transplanted under the kidney capsule of immunodeficient diabetic mice and treated with 6, 60 or 100 mg/kg per day of a GPR44 antagonist starting from the transplantation day until day 4 (short-term study) or day 17 (long-term study) post transplantation. IVGTT was performed on mice at day 10 and day 15 post transplantation. After termination of the study, metabolic variables, circulating human proinflammatory cytokines, and hepatocyte growth factor (HGF) were analysed in the grafted human islets. Results PGD(2) or proinflammatory cytokines induced apoptosis in human islets whereas GPR44 inhibition reversed this effect. GPR44 inhibition antagonised the reduction in glucose-stimulated insulin secretion induced by HG and IL-1 beta in human islets. This was accompanied by activation of the Akt-glycogen synthase kinase 3 beta signalling pathway together with phosphorylation and inactivation of forkhead box O-1and upregulation of pancreatic and duodenal homeobox-1 and HGF. Administration of the GPR44 antagonist for up to 17 days to diabetic mice transplanted with a marginal number of human islets resulted in reduced fasting blood glucose and lower glucose excursions during IVGTT. Improved glucose regulation was supported by increased human C-peptide levels compared with the vehicle group at day 4 and throughout the treatment period. GPR44 inhibition reduced plasma levels of TNF-alpha and growth-regulated oncogene-alpha/chemokine (C-X-C motif) ligand 1 and increased the levels of HGF in human islets. Conclusions/interpretation Inhibition of GPR44 in human islets has the potential to improve islet function and survival rate under inflammatory and hyperglycaemic stress. This may have implications for better survival rate of islets following transplantation.

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  • 3.
    Abels, M.
    et al.
    Lund Univ, Ctr Diabet, Malmo, Sweden..
    Riva, M.
    Lund Univ, Ctr Diabet, Malmo, Sweden..
    Poon, W.
    Lund Univ, Ctr Diabet, Malmo, Sweden..
    Bennet, H.
    Lund Univ, Ctr Diabet, Malmo, Sweden..
    Nagaraj, V.
    Lund Univ, Ctr Diabet, Malmo, Sweden..
    Dyachok, Oleg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Isomaa, B.
    Folkhalsan Res Ctr, Helsinki, Finland.;Dept Social Serv & Hlth Care, Jacobstad, Finland..
    Tuomi, T.
    Folkhalsan Res Ctr, Helsinki, Finland.;Dept Med, Helsinki, Finland..
    Ahren, B.
    Lund Univ, Ctr Diabet, Lund, Sweden..
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Fex, M.
    Lund Univ, Ctr Diabet, Malmo, Sweden..
    Renstrom, E.
    Lund Univ, Ctr Diabet, Malmo, Sweden..
    Groop, L.
    Lund Univ, Ctr Diabet, Malmo, Sweden..
    Lyssenko, V.
    Lund Univ, Ctr Diabet, Malmo, Sweden..
    Wierup, N.
    Lund Univ, Ctr Diabet, Malmo, Sweden..
    CART is a novel glucose-dependent peptide with antidiabetic actions in humans2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no Suppl. 1, p. S279-S280Article in journal (Other academic)
  • 4.
    Abels, Mia
    et al.
    Lund Univ, Ctr Diabet, Skane Univ Hosp, Lund, Sweden.;Lund Univ, Ctr Diabet, Skane Univ Hosp, Malmo, Sweden..
    Riva, Matteo
    Lund Univ, Ctr Diabet, Skane Univ Hosp, Lund, Sweden.;Lund Univ, Ctr Diabet, Skane Univ Hosp, Malmo, Sweden..
    Bennet, Hedvig
    Lund Univ, Ctr Diabet, Skane Univ Hosp, Lund, Sweden.;Lund Univ, Ctr Diabet, Skane Univ Hosp, Malmo, Sweden..
    Ahlqvist, Emma
    Lund Univ, Ctr Diabet, Skane Univ Hosp, Lund, Sweden.;Lund Univ, Ctr Diabet, Skane Univ Hosp, Malmo, Sweden..
    Dyachok, Oleg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Nagaraj, Vini
    Lund Univ, Ctr Diabet, Skane Univ Hosp, Lund, Sweden.;Lund Univ, Ctr Diabet, Skane Univ Hosp, Malmo, Sweden..
    Shcherbina, Liliya
    Lund Univ, Ctr Diabet, Skane Univ Hosp, Lund, Sweden.;Lund Univ, Ctr Diabet, Skane Univ Hosp, Malmo, Sweden..
    Fred, Rikard G.
    Lund Univ, Ctr Diabet, Skane Univ Hosp, Lund, Sweden.;Lund Univ, Ctr Diabet, Skane Univ Hosp, Malmo, Sweden..
    Poon, Wenny
    Lund Univ, Ctr Diabet, Skane Univ Hosp, Lund, Sweden.;Lund Univ, Ctr Diabet, Skane Univ Hosp, Malmo, Sweden..
    Sorhede-Winzell, Maria
    Lund Univ, Ctr Diabet, Skane Univ Hosp, Lund, Sweden.;Lund Univ, Ctr Diabet, Skane Univ Hosp, Malmo, Sweden..
    Fadista, Joao
    Lund Univ, Ctr Diabet, Skane Univ Hosp, Lund, Sweden.;Lund Univ, Ctr Diabet, Skane Univ Hosp, Malmo, Sweden..
    Lindqvist, Andreas
    Lund Univ, Ctr Diabet, Skane Univ Hosp, Lund, Sweden.;Lund Univ, Ctr Diabet, Skane Univ Hosp, Malmo, Sweden..
    Kask, Lena
    Lund Univ, Ctr Diabet, Skane Univ Hosp, Lund, Sweden.;Lund Univ, Ctr Diabet, Skane Univ Hosp, Malmo, Sweden..
    Sathanoori, Ramasri
    Lund Univ, Ctr Diabet, Skane Univ Hosp, Lund, Sweden.;Lund Univ, Ctr Diabet, Skane Univ Hosp, Malmo, Sweden..
    Dekker-Nitert, Marloes
    Lund Univ, Ctr Diabet, Skane Univ Hosp, Lund, Sweden.;Lund Univ, Ctr Diabet, Skane Univ Hosp, Malmo, Sweden..
    Kuhar, Michael J.
    Emory Univ, Yerkes Res Ctr, Atlanta, GA 30322 USA..
    Ahren, Bo
    Lund Univ, Ctr Diabet, Skane Univ Hosp, Lund, Sweden.;Lund Univ, Ctr Diabet, Skane Univ Hosp, Malmo, Sweden..
    Wollheim, Claes B.
    Univ Med Ctr, Dept Cell Physiol & Metab, Geneva, Switzerland..
    Hansson, Ola
    Lund Univ, Ctr Diabet, Skane Univ Hosp, Lund, Sweden.;Lund Univ, Ctr Diabet, Skane Univ Hosp, Malmo, Sweden..
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Fex, Malin
    Lund Univ, Ctr Diabet, Skane Univ Hosp, Lund, Sweden.;Lund Univ, Ctr Diabet, Skane Univ Hosp, Malmo, Sweden..
    Renström, Erik
    Lund Univ, Ctr Diabet, Skane Univ Hosp, Lund, Sweden.;Lund Univ, Ctr Diabet, Skane Univ Hosp, Malmo, Sweden..
    Groop, Leif
    Lund Univ, Ctr Diabet, Skane Univ Hosp, Lund, Sweden.;Lund Univ, Ctr Diabet, Skane Univ Hosp, Malmo, Sweden..
    Lyssenko, Valeriya
    Lund Univ, Ctr Diabet, Skane Univ Hosp, Lund, Sweden.;Lund Univ, Ctr Diabet, Skane Univ Hosp, Malmo, Sweden.;Steno Diabet Ctr AS, Gentofte, Denmark..
    Wierup, Nils
    Lund Univ, Ctr Diabet, Skane Univ Hosp, Lund, Sweden.;Lund Univ, Ctr Diabet, Skane Univ Hosp, Malmo, Sweden.;Lund Univ, Clin Res Ctr 91 12, Ctr Diabet, Skane Univ Hosp,Dept Clin Sci Malmo,Unit Neuroend, Jan Waldenstroms Gata 35, S-20502 Malmo, Sweden..
    CART is overexpressed in human type 2 diabetic islets and inhibits glucagon secretion and increases insulin secretion2016In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, no 9, p. 1928-1937Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis Insufficient insulin release and hyperglucagonaemia are culprits in type 2 diabetes. Cocaine- and amphetamine-regulated transcript (CART, encoded by Cartpt) affects islet hormone secretion and beta cell survival in vitro in rats, and Cart(-/-) mice have diminished insulin secretion. We aimed to test if CART is differentially regulated in human type 2 diabetic islets and if CART affects insulin and glucagon secretion in vitro in humans and in vivo in mice. Methods CART expression was assessed in human type 2 diabetic and non-diabetic control pancreases and rodent models of diabetes. Insulin and glucagon secretion was examined in isolated islets and in vivo in mice. Ca2+ oscillation patterns and exocytosis were studied in mouse islets. Results We report an important role of CART in human islet function and glucose homeostasis in mice. CART was found to be expressed in human alpha and beta cells and in a subpopulation of mouse beta cells. Notably, CART expression was several fold higher in islets of type 2 diabetic humans and rodents. CART increased insulin secretion in vivo in mice and in human and mouse islets. Furthermore, CART increased beta cell exocytosis, altered the glucose-induced Ca2+ signalling pattern in mouse islets from fast to slow oscillations and improved synchronisation of the oscillations between different islet regions. Finally, CART reduced glucagon secretion in human and mouse islets, as well as in vivo in mice via diminished alpha cell exocytosis. Conclusions/interpretation We conclude that CART is a regulator of glucose homeostasis and could play an important role in the pathophysiology of type 2 diabetes. Based on the ability of CART to increase insulin secretion and reduce glucagon secretion, CART-based agents could be a therapeutic modality in type 2 diabetes.

  • 5.
    Abrahamsson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    On the Impact of Bariatric Surgery on Glucose Homeostasis2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Obesity has grown to epidemic proportions, and in lack of efficient life-style and medical treatments, the bariatric surgeries are performed in rising numbers. The most common surgery is the Gastric Bypass (GBP) surgery, with the Biliopancreatic diversion with duodenal switch (DS) as an option for the most extreme cases with a BMI>50 kg/m2.

    In paper I 20 GBP-patients were examined during the first post-operative year regarding the natriuretic peptide, NT-ProBNP, which is secreted from the cardiac ventricles. Levels of NT-ProBNP quickly increased during the first post-surgery week, and later established itself on a higher level than pre-surgery.

    In paper II we report of 5 patient-cases after GBP-surgery with severe problems with postprandial hypoglycaemia that were successfully treated with GLP-1-analogs. The effect of treatment could be observed both symptomatically and in some cases using continuous glucose measuring systems (CGMS).

    In paper III three groups of subjects; 15 post-GBP patients, 15 post-DS, and 15 obese controls were examined for three days using CGMS during everyday life. The post-GBP group had high glucose variability as measured by MAGE and CONGA, whereas the post-DS group had low variability. Both post-operative groups exhibited significant time in hypoglycaemia, about 40 and 80 minutes per day <3.3mmol/l and 20 and 40 minutes < 2.8mmol/l, respectively, longer time for DS-group. Remarkably, only about 20% of these hypoglycaemic episodes were accompanied with symptoms.

    In Paper IV the hypoglycaemia counter regulatory system was investigated; 12 patients were examined before and after GBP-surgery with a stepped hypoglycaemic hyperinsulinemic clamp. The results show a downregulation of symptoms, counter regulatory hormones (glucagon, cortisol, epinephrine, norepinephrine, growth hormone), incretin hormones (GLP-1 and GIP), and sympathetic nervous response.

    In conclusion patients post bariatric surgery exhibit a downregulated counter regulatory response to hypoglycaemia, accompanied by frequent asymptomatic hypoglycaemic episodes in everyday life. Patients suffering from severe hypoglycaemic episodes can often be treated successfully with GLP-1-analogues.

    List of papers
    1. Gastric Bypass Surgery Elevates NT-ProBNP Levels
    Open this publication in new window or tab >>Gastric Bypass Surgery Elevates NT-ProBNP Levels
    2013 (English)In: Obesity Surgery, ISSN 0960-8923, E-ISSN 1708-0428, Vol. 23, no 9, p. 1421-1426Article in journal (Refereed) Published
    Abstract [en]

    Background

    Brain natriuretic peptide (BNP) is produced in the heart in response to stretching of the myocardium. BNP levels are negatively correlated to obesity, and in obese subjects, a reduced BNP responsiveness has been described. Diet-induced weight loss has been found to lower or to have no effect on BNP levels, whereas gastric banding and gastric bypass have reported divergent results. We studied obese patients undergoing gastric bypass (GBP) surgery during follow-up of 1 year.

    Methods

    Twenty patients, 18 women, mean 41 (SD 9.5) years old, with a mean preoperative BMI of 44.6 (SD 5.5) kg/m2 were examined. N-terminal pro-brain natriuretic peptide (NT-ProBNP), glucose and insulin were measured preoperatively, at day 6 and months 1, 6 and 12. In 14 of the patients, samples were also taken at days 1, 2 and 4.

    Results

    The NT-ProBNP levels showed a marked increase during the postoperative week (from 54 pg/mL preop to 359 pg/mL on day 2 and fell to 155 on day 6). At 1 year, NT-ProBNP was 122 pg/mL (125 % increase, p = 0.01). Glucose, insulin and HOMA indices decreased shortly after surgery without correlation to NT-ProBNP change. Mean BMI was reduced from 44.6 to 30.5 kg/m2 at 1 year and was not related to NT-ProBNP change.

    Conclusions

    The data indicate that GBP surgery rapidly alters the tone of BNP release, by a mechanism not related to weight loss or to changes in glucometabolic parameters. The GBP-induced conversion of obese subjects, from low to high NT-ProBNP responders, is likely to influence the evaluation of cardiac function in GBP operated individuals.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-199870 (URN)10.1007/s11695-013-0889-z (DOI)000322494800011 ()23456799 (PubMedID)
    Available from: 2013-05-17 Created: 2013-05-17 Last updated: 2017-12-06Bibliographically approved
    2. GLP1 analogs as treatment of postprandial hypoglycemia following gastric bypass surgery: a potential new indication?
    Open this publication in new window or tab >>GLP1 analogs as treatment of postprandial hypoglycemia following gastric bypass surgery: a potential new indication?
    2013 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 169, no 6, p. 885-889Article in journal (Refereed) Published
    Abstract [en]

    Objective: The number of morbidly obese subjects submitted to bariatric surgery is rising worldwide. In a fraction of patients undergoing gastric bypass (GBP), episodes with late postprandial hypoglycemia (PPHG) develop 1-3 years after surgery. The pathogenesis of this phenomenon is not fully understood; meal-induced rapid and exaggerated increases of circulating incretins and insulin appear to be at least partially responsible. Current treatments include low-carbohydrate diets, inhibition of glucose intestinal uptake, reduction of insulin secretion with calcium channel blockers, somatostatin analogs, or diazoxide, a KATP channel opener. Even partial pancreatectomy has been advocated. In type 2 diabetes, GLP1 analogs have a well-documented effect of stabilizing glucose levels without causing hypoglycemia. Design: We explored GLP1 analogs as open treatment in five consecutive GBP cases seeking medical attention because of late postprandial hypoglycemic symptoms. Results: Glucose measured in connection with the episodes in four of the cases had been 2.7, 2.5, 1.8, and 1.6 mmol/l respectively. The patients consistently described that the analogs eliminated their symptoms, which relapsed in four of the five patients when treatment was reduced/discontinued. The drug effect was further documented in one case by repeated 24-h continuous glucose measurements. Conclusion: These open, uncontrolled observations suggest that GLP1 analogs might provide a new treatment option in patients with problems of late PPHG.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-213465 (URN)10.1530/EJE-13-0504 (DOI)000327539100021 ()
    Available from: 2014-01-02 Created: 2013-12-23 Last updated: 2017-12-06Bibliographically approved
    3. Hypoglycemia in everyday life after gastric bypass and duodenal switch
    Open this publication in new window or tab >>Hypoglycemia in everyday life after gastric bypass and duodenal switch
    2015 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 173, no 1, p. 91-100Article in journal (Refereed) Published
    Abstract [en]

    Design: Gastric bypass (GBP) and duodenal switch (DS) in morbid obesity are accompanied by marked metabolic improvements, particularly in glucose control. In recent years, episodes of severe late postprandial hypoglycemia have been increasingly described in GBP patients; data in DS patients are scarce. We recruited three groups of subjects; 15 GBP, 15 DS, and 15 non-operated overweight controls to examine to what extent hypoglycemia occurs in daily life. Methods: Continuous glucose monitoring (CGM) was used during 3 days of normal activity. The glycemic variability was measured by mean amplitude of glycemic excursion and continuous overall net glycemic action. Fasting blood samples were drawn, and the patients kept a food and symptom log throughout the study. Results: The GBP group displayed highly variable CGM curves, and 2.9% of their time was spent in hypoglycemia (< 3.3 mmol/l, or 60 mg/dl). The DS group had twice as much time in hypoglycemia (5.9%) and displayed CGM curves with little variation as well as lower HbA1c levels (29.3 vs 35.9 mmol/mol, P < 0.05). Out of a total of 72 hypoglycemic episodes registered over the 3-day period, 70 (97%) occurred in the postprandial state and only about one-fifth of the hypoglycemic episodes in the GBP and DS groups were accompanied by symptoms. No hypoglycemias were seen in controls during the 3-day period. Conclusion: Both types of bariatric surgery induce marked, but different, changes in glucose balance accompanied by frequent, but mainly unnoticed, hypoglycemic episodes. The impact and mechanism of hypoglycemic unawareness after weight-reduction surgery deserves to be clarified.

    National Category
    Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-261313 (URN)10.1530/EJE-14-0821 (DOI)000358947700018 ()25899582 (PubMedID)
    Available from: 2015-09-03 Created: 2015-09-01 Last updated: 2017-12-04Bibliographically approved
    4. Gastric bypass reduces symptoms and hormonal responses to hypoglycemia
    Open this publication in new window or tab >>Gastric bypass reduces symptoms and hormonal responses to hypoglycemia
    Show others...
    2016 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, no 9, p. 2667-2675Article in journal (Refereed) Published
    Abstract [en]

    Gastric bypass (GBP) surgery, one of the most common bariatric procedures, induces weight loss and metabolic effects. The mechanisms are not fully understood, but reduced food intake and effects on gastrointestinal hormones are thought to contribute. We recently observed that GBP patients have lowered glucose levels and frequent asymptomatic hypoglycemic episodes. Here, we subjected patients before and after undergoing GBP surgery to hypoglycemia and examined symptoms and hormonal and autonomic nerve responses. Twelve obese patients without diabetes (8 women, mean age 43.1 years [SD 10.8] and BMI 40.6 kg/m(2) [SD 3.1]) were examined before and 23 weeks (range 19-25) after GBP surgery with hyperinsulinemic-hypoglycemic clamp (stepwise to plasma glucose 2.7 mmol/L). The mean change in Edinburgh Hypoglycemia Score during clamp was attenuated from 10.7 (6.4) before surgery to 5.2 (4.9) after surgery. There were also marked postsurgery reductions in levels of glucagon, cortisol, and catecholamine and the sympathetic nerve responses to hypoglycemia. In addition, growth hormone displayed a delayed response but to a higher peak level. Levels of glucagon-like peptide 1 and gastric inhibitory polypeptide rose during hypoglycemia but rose less postsurgery compared with presurgery. Thus, GBP surgery causes a resetting of glucose homeostasis, which reduces symptoms and neurohormonal responses to hypoglycemia. Further studies should address the underlying mechanisms as well as their impact on the overall metabolic effects of GBP surgery.

    Keywords
    Gastric bypass, hypoglycemia
    National Category
    Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-276380 (URN)10.2337/db16-0341 (DOI)000382099800021 ()27313315 (PubMedID)
    Funder
    Swedish Diabetes Association
    Available from: 2016-02-12 Created: 2016-02-12 Last updated: 2017-11-30Bibliographically approved
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  • 6.
    Abrahamsson, Niclas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Engström, Britt Edén
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Karlsson, Anders F.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Hypoglycemia in everyday life after gastric bypass and duodenal switch2015In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 173, no 1, p. 91-100Article in journal (Refereed)
    Abstract [en]

    Design: Gastric bypass (GBP) and duodenal switch (DS) in morbid obesity are accompanied by marked metabolic improvements, particularly in glucose control. In recent years, episodes of severe late postprandial hypoglycemia have been increasingly described in GBP patients; data in DS patients are scarce. We recruited three groups of subjects; 15 GBP, 15 DS, and 15 non-operated overweight controls to examine to what extent hypoglycemia occurs in daily life. Methods: Continuous glucose monitoring (CGM) was used during 3 days of normal activity. The glycemic variability was measured by mean amplitude of glycemic excursion and continuous overall net glycemic action. Fasting blood samples were drawn, and the patients kept a food and symptom log throughout the study. Results: The GBP group displayed highly variable CGM curves, and 2.9% of their time was spent in hypoglycemia (< 3.3 mmol/l, or 60 mg/dl). The DS group had twice as much time in hypoglycemia (5.9%) and displayed CGM curves with little variation as well as lower HbA1c levels (29.3 vs 35.9 mmol/mol, P < 0.05). Out of a total of 72 hypoglycemic episodes registered over the 3-day period, 70 (97%) occurred in the postprandial state and only about one-fifth of the hypoglycemic episodes in the GBP and DS groups were accompanied by symptoms. No hypoglycemias were seen in controls during the 3-day period. Conclusion: Both types of bariatric surgery induce marked, but different, changes in glucose balance accompanied by frequent, but mainly unnoticed, hypoglycemic episodes. The impact and mechanism of hypoglycemic unawareness after weight-reduction surgery deserves to be clarified.

  • 7.
    Abrahamsson, Niclas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Lau Börjesson, Joey
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Wiklund, Urban
    Umea Univ, Biomed Engn, Dept Radiat Sci, Umea, Sweden.
    Karlsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Eriksson, Jan W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Gastric bypass reduces symptoms and hormonal responses to hypoglycemia2016In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, no 9, p. 2667-2675Article in journal (Refereed)
    Abstract [en]

    Gastric bypass (GBP) surgery, one of the most common bariatric procedures, induces weight loss and metabolic effects. The mechanisms are not fully understood, but reduced food intake and effects on gastrointestinal hormones are thought to contribute. We recently observed that GBP patients have lowered glucose levels and frequent asymptomatic hypoglycemic episodes. Here, we subjected patients before and after undergoing GBP surgery to hypoglycemia and examined symptoms and hormonal and autonomic nerve responses. Twelve obese patients without diabetes (8 women, mean age 43.1 years [SD 10.8] and BMI 40.6 kg/m(2) [SD 3.1]) were examined before and 23 weeks (range 19-25) after GBP surgery with hyperinsulinemic-hypoglycemic clamp (stepwise to plasma glucose 2.7 mmol/L). The mean change in Edinburgh Hypoglycemia Score during clamp was attenuated from 10.7 (6.4) before surgery to 5.2 (4.9) after surgery. There were also marked postsurgery reductions in levels of glucagon, cortisol, and catecholamine and the sympathetic nerve responses to hypoglycemia. In addition, growth hormone displayed a delayed response but to a higher peak level. Levels of glucagon-like peptide 1 and gastric inhibitory polypeptide rose during hypoglycemia but rose less postsurgery compared with presurgery. Thus, GBP surgery causes a resetting of glucose homeostasis, which reduces symptoms and neurohormonal responses to hypoglycemia. Further studies should address the underlying mechanisms as well as their impact on the overall metabolic effects of GBP surgery.

  • 8.
    Adam, Sumaiya
    et al.
    Univ Pretoria, Fac Hlth Sci, Sch Med, Dept Obstet & Gynecol, Pretoria, South Africa.;Univ Pretoria, Fac Hlth Sci, Diabet Res Ctr, Pretoria, South Africa..
    McIntyre, Harold David
    Univ Queensland, Mater Hlth, Mater Hlth Campus, South Brisbane, Qld, Australia..
    Tsoi, Kit Ying
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Peoples R China..
    Kapur, Anil
    World Diabet Fdn, Copenhagen, Denmark..
    Ma, Ronald C.
    Chinese Univ Hong Kong, Dept Med & Therapeut, Hong Kong, Peoples R China.;Chinese Univ Hong Kong, Hong Kong Inst Diabet & Obes, Hong Kong, Peoples R China..
    Dias, Stephanie
    South African Med Res Council, Biomed Res & Innovat Platform BRIP, Cape Town, South Africa..
    Okong, Pius
    St Francis Hosp Nsambya, Dept Obstet & Gynecol, Kampala, Uganda..
    Hod, Moshe
    Helen Schneider Hosp Women, Rabin Med Ctr, Petah Tiqwa, Israel.;Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel..
    Poon, Liona C.
    Chinese Univ Hong Kong, Prince Wales Hosp, Dept Obstet & Gynecol, Hong Kong, Peoples R China..
    Smith, Graeme N.
    Queens Univ, Kingston Hlth Sci Ctr, Dept Obstet & Gynecol, Kingston, ON, Canada..
    Bergman, Lina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Clinical Obstetrics. Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Dept Obstet & Gynecol, Gothenburg, Sweden; Stellenbosch Univ, Dept Obstet & Gynecol, Cape Town, South Africa.
    Algurjia, Esraa
    World Assoc Trainees Obstet & Gynecol WATOG, Paris, France.;Elwya Matern Hosp, Baghdad, Iraq..
    O'Brien, Patrick
    UCL, Inst Womens Hlth, London, England..
    Medina, Virna P.
    Univ Valle, Univ Libre, Fac Hlth, Dept Obstet & Gynecol,Clin Imbanaco Quiron Salud, Cali, Colombia..
    Maxwell, Cynthia, V
    Univ Toronto, Maternal Fetal Med, Sinai Hlth, Toronto, ON, Canada.;Univ Toronto, Womens Coll Hosp, Ontario, ON, Canada..
    Regan, Lesley
    Imperial Coll London, London, England..
    Rosser, Mary L.
    Columbia Univ, Dept Obstet & Gynecol, Irving Med Ctr, New York, NY USA..
    Jacobsson, Bo
    Sahlgrens Univ Hosp, Dept Obstet & Gynecol, Gothenburg, Sweden.;Inst Publ Hlth, Dept Genet & Bioinformat, Domain Hlth Data & Digitalisat, Oslo, Norway..
    Hanson, Mark A.
    Univ Hosp Southampton, Inst Dev Sci, Southampton, Hants, England.;Univ Southampton, NIHR Southampton Biomed Res Ctr, Southampton, Hants, England..
    O'Reilly, Sharleen L.
    Univ Coll Dublin, Natl Matern Hosp, UCD Perinatal Res Ctr, Sch Med, Dublin, Ireland.;Univ Coll Dublin, Sch Agr & Food Sci, Dublin, Ireland..
    McAuliffe, Fionnuala M.
    Univ Coll Dublin, Natl Matern Hosp, UCD Perinatal Res Ctr, Sch Med, Dublin, Ireland..
    Pregnancy as an opportunity to prevent type 2 diabetes mellitus: FIGO Best Practice Advice2023In: International Journal of Gynecology & Obstetrics, ISSN 0020-7292, E-ISSN 1879-3479, Vol. 160, no S1, p. 56-67Article in journal (Refereed)
    Abstract [en]

    Gestational diabetes (GDM) impacts approximately 17 million pregnancies worldwide. Women with a history of GDM have an 8-10-fold higher risk of developing type 2 diabetes and a 2-fold higher risk of developing cardiovascular disease (CVD) compared with women without prior GDM. Although it is possible to prevent and/or delay progression of GDM to type 2 diabetes, this is not widely undertaken. Considering the increasing global rates of type 2 diabetes and CVD in women, it is essential to utilize pregnancy as an opportunity to identify women at risk and initiate preventive intervention. This article reviews existing clinical guidelines for postpartum identification and management of women with previous GDM and identifies key recommendations for the prevention and/or delayed progression to type 2 diabetes for global clinical practice.

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  • 9.
    Adolfsson, Eva Thors
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Diabetes Nursing Research.
    Rosenblad, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centre for Clinical Research, County of Västmanland.
    Wikblad, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Diabetes Nursing Research.
    The Swedish National Survey of the Quality and Organization of Diabetes Care in Primary Healthcare—Swed-QOP2010In: Primary Care Diabetes, ISSN 1751-9918, E-ISSN 1878-0210, Vol. 4, no 2, p. 91-97Article in journal (Refereed)
    Abstract [en]

    AIM:

    To describe the quality and organization of diabetes care in primary healthcare in Sweden regarding resources and ways of working.

    METHOD:

    A questionnaire was used to collect data from all 921 primary healthcare centres (PHCCs) in Sweden. Of these, 74.3% (n=684) responded to the questionnaire covering list size of the PHCCs, number of diabetic patients, personnel resources and ways of working.

    RESULTS:

    The median list size reported from the PHCCs was 9,000 patients, 294 of whom were diabetic patients. The majority (72%) of PHCCs had diabetes-responsible general practitioners (GPs) and almost all (97%) had diabetes specialist nurses (DSNs) with some degree of postgraduate education in diabetes. The PHCCs reported that they used regional/local diabetes guidelines (93%), were engaged in call-recall diabetic reviews by GP(s) (66%) and DSN(s) (89%), checked that patients had participated in the reviews by GP(s) (69%) and DSN(s) (78%), arranged group education programmes (23%) and reported data to a National Diabetes Register (82%).

    CONCLUSIONS:

    The presence of diabetes-responsible GP(s) and DSN(s) who use guidelines may contribute to good and equal quality of care. It is, however, necessary to improve the call-recall system and there is an urgent need for all diabetic patients to receive patient education.

  • 10.
    Adolfsson, Peter
    et al.
    Department of Pediatrics, The Hospital of Halland, Kungsbacka, Sweden.; Institute of Clinical Sciences, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden..
    Hartvig, Niels Væver
    Data Science, Novo Nordisk A/S, Søborg, Denmark.
    Kaas, Anne
    Medical & Science, and Novo Nordisk A/S, Søborg, Denmark..
    Møller, Jonas Bech
    Digital Health, Novo Nordisk A/S, Søborg, Denmark.
    Hellman, Jarl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Increased Time in Range and Fewer Missed Bolus Injections After Introduction of a Smart Connected Insulin Pen2020In: Diabetes Technology & Therapeutics, ISSN 1520-9156, E-ISSN 1557-8593, Vol. 22, no 10, p. 709-718Article in journal (Refereed)
    Abstract [en]

    Background: This observational study investigated whether the connected NovoPen® 6 could influence insulin regimen management and glycemic control in people with type 1 diabetes (T1D) using a basal-bolus insulin regimen and continuous glucose monitoring in a real-world setting. Methods: Participants from 12 Swedish diabetes clinics downloaded pen data at each visit (final cohort: n = 94). Outcomes included time in range (TIR; sensor glucose 3.9-10.0 mmol/L), time in hyperglycemia (>10 mmol/L), and hypoglycemia (L1: 3.0- <3.9 mmol/L; L2: <3.0 mmol/L). Missed bolus dose (MBD) injections were meals without bolus injection within -15 and +60 min from the start of a meal. Outcomes were compared between the baseline and follow-up periods (≥5 health care professional visits). Data were analyzed from the first 14 days following each visit. For the TIR and total insulin dose analyses (n = 94), a linear mixed model was used, and for the MBD analysis (n = 81), a mixed Poisson model was used. Results: TIR significantly increased (+1.9 [0.8; 3.0]95% CI h/day; P < 0.001) from baseline to follow-up period, with a corresponding reduction in time in hyperglycemia (-1.8 [-3.0; -0.6]95% CI h/day; P = 0.003) and L2 hypoglycemia (-0.3 [-0.6; -0.1]95% CI h/day; P = 0.005), and no change in time in L1 hypoglycemia. MBD injections decreased by 43% over the study (P = 0.002). Change in MBD injections corresponded to a decrease from 25% to 14% based on the assumption that participants had three main meals per day. Conclusions: Our study highlights the potential benefit on glycemic control and dosing behavior when reliable insulin dose data from a connected pen contribute to insulin management in people with T1D.

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  • 11.
    Aguggia, Julieta P.
    et al.
    Natl Univ La Plata, Argentine Res Council CONICET, Multidisciplinary Inst Cell Biol IMBICE, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    Cornejo, Maria P.
    Natl Univ La Plata, Argentine Res Council CONICET, Multidisciplinary Inst Cell Biol IMBICE, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    Fernandez, Gimena
    Natl Univ La Plata, Argentine Res Council CONICET, Multidisciplinary Inst Cell Biol IMBICE, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    De Francesco, Pablo N.
    Natl Univ La Plata, Argentine Res Council CONICET, Multidisciplinary Inst Cell Biol IMBICE, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    Mani, Bharath K.
    UT Southwestern Med Ctr, Ctr Hypothalam Res, Dept Internal Med, Dallas, TX USA..
    Cassano, Daniela
    Natl Univ La Plata, Argentine Res Council CONICET, Multidisciplinary Inst Cell Biol IMBICE, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    Cabral, Agustina
    Natl Univ La Plata, Argentine Res Council CONICET, Multidisciplinary Inst Cell Biol IMBICE, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    Valdivia, Spring
    Natl Univ La Plata, Argentine Res Council CONICET, Multidisciplinary Inst Cell Biol IMBICE, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    Garcia Romero, Guadalupe
    Natl Univ La Plata, Argentine Res Council CONICET, Multidisciplinary Inst Cell Biol IMBICE, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    Reynaldo, Mirta
    Natl Univ La Plata, Argentine Res Council CONICET, Multidisciplinary Inst Cell Biol IMBICE, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    Fehrentz, Jean-Alain
    Univ Montpellier, Fac Pharm, Inst Biomol Max Mousseron, UMR 5247 CNRS,ENSCM, Montpellier, France..
    Zigman, Jeffrey M.
    UT Southwestern Med Ctr, Ctr Hypothalam Res, Dept Internal Med, Dallas, TX USA..
    Perello, Mario
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Functional Pharmacology and neuroscience. Natl Univ La Plata, Argentine Res Council CONICET, Multidisciplinary Inst Cell Biol IMBICE, Lab Neurophysiol, La Plata, Buenos Aires, Argentina.;Natl Univ La Plata, Sci Res Commiss, Prov Buenos Aires CIC PBA, La Plata, Buenos Aires, Argentina..
    Growth hormone secretagogue receptor signaling in the supramammillary nucleus targets nitric oxide-producing neurons and controls recognition memory in mice2022In: Psychoneuroendocrinology, ISSN 0306-4530, E-ISSN 1873-3360, Vol. 139, article id 105716Article in journal (Refereed)
    Abstract [en]

    Ghrelin is a stomach-derived hormone that acts via the growth hormone secretagogue receptor (GHSR). Recent evidence suggests that some of ghrelin's actions may be mediated via the supramammillary nucleus (SuM). Not only does ghrelin bind to cells within the mouse SuM, but ghrelin also activates SuM cells and intra-SuM ghrelin administration induces feeding in rats. In the current study, we aimed to further characterize ghrelin action in the SuM. We first investigated a mouse model expressing enhanced green fluorescent protein (eGFP) under the promoter of GHSR (GHSR-eGFP mice). We found that the SuM of GHSR-eGFP mice contains a significant amount of eGFP cells, some of which express neuronal nitric oxide synthase. Centrally-, but not systemically-, injected ghrelin reached the SuM, where it induced c-Fos expression. Furthermore, a 5-day 40% calorie restriction protocol, but not a 2-day fast, increased c-Fos expression in non-eGFP+ cells of the SuM of GHSR-eGFP mice, whereas c-Fos induction by calorie restriction was not observed in GHSR-deficient mice. Exposure of satiated mice to a binge-like eating protocol also increased c-Fos expression in non-eGFP+ cells of the SuM of GHSR-eGFP mice in a GHSR-dependent manner. Finally, intra-SuM-injected ghrelin did not acutely affect food intake, locomotor activity, behavioral arousal or spatial memory but increased recognition memory. Thus, we provide a compelling neuroanatomical characterization of GHSR SuM neurons and its behavioral implications in mice.

  • 12.
    Ahlgren, Kerstin M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Fall, Tove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    von Euler, Henrik
    Sundberg, Katarina
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lobell, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hedhammar, Åke
    Andersson, Göran
    Hansson-Hamlin, Helene
    Lernmark, Åke
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lack of evidence for a role of islet autoimmunity in the aetiology of canine diabetes mellitus2014In: PLOS ONE, E-ISSN 1932-6203, Vol. 9, no 8, p. e105473-Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS:

    Diabetes mellitus is one of the most common endocrine disorders in dogs and is commonly proposed to be of autoimmune origin. Although the clinical presentation of human type 1 diabetes (T1D) and canine diabetes are similar, the aetiologies may differ. The aim of this study was to investigate if autoimmune aetiology resembling human T1D is as prevalent in dogs as previously reported.

    METHODS:

    Sera from 121 diabetic dogs representing 40 different breeds were tested for islet cell antibodies (ICA) and GAD65 autoantibodies (GADA) and compared with sera from 133 healthy dogs. ICA was detected by indirect immunofluorescence using both canine and human frozen sections. GADA was detected by in vitro transcription and translation (ITT) of human and canine GAD65, followed by immune precipitation. Sections of pancreata from five diabetic dogs and two control dogs were examined histopathologically including immunostaining for insulin, glucagon, somatostatin and pancreas polypeptide.

    RESULTS:

    None of the canine sera analysed tested positive for ICA on sections of frozen canine or human ICA pancreas. However, serum from one diabetic dog was weakly positive in the canine GADA assay and serum from one healthy dog was weakly positive in the human GADA assay. Histopathology showed marked degenerative changes in endocrine islets, including vacuolisation and variable loss of immune-staining for insulin. No sign of inflammation was noted.

    CONCLUSIONS/INTERPRETATIONS:

    Contrary to previous observations, based on results from tests for humoral autoreactivity towards islet proteins using four different assays, and histopathological examinations, we do not find any support for an islet autoimmune aetiology in canine diabetes mellitus.

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  • 13.
    Ahlqvist, E.
    et al.
    Lund Univ, Ctr Diabet, Malmo, Sweden..
    Karajamaki, A.
    Vaasa Cent Hosp, Primary Hlth Care, Vaasa, Finland..
    Martinell, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Storm, P.
    Lund Univ, Ctr Diabet, Malmo, Sweden..
    Dorkhan, M.
    Lund Univ, Ctr Diabet, Malmo, Sweden..
    Vikman, P.
    Lund Univ, Ctr Diabet, Malmo, Sweden..
    Prasad, R. B.
    Lund Univ, Ctr Diabet, Malmo, Sweden..
    Aly, D. Mansour
    Lund Univ, Ctr Diabet, Malmo, Sweden..
    Shaat, N.
    Lund Univ, Ctr Diabet, Malmo, Sweden..
    Lindholm, E.
    Lund Univ, Ctr Diabet, Malmo, Sweden..
    Tuomi, T.
    Univ Helsinki, Finnish Inst Mol Med, Helsinki, Finland.;Folkhalsan Res Ctr, Helsinki, Finland..
    Rosengren, A. H.
    Lund Univ, Ctr Diabet, Malmo, Sweden..
    Groop, L.
    Lund Univ, Ctr Diabet, Malmo, Sweden.;Univ Helsinki, Finnish Inst Mol Med, Helsinki, Finland..
    Clustering of diabetes into novel subgroups provides improved prediction of outcome2017In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, p. S117-S117Article in journal (Other academic)
  • 14.
    Ahlqvist, Emma
    et al.
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Storm, Petter
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Käräjämäki, Annemarie
    Department of Primary Health Care, Vaasa Central Hospital, Finland.
    Martinell, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Dorkhan, Mozhgan
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Carlsson, Annelie
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital, SE-22185 Lund, Sweden.
    Vikman, Petter
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Prasad, Rashmi
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Mansour Aly, Dina
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Almgren, Peter
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Wessman, Ylva
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Shaat, Nael
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Spegel, Peter
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Mulder, Hindrik
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Lindholm, Eero
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Melander, Olle
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Hansson, Ola
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Malmqvist, Ulf
    Clinical Research and Trial Center, Lund University Hospital, Sweden.
    Lernmark, Åke
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Lahti, Kaj
    Department of Primary Health Care, Vaasa Central Hospital, Finland.
    Forsén, Tom
    Department of Primary Health Care, Vaasa Central Hospital, Finland.
    Tuomi, Tiinamaija
    Abdominal Center, Endocrinology, Helsinki University Central Hospital; Research Program for Diabetes and Obesity, University of Helsinki, Helsinki, Finland.
    Rosengren, Anders
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Groop, Leif
    Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital.
    Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables2018In: The Lancet Diabetes and Endocrinology, ISSN 2213-8587, E-ISSN 2213-8595, Vol. 6, no 5, p. 361-369Article in journal (Refereed)
    Abstract [en]

     Background

    Diabetes is presently classified into two main forms, type 1 and type 2 diabetes, but type 2 diabetes in particular is highly heterogeneous. A refined classification could provide a powerful tool to individualise treatment regimens and identify individuals with increased risk of complications at diagnosis.

    Methods

    We did data-driven cluster analysis (k-means and hierarchical clustering) in patients with newly diagnosed diabetes (n=8980) from the Swedish All New Diabetics in Scania cohort. Clusters were based on six variables (glutamate decarboxylase antibodies, age at diagnosis, BMI, HbA1c, and homoeostatic model assessment 2 estimates of β-cell function and insulin resistance), and were related to prospective data from patient records on development of complications and prescription of medication. Replication was done in three independent cohorts: the Scania Diabetes Registry (n=1466), All New Diabetics in Uppsala (n=844), and Diabetes Registry Vaasa (n=3485). Cox regression and logistic regression were used to compare time to medication, time to reaching the treatment goal, and risk of diabetic complications and genetic associations.

    Findings

    We identified five replicable clusters of patients with diabetes, which had significantly different patient characteristics and risk of diabetic complications. In particular, individuals in cluster 3 (most resistant to insulin) had significantly higher risk of diabetic kidney disease than individuals in clusters 4 and 5, but had been prescribed similar diabetes treatment. Cluster 2 (insulin deficient) had the highest risk of retinopathy. In support of the clustering, genetic associations in the clusters differed from those seen in traditional type 2 diabetes.

    Interpretation

    We stratified patients into five subgroups with differing disease progression and risk of diabetic complications. This new substratification might eventually help to tailor and target early treatment to patients who would benefit most, thereby representing a first step towards precision medicine in diabetes.

  • 15.
    Ahlström, Stina
    et al.
    Natl Board Forens Med, Dept Forens Med, Uppsala, Sweden; Linköping Univ, Fac Med & Hlth Sci, Dept Biomed & Clin Sci, Div Drug Res, Linköping, Sweden.
    Thiblin, Ingemar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Forensic Medicine. Natl Board Forens Med, Dept Forens Med, Uppsala, Sweden.
    Jönsson, Anna K.
    Linköping Univ, Fac Med & Hlth Sci, Dept Biomed & Clin Sci, Div Drug Res, Linköping, Sweden; Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, Linköping, Sweden.
    Green, Henrik
    Linköping Univ, Fac Med & Hlth Sci, Dept Biomed & Clin Sci, Div Drug Res, Linköping, Sweden; Natl Board Forens Med, Dept Forens Genet & Forens Toxicol, Linköping, Sweden.
    Characteristics of post-mortem beta-hydroxybutyrate-positivet cases: A retrospective study on age, sex and BMI in 1407 forensic autopsies2021In: Forensic Science International, ISSN 0379-0738, E-ISSN 1872-6283, Vol. 325, article id 110878Article in journal (Refereed)
    Abstract [en]

    Background

    Post-mortem biochemistry, including the analysis of beta-hydroxybutyrate (BHB), is increasingly employed in forensic medicine, especially in conditions such as diabetes and chronic alcoholism. However, not much is known about the associations between age, body mass index (BMI), and sex and BHB concentrations in ketoacidotic conditions.

    Aim

    To retrospectively study the association between age, BMI and sex in several conditions, such as diabetic ketoacidosis (DKA), alcoholic ketoacidosis (AKA), and elevated post-mortem BHB concentrations.

    Methods

    1407 forensic autopsy cases analysed for BHB were grouped by diagnosis: DKA, AKA, HHS [hyperosmolar hyperglycaemic state], acidosis NOS [not otherwise specified], or hypothermia. Age, sex, BMI and the concentrations of blood alcohol, vitreous glucose and blood BHB were recorded.

    Results

    Cases of AKA and DKA were most numerous (184 and 156, respectively). In DKA and in its male subgroup, cases with severe ketosis (BHB>1000 µg/g) were younger and had a lower BMI than those with moderate ketosis (BHB 250–1000 µg/g) and controls (P<0.001). In DKA and in its female subgroup, cases with moderate ketosis cases were older (P = 0.0218 and P = 0.0083) than controls. In AKA and in its male subgroup, cases with severe ketosis had a lower BMI than those with moderate ketosis (P = 0.0391 and P = 0.0469) and controls (P<0.001). Cases with moderate ketosis had a lower BMI than controls (P<0.001).

    Conclusions

    BHB concentration is associated with BMI in DKA and AKA, and with both BMI and age in DKA. Constitutional factors should, therefore, be considered in potential AKA and DKA cases.

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  • 16. Ahmad, S.
    et al.
    Heraclides, A.
    Sun, Q.
    Elgzyri, T.
    Rönn, T.
    Ling, C.
    Isomaa, B.
    Eriksson, K.-F.
    Groop, L.
    Franks, P. W.
    Hansson, O.
    Telomere length in blood and skeletal muscle in relation to measures of glycaemia and insulinaemia2012In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 29, no 10, p. e377-e381Article in journal (Refereed)
  • 17. Ahmad, S
    et al.
    Poveda, A
    Shungin, D
    Barroso, I
    Hallmans, G
    Renström, F
    Franks, P W
    Established BMI-associated genetic variants and their prospective associations with BMI and other cardiometabolic traits: the GLACIER Study2016In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 40, no 9, p. 1346-1352Article in journal (Refereed)
  • 18. Ahmad, S
    et al.
    Zhao, W
    Renström, F
    Rasheed, A
    Zaidi, M
    Samuel, M
    Shah, N
    Mallick, N H
    Shungin, D
    Zaman, K S
    Ishaq, M
    Rasheed, S Z
    Memon, F-ur-R
    Hanif, B
    Lakhani, M S
    Ahmed, F
    Kazmi, S U
    Deloukas, P
    Frossard, P
    Franks, P W
    Saleheen, D
    A novel interaction between the FLJ33534 locus and smoking in obesity: a genome-wide study of 14 131 Pakistani adults2015In: International Journal of Obesity, ISSN 0307-0565, E-ISSN 1476-5497, Vol. 40, no 1, p. 186-190Article in journal (Refereed)
  • 19.
    Ahmad, Shafqat
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Harvard Med Sch, Div Prevent Med, Brigham & Womens Hosp, Boston, MA 02115 USA;Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.
    Ahluwalia, Tarunveer S.
    Steno Diabet Ctr Copenhagen, Gentofte, Denmark.
    Editorial: The Role of Genetic and Lifestyle Factors in Metabolic Diseases2019In: Frontiers in Endocrinology, E-ISSN 1664-2392, Vol. 10, article id 475Article in journal (Other academic)
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  • 20.
    Ahmad, Shafqat
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Harvard Med Sch, Prevent Med Div, Brigham & Womens Hosp, Boston, MA 02115 USA;Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA.
    Fatima, Syeda Sadia
    Aga Khan Univ, Dept Biol & Biomed Sci, Karachi, Pakistan.
    Rukh, Gull
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Smith, Caren E.
    Tufts Univ, Res Ctr Aging, Jean Mayer US Dept Agr, Nutr & Genom Lab, Boston, MA 02111 USA.
    Gene Lifestyle Interactions With Relation to Obesity, Cardiometabolic, and Cardiovascular Traits Among South Asians2019In: Frontiers in Endocrinology, E-ISSN 1664-2392, Vol. 10, article id 221Article, review/survey (Refereed)
    Abstract [en]

    The rapid rise of obesity, type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) during the last few decades among South Asians has been largely attributed to a major shift in lifestyles including physical inactivity, unhealthy dietary patterns, and an overall pattern of sedentary lifestyle. Genetic predisposition to these cardiometabolic risk factors may have interacted with these obesogenic environments in determining the higher cardiometabolic disease prevalence. Based on the premise that gene-environment interactions cause obesity and cardiometabolic diseases, we systematically searched the literature and considered the knowledge gaps that future studies might ful fill. We identified only seven published studies that focused specifically on gene-environment interactions for cardiometabolic traits in South Asians, most of which were limited by relatively small sample and lack of replication. Some studies reported that the differences in metabolic response to higher physical activity and low caloric diet might be modified by genetic risk related to these cardiometabolic traits. Although studies on gene lifestyle interactions in cardiometabolic traits report significant interactions, future studies must focus on more precise assessment of lifestyle factors, investigation of a larger set of genetic variants and the application of powerful statistical methods to facilitate translatable approaches. Future studies should also be integrated with findings both using mechanistic studies through laboratory settings and randomized clinical trials for clinical outcomes.

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  • 21.
    Ahmad, Shafqat
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hammar, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kennedy, Beatrice
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Salihovic, Samira
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. School of Medical Sciences, Örebro University, Örebro, Sweden.
    Ganna, Andrea
    Program in Medical and Population Genetics, Broad Institute of MIT and Harvard; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet.
    Lind, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Epidemiology. The George Institute for Global Health, Sydney, Australia.
    Ärnlöv, Johan
    Division of and Primary Care, Department of Neurobiology, Care Sciences, and Society, Karolinska Institutet; School of Health and Social Studies, Dalarna University.
    Berne, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Magnusson, Patrik KE
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet.
    Larsson, Susanna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Medical epidemiology. Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden..
    Fall, Tove
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Effect of General Adiposity and Central Body Fat Distribution on the Circulating Metabolome: A Multi-Cohort Nontargeted Metabolomics Observational and Mendelian Randomization Study2022In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 71, no 2, p. 329-339Article in journal (Refereed)
    Abstract [en]

    Obesity is associated with adverse health outcomes, but the metabolic effects have not yet been fully elucidated. We aimed to investigate the association between adiposity with circulating metabolites and to address causality with Mendelian randomization (MR). Metabolomics data was generated by non-targeted ultra-performance liquid-chromatography coupled to time-of-flight mass-spectrometry in plasma and serum from three population-based Swedish cohorts: ULSAM (N=1,135), PIVUS (N=970), and TwinGene (N=2,059). We assessed associations between general adiposity measured as body mass index (BMI) and central body fat distribution measured as waist-to-hip ratio adjusted for BMI (WHRadjBMI) with 210 annotated metabolites. We employed MR analysis to assess causal effects. Lastly, we attempted to replicate the MR findings in the KORA and TwinsUK cohorts (N=7,373), the CHARGE consortium (N=8,631), the Framingham Heart Study (N=2,076) and the DIRECT consortium (N=3,029). BMI was associated with 77 metabolites, while WHRadjBMI was associated with 11 and 3 metabolites in women and men, respectively. The MR analyses in the Swedish cohorts suggested a causal association (p-value <0.05) of increased general adiposity and reduced levels of arachidonic acid, dodecanedioic acid and lysophosphatidylcholine (P-16:0) as well as with increased creatine levels. The replication effort provided support for a causal association of adiposity on reduced levels of arachidonic acid (p-value 0.03). Adiposity is associated with variation of large parts of the circulating metabolome, however causality needs further investigation in well-powered cohorts.

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  • 22. Ahmad, Shafqat
    et al.
    Rukh, Gull
    Varga, Tibor V.
    Ali, Ashfaq
    Kurbasic, Azra
    Shungin, Dmitry
    Ericson, Ulrika
    Koivula, Robert W.
    Chu, Audrey Y.
    Rose, Lynda M.
    Ganna, Andrea
    Qi, Qibin
    Stančáková, Alena
    Sandholt, Camilla H.
    Elks, Cathy E.
    Curhan, Gary
    Jensen, Majken K.
    Tamimi, Rulla M.
    Allin, Kristine H.
    Jørgensen, Torben
    Brage, Soren
    Langenberg, Claudia
    Aadahl, Mette
    Grarup, Niels
    Linneberg, Allan
    Paré, Guillaume
    Magnusson, Patrik K. E.
    Pedersen, Nancy L.
    Boehnke, Michael
    Hamsten, Anders
    Mohlke, Karen L.
    Pasquale, Louis T.
    Pedersen, Oluf
    Scott, Robert A.
    Ridker, Paul M.
    Ingelsson, Erik
    Laakso, Markku
    Hansen, Torben
    Qi, Lu
    Wareham, Nicholas J.
    Chasman, Daniel I.
    Hallmans, Göran
    Hu, Frank B.
    Renström, Frida
    Orho-Melander, Marju
    Franks, Paul W.
    Gene × Physical Activity Interactions in Obesity: Combined Analysis of 111,421 Individuals of European Ancestry2013In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 9, no 7, p. e1003607-e1003607Article in journal (Refereed)
  • 23. Ahmad, Shafqat
    et al.
    Varga, Tibor V.
    Franks, Paul W.
    Gene <b>×</b> Environment Interactions in Obesity: The State of the Evidence2013In: Human Heredity, ISSN 0001-5652, E-ISSN 1423-0062, Vol. 75, no 2-4, p. 106-115Article in journal (Refereed)
  • 24. Ahmad, Shafqat
    et al.
    Zhao, Wei
    Renström, Frida
    Rasheed, Asif
    Samuel, Maria
    Zaidi, Mozzam
    Shah, Nabi
    Mallick, Nadeem Hayyat
    Zaman, Khan Shah
    Ishaq, Mohammad
    Rasheed, Syed Zahed
    Memon, Fazal-ur-Rheman
    Hanif, Bashir
    Lakhani, Muhammad Shakir
    Ahmed, Faisal
    Kazmi, Shahana Urooj
    Frossard, Philippe
    Franks, Paul W.
    Saleheen, Danish
    Physical activity, smoking, and genetic predisposition to obesity in people from Pakistan: the PROMIS study2015In: BMC Medical Genetics, E-ISSN 1471-2350, Vol. 16, no 1, article id 114Article in journal (Refereed)
  • 25.
    Ahmed, Fozia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Hetty, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Vranic, Milica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Fanni, Giovanni
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Pereira, Maria J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Eriksson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    ESR2 expression in subcutaneous adipose tissue is related to body fat distribution in women, and knockdown impairs preadipocyte differentiation2022In: Adipocyte, ISSN 2162-3945, E-ISSN 2162-397X, Vol. 11, no 1, p. 434-447Article in journal (Refereed)
    Abstract [en]

    Oestrogen receptor 2 (ESR2) expression has been shown to be higher in subcutaneous adipose tissue (SAT) from postmenopausal compared to premenopausal women. The functional significance of altered ESR2 expression is not fully known. This study investigates the role of ESR2 for adipose tissue lipid and glucose metabolism. SAT biopsies were obtained from 44 female subjects with or without T2D. Gene expression of ESR2 and markers of adipose function and metabolism was assessed. ESR2 knockdown was performed using CRISPR/Cas9 in preadipocytes isolated from SAT of females, and differentiation rate, lipid storage, and glucose uptake were measured. ESR2 expression was inversely correlated with measures of central obesity and expression of some fatty acid oxidation markers, and positively correlated with lipid storage and glucose transport markers. Differentiation was reduced in ESR2 knockdown preadipocytes. This corresponded to reduced expression of markers of differentiation and lipogenesis. Glucose uptake was reduced in knockdown adipocytes. Our results indicate that ESR2 deficiency in women is associated with visceral adiposity and impaired subcutaneous adipocyte differentiation as well as glucose and lipid utilization. High ESR2 expression, as seen after menopause, could be a contributing factor to SAT expansion. This may support a possible target to promote a healthy obesity phenotype.

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  • 26.
    Ahmed, Fozia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Kamble, Prasad G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Hetty, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Fanni, Giovanni
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Vranic, Milica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Sarsenbayeva, Assel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Kristofi, Robin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Almby, Kristina E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Svensson, Maria K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Renal Medicine.
    Pereira, Maria J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Eriksson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Role of Estrogen and Its Receptors in Adipose Tissue Glucose Metabolism in Pre- and Postmenopausal Women2022In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 107, no 5, p. E1879-E1889Article in journal (Refereed)
    Abstract [en]

    Context: Reduced estrogen levels in postmenopausal women predispose them to metabolic side effects, including insulin resistance and type 2 diabetes; however, the cellular mechanisms are not well understood.

    Objective: This work aimed to study the expression of estrogen receptors in adipose tissue from pre- and postmenopausal women and the effects of estradiol (E2) on glucose uptake of adipocytes.

    Methods: Subcutaneous (SAT) and visceral adipose tissue (VAT) obtained from pre- and postmenopausal women (19-51 and 46-75 years old, respectively) were used to measure gene expression of ESR1 and ESR2. SAT tissue was incubated with E2, and glucose uptake and estrogen receptor levels were measured. Polymorphisms in ESR1 and ESR2 were addressed in public databases to identify single nucleotide polymorphisms associated with metabolic traits.

    Results: ESR2 expression was lower in pre- vs postmenopausal women, corresponding to lower ESR1:ESR2 gene expression ratio in postmenopausal women. In premenopausal women, the expression of ESR1 was higher in VAT than in SAT. In both pre- and postmenopausal women, ESR2 expression was lower in VAT than in SAT. In late, but not pre- or early postmenopausal women, E2 reduced glucose uptake and GLUT4 protein and increased expression of ESR2. ESR1 polymorphisms were associated with weight, body fat distribution, and total cholesterol, and ESR2 polymorphisms were associated with total cholesterol and triglyceride levels and with body fat percentage.

    Conclusion: E2 inhibits glucose utilization in human adipocytes in late postmenopausal women. Changes in glucose utilization over time since menopause may be explained by a lower ESR1:ESR2 ratio. This can have clinical implications on the timing of estrogen treatment in postmenopausal women.

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  • 27.
    Ahmed, Fozia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism. Inst Savoir Montfort, 1E103,713 Montreal Rd, Ottawa, ON K1K 0T2, Canada.;Univ Ottawa, Fac Med, Dept Biochem Microbiol & Immunol, Ottawa, ON K1N 6N5, Canada..
    Pereira, Maria João
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Aguer, Celine
    Inst Savoir Montfort, 1E103,713 Montreal Rd, Ottawa, ON K1K 0T2, Canada.;Univ Ottawa, Fac Med, Dept Biochem Microbiol & Immunol, Ottawa, ON K1N 6N5, Canada.;Univ Ottawa, Fac Hlth Sci, Sch Human Kinet, Ottawa, ON K1N 6N5, Canada.;Univ Ottawa, Fac Hlth Sci, Interdisciplinary Sch Hlth Sci, Ottawa, ON K1N 6N5, Canada..
    Bisphenols and the Development of Type 2 Diabetes: The Role of the Skeletal Muscle and Adipose Tissue2021In: Environments, E-ISSN 2076-3298, Vol. 8, no 4, article id 35Article, review/survey (Refereed)
    Abstract [en]

    Bisphenol A (BPA) and bisphenol S (BPS) are environmental contaminants that have been associated with the development of insulin resistance and type 2 diabetes (T2D). Two organs that are often implicated in the development of insulin resistance are the skeletal muscle and the adipose tissue, however, seldom studies have investigated the effects of bisphenols on their metabolism. In this review we discuss metabolic perturbations that occur in both the skeletal muscle and adipose tissue affected with insulin resistance, and how exposure to BPA or BPS has been linked to these changes. Furthermore, we highlight the possible effects of BPA on the cross-talk between the skeletal muscle and adipose tissue.

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  • 28.
    Ahmed, Fozia
    et al.
    Inst Savoir Montfort Rech, 1E103,713 Montreal Rd, Ottawa, ON K1K 0T2, Canada; Univ Ottawa, Fac Med, Dept Biochem Microbiol & Immunol, Ottawa, ON, Canada.
    Sarsenbayeva, Assel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Katsogiannos, Petros
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Aguer, Céline
    Inst Savoir Montfort Rech, 1E103,713 Montreal Rd, Ottawa, ON K1K 0T2, Canada; Univ Ottawa, Fac Med, Dept Biochem Microbiol & Immunol, Ottawa, ON, Canada; Univ Ottawa, Fac Hlth Sci, Sch Human Kinet, Ottawa, ON, Canada; Univ Ottawa, Fac Hlth Sci, Interdisciplinary Sch Hlth Sci, Ottawa, ON, Canada.
    Pereira, Maria J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    The effects of bisphenol A and bisphenol S on adipokine expression and glucose metabolism in human adipose tissue2020In: Toxicology, ISSN 0300-483X, E-ISSN 1879-3185, Vol. 445, article id 152600Article in journal (Refereed)
    Abstract [en]

    Purpose

    The environmental endocrine disruptors, bisphenol A (BPA) and bisphenol S (BPS) are associated with the development of type 2 diabetes. We aim to study the effects of BPA or BPS exposure on adipokine expression in human adipose tissue and on adipocyte glucose uptake.

    Methods

    Human subcutaneous adipose tissue was treated for 24 or 72 h with environmentally-relevant and supraphysiological concentrations of BPA or BPS (1–104 nM). Following exposure, gene expression of proinflammatory cytokines, adipokines, and estrogen receptors was measured in adipose tissue. Glucose uptake and the insulin signalling pathway were analyzed in isolated adipocytes following adipose tissue culture with BPA for 24 h.

    Results

    Adipose tissue treated with BPA for 24 h had reduced expression of the proinflammatory genes (IL6, IL1B, TNFA) and adipokines (ADIPOQ, FABP4). BPA and BPS had no effect on the expression of other proinflammatory genes (IL33), adipokines (LEP), or receptors (ESR1, ESR2) after 72-h exposure. Adipose tissue treated with environmentally-relevant concentrations of BPA for 24 h had reduced insulin-stimulated glucose uptake, without altered gene and protein levels of key insulin signalling pathway markers.

    Conclusions

    We found that human adipose tissue treated with environmentally-relevant concentrations of BPA for 24 h, but not BPS, reduced expression of proinflammatory genes and adipokines. Furthermore, BPA reduced glucose uptake in adipocytes independently of insulin signalling. Such mechanisms can contribute to the development of insulin resistance associated with BPA exposure.

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  • 29.
    Ahmed, Fozia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Vranic, Milica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Hetty, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Mathioudaki, Argyri
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Patsoukaki, Vagia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Fanni, Giovanni
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Pereira, Maria J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Eriksson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Increased OCT3 Expression in Adipose Tissue With Aging: Implications for Catecholamine and Lipid Turnover and Insulin Resistance in Women2023In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 165, no 1, article id bqad172Article in journal (Refereed)
    Abstract [en]

    Background Catecholamine-stimulated lipolysis is reduced with aging, which may promote adiposity and insulin resistance. Organic cation transporter 3 (OCT3), which is inhibited by estradiol (E2), mediates catecholamine transport into adipocytes for degradation, thus decreasing lipolysis. In this study, we investigated the association of OCT3 mRNA levels in subcutaneous adipose tissue (SAT) with aging and markers of insulin resistance in women.Methods SAT biopsies were obtained from 66 women with (19) or without (47) type 2 diabetes (age 22-76 years, 20.0-40.1 kg/m2). OCT3 mRNA and protein levels were measured for group comparisons and correlation analysis. SAT was incubated with E2 and OCT3 mRNA levels were measured. Associations between OCT3 single nucleotide polymorphisms (SNPs) and diabetes-associated traits were assessed.Results OCT3 mRNA and protein levels in SAT increased with aging. SAT from postmenopausal women had higher levels of OCT3 than premenopausal women, and there was a dose-dependent reduction in OCT3 mRNA levels in SAT treated with E2. OCT3 mRNA levels were negatively associated with markers of insulin resistance, and ex vivo lipolysis. OCT3 SNPs were associated with BMI, waist to hip ratio, and circulating lipids (eg, triglycerides).Conclusion OCT3 mRNA and protein levels in SAT increased with aging, and mRNA levels were negatively associated with markers of insulin resistance. E2 incubation downregulated OCT3 mRNA levels, which may explain lower OCT3 mRNA in premenopausal vs postmenopausal women. High OCT3 protein levels in adipose tissue may result in increased catecholamine degradation, and this can contribute to the reduction in lipolysis observed in women with aging.

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  • 30.
    Akerblom, Hanna
    et al.
    Reg Vastmanland, Dept Ophthalmol, S-72189 Västerås, Sweden..
    Franzen, Stefan
    Ctr Registers, Gothenburg, Sweden.;Univ Gothenburg, Sahlgrenska Acad, Hlth Metr Unit, Gothenburg, Sweden..
    Zhou, Caddie
    Ctr Registers, Gothenburg, Sweden..
    Moren, Asa
    Reg Vastmanland, Dept Ophthalmol, S-72189 Västerås, Sweden..
    Ottosson, Johan
    Örebro Univ, Fac Med & Hlth, Dept Surg, Örebro, Sweden..
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Eliasson, Bjorn
    Univ Gothenburg, Dept Mol & Clin Med, Gothenburg, Sweden..
    Svensson, Ann-Marie
    Ctr Registers, Gothenburg, Sweden.;Univ Gothenburg, Dept Mol & Clin Med, Gothenburg, Sweden..
    Granstam, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Centre for Clinical Research, County of Västmanland. Reg Vastmanland, Dept Ophthalmol, S-72189 Västerås, Sweden..
    Association of Gastric Bypass Surgery With Risk of Developing Diabetic Retinopathy Among Patients With Obesity and Type 2 Diabetes in Sweden: An Observational Study2021In: JAMA ophthalmology, ISSN 2168-6165, E-ISSN 2168-6173, Vol. 139, no 2, p. 200-205Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Knowledge of the incidence and progression of diabetic retinopathy (DR) after gastric bypass surgery (GBP) in patients with obesity and diabetes could guide the management of these patients. OBJECTIVE To investigate the incidence of diabetic ocular complications in patients with type 2 diabetes after GBP compared with the incidence of diabetic ocular complications in a matched cohort of patients with obesity and diabetes who have not undergone GBP. DESIGN, SETTING, AND PARTICIPANTS Data from 2 nationwide registers in Sweden, the Scandinavian Obesity Surgery Registry and the National Diabetes Register, were used for this cohort study. A total of 5321 patients with diabetes from the Scandinavian Obesity Surgery Registry who had undergone GBP from January 1, 2007, to December 31, 2013, were matched with 5321 patients with diabetes from the National Diabetes Register who had not undergone GBP, based on sex, age, body mass index (BMI), and calendar time (2007-2013). Follow-up data were obtained until December 31, 2015. Statistical analysis was performed from October 5, 2018, to September 30, 2019. EXPOSURE Gastric bypass surgery. MAIN OUTCOMES AND MEASURES Incidence of new DR and other diabetic ocular complications. RESULTS The study population consisted of 5321 patients who had undergone GBP (3223 women [60.6%]; mean [SD] age, 49.0 [9.5] years) and 5321 matched controls (3395 women [63.8%]; mean [SD] age, 47.1 [11.5] years). Mean (SD) follow-up was 4.5 (1.6) years. The mean (SD) BMI and hemoglobin A1c concentration at baseline were 42.0 (5.7) and 7.6%(1.5%), respectively, in the GBP group and 40.9 (7.3) and 7.5%(1.5%), respectively, in the control group. The mean (SD) duration of diabetes was 6.8 (6.3) years in the GBP group and 6.4 (6.4) years in the control group. The risk for new DR was reduced in the patients who underwent GBP (hazard ratio, 0.62 [95% CI, 0.49-0.78]; P <.001). The dominant risk factors for development of DR at baseline were diabetes duration, hemoglobin A1c concentration, use of insulin, glomerular filtration rate, and BMI. CONCLUSIONS AND RELEVANCE This nationwide matched cohort study suggests that there is a reduced risk of developing new DR associated with GBP, and no evidence of an increased risk of developing DR that threatened sight or required treatment.

  • 31.
    Albertsson-Wikland, Kerstin
    et al.
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Physiol Endocrinol, Medicinargatan 11, SE-40530 Gothenburg, Sweden..
    Martensson, Anton
    Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Physiol Endocrinol, Medicinargatan 11, SE-40530 Gothenburg, Sweden.;Stat Konsultgrp, SE-41319 Gothenburg, Sweden..
    Savendahl, Lars
    Karolinska Univ Hosp, Dept Womens & Childrens Hlth, Karolinska Inst, SE-17176 Stockholm, Sweden.;Karolinska Univ Hosp, Pediat Endocrinol Unit, SE-17176 Stockholm, Sweden..
    Niklasson, Aimon
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Gothenburg Pediat Growth Res Ctr,Dept Pediat, SE-41685 Gothenburg, Sweden..
    Bang, Peter
    Linkoping Univ, Dept Clin & Expt Med, Div Pediat, SE-58185 Linkoping, Sweden..
    Dahlgren, Jovanna
    Univ Gothenburg, Sahlgrenska Acad, Inst Clin Sci, Gothenburg Pediat Growth Res Ctr,Dept Pediat, SE-41685 Gothenburg, Sweden..
    Gustafsson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Kristrom, Berit
    Umea Univ, Dept Clin Sci, Pediat, SE-90185 Umea, Sweden..
    Norgren, Svante
    Karolinska Univ Hosp, Dept Womens & Childrens Hlth, Karolinska Inst, SE-17176 Stockholm, Sweden.;Karolinska Univ Hosp, Pediat Endocrinol Unit, SE-17176 Stockholm, Sweden..
    Pehrsson, Nils-Gunnar
    Stat Konsultgrp, SE-41319 Gothenburg, Sweden..
    Oden, Anders
    Stat Konsultgrp, SE-41319 Gothenburg, Sweden.;Chalmers, Dept Math Sci, SE-41296 Gothenburg, Sweden..
    Mortality Is Not Increased in Recombinant Human Growth Hormone-treated Patients When Adjusting for Birth Characteristics2016In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 101, no 5, p. 2149-2159Article in journal (Refereed)
    Abstract [en]

    Objective: This study aimed to investigate whether reported high mortality in childhood recombinant human GH (rhGH)-treated patients was related to birth-characteristics and/or rhGH treatment. Design and Setting: We sought to develop a mortality model of the Swedish general population born between 1973 and 2010, using continuous-hazard functions adjusting for birth characteristics, sex, age intervals, and calendar year to estimate standardized mortality ratio (SMR) and to apply this model to assess expected deaths in Swedish rhGH-treated patients with idiopathic isolated GH deficiency (IGHD), idiopathic short stature (155) or born small for gestational age (SGA). Participants:The general population: Swedish Medical Birth Register (1973-2010: 1 880 668 males; 1 781 131 females) and Cause of Death Register (1985-2010). Intervention Population: Three thousand eight hundred forty-seven patients starting rhGH treatment between 1985 and 2010 and followed in the National GH Register and/or in rhGH trials diagnosed with IGHD (n = 1890), ISS (n = 975), or SGA (n=982). Main Outcome Measures: Death. Results: Using conventional models adjusting for age, sex, and calendar-year, the SMR was 1.43 (95% confidence interval, 0.89-2.19), P = .14, observed/expected deaths 21/14.68. The rhGH population differed (P < .001) from the general population regarding birth weight, birth length, and congenital malformations. Application of an Advanced Model: When applying the developed mortality model of the general population, the ratio of observed/expected deaths in rhGH-treated patients was 21/21.99; SMR = 0.955 (0.591-1.456)P = .95. Model Comparison: Expected number of deaths were 14.68 (14.35-14.96) using the conventional model, and 21.99 (21.24-22.81) using the advanced model, P < .001, which had at all ages a higher gradient of risk per SD of the model, 24% (range, 18-42%; P < .001). Conclusions: Compared with the general Swedish population, the ratio of observed/expected deaths (21/21.99) was not increased in childhood rhGH-treated IGHD, ISS, and SGA patients when applying an advanced sex-specific mortality model adjusting for birth characteristics.

  • 32.
    Alenkvist, Ida
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Dyachok, Oleg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tian, Geng
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Li, Jia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Mehrabanfar, Saba
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Jin, Yang
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Welsh, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Absence of Shb impairs insulin secretion by elevated FAK activity in pancreatic islets2014In: Journal of Endocrinology, ISSN 0022-0795, E-ISSN 1479-6805, Vol. 223, no 3, p. 267-275Article in journal (Refereed)
    Abstract [en]

    The Src homology-2 domain containing protein B (SHB) has previously been shown to function as a pleiotropic adapter protein, conveying signals from receptor tyrosine kinases to intracellular signaling intermediates. The overexpression of Shb in β-cells promotes β-cell proliferation by increased insulin receptor substrate (IRS) and focal adhesion kinase (FAK) activity, whereas Shb deficiency causes moderate glucose intolerance and impaired first-peak insulin secretion. Using an array of techniques, including live-cell imaging, patch-clamping, immunoblotting, and semi-quantitative PCR, we presently investigated the causes of the abnormal insulin secretory characteristics in Shb-knockout mice. Shb-knockout islets displayed an abnormal signaling signature with increased activities of FAK, IRS, and AKT. β-catenin protein expression was elevated and it showed increased nuclear localization. However, there were no major alterations in the gene expression of various proteins involved in the β-cell secretory machinery. Nor was Shb deficiency associated with changes in glucose-induced ATP generation or cytoplasmic Ca(2) (+) handling. In contrast, the glucose-induced rise in cAMP, known to be important for the insulin secretory response, was delayed in the Shb-knockout compared with WT control. Inhibition of FAK increased the submembrane cAMP concentration, implicating FAK activity in the regulation of insulin exocytosis. In conclusion, Shb deficiency causes a chronic increase in β-cell FAK activity that perturbs the normal insulin secretory characteristics of β-cells, suggesting multi-faceted effects of FAK on insulin secretion depending on the mechanism of FAK activation.

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  • 33.
    Alexander, Lind
    et al.
    Lund Univ CRC, Dept Clin Sci Malmo, Jan Waldenstromsgata 35, SE-21428 Malmo, Sweden..
    Yang, Cao
    Orebro Univ, Fac Med & Hlth, Sch Med Sci, Clin Epidemiol & Biostat, Orebro, Sweden.;Karolinska Inst, Unit Integrat Epidemiol, Inst Environm Med, Stockholm, Sweden..
    Hugo, Hesser
    Orebro Univ, Ctr Hlth & Med Psychol, Sch Behav Social & Legal Sci, Orebro, Sweden.;Linkoping Univ, Dept Behav Sci & Learning, Linkoping, Sweden..
    Hårdstedt, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Disciplinary Domain of Medicine and Pharmacy, research centers etc., Center for Clinical Research Dalarna. Orebro Univ, Sch Med Sci, Fac Med & Hlth, Orebro, Sweden.;Vansbro Primary Hlth Care Ctr, Vansbro, Sweden..
    Jansson, Stefan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine. Orebro Univ, Univ Hlth Care Res Ctr, Sch Med Sci, Orebro, Sweden..
    Åke, Lernmark
    Lund Univ, Dept Clin Sci Malmo, Malmo, Sweden..
    Martin, Sundqvist
    Orebro Univ, Sch Med Sci, Fac Med & Hlth, Orebro, Sweden..
    Staffan, Tevell
    Orebro Univ, Sch Med Sci, Fac Med & Hlth, Orebro, Sweden.;Karlstad Hosp, Dept Infect Dis, Karlstad, Sweden.;Reg Varmland, Ctr Clin Res & Educ, Karlstad, Sweden..
    Cheng-ting, Tsai
    Enable Biosci Inc, South San Francisco, CA USA..
    Jeanette, Wahlberg
    Orebro Univ, Sch Med Sci, Fac Med & Hlth, Orebro, Sweden..
    Johan, Jendle
    Orebro Univ, Sch Med Sci, Fac Med & Hlth, Orebro, Sweden..
    Anxiety, depression and quality of life in relation to SARS-CoV-2 antibodies in individuals living with diabetes during the second wave of COVID-192024In: Diabetes Epidemiology and Management, E-ISSN 2666-9706, Vol. 13, article id 100194Article in journal (Refereed)
    Abstract [en]

    Aims: The objective was to compare anxiety, depression, and quality of life (QoL) in individuals living with type 1 (T1D) and type 2 (T2D) diabetes with matched controls during the second wave of the COVID-19 pandemic. Methods: Via randomization, individuals living with diabetes T1D (n = 203) and T2D (n = 413), were identified during February-July 2021 through health-care registers. Population controls (n = 282) were matched for age, gender, and residential area. Questionnaires included self-assessment of anxiety, depression, QoL, and demographics in relation to SARS-CoV-2 exposure. Blood was collected through home-capillary sampling, and SARS-CoV-2 Nucleocapsid (NCP) and Spike antibodies (SC2_S1) were determined by multiplex Antibody Detection by Agglutination-PCR (ADAP) assays. Results: Younger age and health issues were related to anxiety, depression, and QoL, with no differences between the study groups. Female gender was associated with anxiety, while obesity was associated with lower QoL. The SARS-CoV-2 NCP seroprevalence was higher in T1D (8.9 %) compared to T2D (3.9 %) and controls (4.0 %), while the SARS-CoV-2 SC2_S1 seroprevalence was higher for controls (25.5 %) compared to T1D (16.8 %) and T2D (14.0 %). Conclusions: A higher SARS-CoV-2 infection rate in T1D may be explained by younger age and higher employment rate, and the associated increased risk for viral exposure.

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  • 34.
    Alhaidan, Yazeid
    et al.
    Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark.;Univ Southern Denmark, Fac Hlth Sci, Dept Clin Res, DK-5000 Odense C, Denmark.;King Abdullah Int Med Res Ctr, Dept Med Genom Res, Riyadh 11426, Saudi Arabia.;King Saud Bin Abdulaziz Univ Hlth Sci, Riyadh, Saudi Arabia..
    Larsen, Martin J.
    Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark.;Univ Southern Denmark, Fac Hlth Sci, Dept Clin Res, DK-5000 Odense C, Denmark..
    Schou, Anders Jorgen
    Odense Univ Hosp, Hans Christian Andersen Childrens Hosp, DK-5000 Odense C, Denmark..
    Stenlid, Maria H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Al Balwi, Mohammed A.
    King Abdullah Int Med Res Ctr, Dept Med Genom Res, Riyadh 11426, Saudi Arabia.;King Saud Bin Abdulaziz Univ Hlth Sci, Riyadh, Saudi Arabia..
    Christesen, Henrik Thybo
    Univ Southern Denmark, Fac Hlth Sci, Dept Clin Res, DK-5000 Odense C, Denmark.;Odense Pancreases Ctr, Www OPA Cnu, Uppsala, Sweden..
    Brusgaard, Klaus
    Odense Univ Hosp, Dept Clin Genet, DK-5000 Odense C, Denmark.;Univ Southern Denmark, Fac Hlth Sci, Dept Clin Res, DK-5000 Odense C, Denmark.;Near East Univ, Nicosia, Cyprus..
    Exome sequencing revealed DNA variants in NCOR1, IGF2BP1, SGLT2 and NEK11 as potential novel causes of ketotic hypoglycemia in children2020In: Scientific Reports, E-ISSN 2045-2322, Vol. 10, no 1, article id 2114Article in journal (Refereed)
    Abstract [en]

    Unexplained or idiopathic ketotic hypoglycemia (KH) is the most common type of hypoglycemia in children. The diagnosis is based on the exclusion of routine hormonal and metabolic causes of hypoglycemia. We aimed to identify novel genes that cause KH, as this may lead to a more targeted treatment. Deep phenotyping of ten preschool age at onset KH patients (boys, n = 5; girls, n = 5) was performed followed by trio exome sequencing and comprehensive bioinformatics analysis. Data analysis revealed four novel candidate genes: (1) NCOR1 in a patient with KH, iron deficiency and loose stools; (2) IGF2BP1 in a proband with KH, short stature and delayed bone age; (3) SLC5A2 in a proband with KH, intermittent glucosuria and extremely elevated p-GLP-1; and (4) NEK11 in a proband with ketotic hypoglycemia and liver affliction. These genes are associated with different metabolic processes, such as gluconeogenesis, translational regulation, and glucose transport. In conclusion, WES identified DNA variants in four different genes as potential novel causes of IKH, suggesting that IKH is a heterogeneous disorder that can be split into several novel diseases: NCOR1-KH, IGF2BP1-KH, SGLT2-KH or familial renal glucosuria KH, and NEK11-KH. Precision medicine treatment based on exome sequencing may lead to advances in the management of IKH.

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  • 35.
    Ali, Abir A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Grönberg, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Hjortland, G. O.
    Univ Oslo, Dept Oncol, Oslo, Norway.
    Grønbæk, H.
    Aarhus Univ Hosp, Dept Hepatol & Gastroenterol, Aarhus, Denmark.
    Ladekarl, M.
    Aarhus Univ Hosp, Dept Oncol, Aarhus, Denmark.
    Langer, S. W.
    Rigshosp, Copenhagen Univ Hosp, Dept Oncol, Copenhagen, Denmark.
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Vestermark, L. W.
    Odense Univ Hosp, Dept Oncol, Odense, Denmark.
    Österlund, P.
    Tampere Helsinki Univ Hosp, Dept Oncol, Tampere, Finland.;Tampere Helsinki Univ, Tampere, Finland.
    Knigge, U.
    Univ Copenhagen, Rigshosp, Fac Hlth Sci, Dept Surg C, Copenhagen, Denmark; Univ Copenhagen, Rigshosp, Fac Hlth Sci, Dept Endocrinol PE, Copenhagen, Denmark.
    Sørbye, H.
    Univ Bergen, Haukeland Univ Hosp, Dept Oncol, Bergen, Norway; Univ Bergen, Dept Clin Sci, Bergen, Norway.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Intravenous versus Oral Etoposide: Efficacy and Correlation to Clinical Outcome in Patients with High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms (WHO G3)2018In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 106, no Supplement: 1, p. 184-184Article in journal (Other academic)
  • 36.
    Ali, Mohammed K.
    et al.
    Hubert Department of Global Health Rollins School of Public Health, Emory University Atlanta Georgia USA;Department of Family and Preventive Medicine School of Medicine, Emory University Atlanta Georgia USA.
    Kadir, M. Masood
    Department of Community Health Sciences Aga Khan University Karachi Pakistan.
    Gujral, Unjali P.
    Hubert Department of Global Health Rollins School of Public Health, Emory University Atlanta Georgia USA.
    Fatima, Syeda Sadia
    Department of Biological and Biomedical Sciences Aga Khan University Karachi Pakistan.
    Iqbal, Romaina
    Department of Community Health Sciences Aga Khan University Karachi Pakistan.
    Sun, Yan V.
    Department of Epidemiology Rollins School of Public Health, Emory University Atlanta Georgia USA.
    Narayan, K. M. Venkat
    Hubert Department of Global Health Rollins School of Public Health, Emory University Atlanta Georgia USA;Department of Epidemiology Rollins School of Public Health, Emory University Atlanta Georgia USA.
    Ahmad, Shafqat
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Preventive Medicine Division Harvard Medical School, Brigham and Women's Hospital Boston Massachusetts USA.
    Obesity‐associated metabolites in relation to type 2 diabetes risk: A prospective nested case‐control study of the CARRS cohort2022In: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 24, no 10, p. 2008-2016Article in journal (Refereed)
    Abstract [en]

    Aims: To determine whether obesity-associated metabolites are associated with type 2 diabetes (T2DM) risk among South Asians.

    Materials and methods: Serum-based nuclear magnetic resonance imaging metabolomics data were generated from two South Asian population-based prospective cohorts from Karachi, Pakistan: CARRS1 (N = 4017) and CARRS2 (N = 4802). Participants in both cohorts were followed up for 5 years and incident T2DM was ascertained. A nested case-control study approach was developed to select participants from CARRS1 (Ncases = 197 and Ncontrols = 195) and CARRS2 (Ncases = 194 and Ncontrols = 200), respectively. First, we investigated the association of 224 metabolites with general obesity based on body mass index and with central obesity based on waist-hip ratio, and then the top obesity-associated metabolites were studied in relation to incident T2DM.

    Results: In a combined sample of the CARRS1 and CARRS2 cohorts, out of 224 metabolites, 12 were associated with general obesity and, of these, one was associated with incident T2DM. Fifteen out of 224 metabolites were associated with central obesity and, of these, 10 were associated with incident T2DM. The higher level of total cholesterol in high-density lipoprotein (HDL) was associated with reduced T2DM risk (odds ratio [OR] 0.68, 95% confidence interval [CI] 0.53, 0.86; P = 1.2 × 10-3 ), while higher cholesterol esters in large very-low-density lipoprotein (VLDL) particles were associated with increased T2DM risk (OR 1.90, 95% CI 1.40, 2.58; P = 3.5 × 10-5 ).

    Conclusion: Total cholesterol in HDL and cholesterol esters in large VLDL particles may be an important biomarker in the identification of early development of obesity-associated T2DM risk among South Asian adults.

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  • 37. Allara, Elias
    et al.
    Lee, Wei-Hsuan
    Burgess, Stephen
    Larsson, Susanna C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Medical epidemiology. Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    Genetically predicted cortisol levels and risk of venous thromboembolism2022In: PLOS ONE, E-ISSN 1932-6203, Vol. 17, no 8, article id e0272807Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: In observational studies, venous thromboembolism (VTE) has been associated with Cushing's syndrome and with persistent mental stress, two conditions associated with higher cortisol levels. However, it remains unknown whether high cortisol levels within the usual range are causally associated with VTE risk. We aimed to assess the association between plasma cortisol levels and VTE risk using Mendelian randomization.

    METHODS: Three genetic variants in the SERPINA1/SERPINA6 locus (rs12589136, rs11621961 and rs2749527) were used to proxy plasma cortisol. The associations of the cortisol-associated genetic variants with VTE were acquired from the INVENT (28 907 cases and 157 243 non-cases) and FinnGen (6913 cases and 169 986 non-cases) consortia. Corresponding data for VTE subtypes were available from the FinnGen consortium and UK Biobank. Two-sample Mendelian randomization analyses (inverse-variance weighted method) were performed.

    RESULTS: Genetic predisposition to higher plasma cortisol levels was associated with a reduced risk of VTE (odds ratio [OR] per one standard deviation increment 0.73, 95% confidence interval [CI] 0.62-0.87, p<0.001). The association was stronger for deep vein thrombosis (OR 0.69, 95% CI 0.55-0.88, p = 0.003) than for pulmonary embolism which did not achieve statistical significance (OR 0.83, 95% CI 0.63-1.09, p = 0.184). Adjusting for genetically predicted systolic blood pressure inverted the direction of the point estimate for VTE, although the resulting CI was wide (OR 1.06, 95% CI 0.70-1.61, p = 0.780).

    CONCLUSIONS: This study provides evidence that genetically predicted plasma cortisol levels in the high end of the normal range are associated with a decreased risk of VTE and that this association may be mediated by blood pressure. This study has implications for the planning of observational studies of cortisol and VTE, suggesting that blood pressure traits should be measured and accounted for.

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  • 38.
    Almby, Kristina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Brain-gut-adipose interplay in the antidiabetic effects of gastric bypass surgery2024Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Gastric bypass surgery (GBP) leads not only to considerable and consistent weight loss but to a number of beneficial metabolic effects, often including a swift remission of type 2 diabetes (T2DM). Increases in the gut hormone GLP-1 are considered central to this effect, although several other mechanism are likely involved. One complication to GBP is post-bariatric hypoglycaemia (PBH), where the individual suffers from episodes of low blood sugar after meals. The mechanism behind this is incompletely understood. 

    Previous research has reported an attenuation of the counterregulatory response to hypoglycaemia in patients after GBP. Many hypoglycaemic episodes also appear to be asymptomatic. Together, this has led to the hypothesis that GBP and PBH may involve an adaptation to lower blood glucose levels, a lowered glycaemic set point. As much of hypoglycaemia counterregulation involves the central nervous system (CNS), such an adaptation would presumably involve neuroendocrine mechanism. Experimental treatment with GLP-1 receptor agonists (GLP-1RA) has been reported as successful against PBH, which is paradoxical as GLP-1RA stimulate insulin release. 

    The aim of this thesis is to further explore the metabolic changes after GBP that may influence glycaemic control. In Paper I, euglycaemic-hypoglycaemic clamps were used to assess whether infusion with GLP-1RA affects the counterregulatory response to hypoglycaemia after GBP. In Paper II, normoglycaemic-hypoglycaemic clamps were performed before and after GBP during simultaneous brain imaging with fMRI and FDG-PET techniques, cognitive testing and assessment of counterregulatory hormones. Paper III details the time course of metabolic changes after GBP in patients with previous T2DM with focus on adipose tissue, including gene expression, and possible anti-inflammatory effects. Paper IV approaches the same question as Paper I, this time in the setting of a standardized meal test. All papers include assessment of heart rate variability (HRV) as a potential reflection of autonomic nervous system (ANS) activity. 

    In Paper I, we do not find indications that GLP-1RA affects counterregulatory hormones, but that it may affect ANS activation during hypoglycaemia. In contrast, Paper IV reports higher cortisol levels with GLP1-RA after a meal, and indications of ANS effects, but no effect on post-prandial glucose levels. Results from Paper II support the hypothesis that GBP attenuates hormonal counterregulatory responses and affects how the CNS responds to hypoglycaemia. In Paper III we report sustained improvements in glucose uptake in adipocytes, potentially indications of decreased low-grade inflammation and signs of transient increases in parasympathetic activity. 

    List of papers
    1. Effects of GLP-1 on counter-regulatory responses during hypoglycemia after GBP surgery
    Open this publication in new window or tab >>Effects of GLP-1 on counter-regulatory responses during hypoglycemia after GBP surgery
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    2019 (English)In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 181, no 2, p. 161-171Article in journal (Refereed) Published
    Abstract [en]

    Objectives: The aim of the study was to explore the role of GLP-1 receptor activation on the counter-regulation and symptoms of hypoglycemia in subjects who have undergone gastric bypass surgery (GBP).

    Design: Experimental hyperinsulinemic-hypoglycemic clamp study.

    Methods: Twelve post-GBP subjects participated in a randomized cross-over study with two hyperinsulinemic, hypoglycemic clamps (glucose nadir 2.7 mmol/L) performed on separate days with concomitant infusions of the GLP-1 analog exenatide or with saline, respectively. Continuous measurements of metabolites and counter-regulatory hormones as well as assessments of heart rate variability and symptoms of hypoglycemia were performed throughout the clamps.

    Results: No effect of GLP-1 receptor activation on counter-regulatory hormones (glucagon, catecholamines, cortisol, GH) or glucose infusion rate was seen, but we found indications of a downregulation of the sympathetic relative to the parasympathetic nerve activity, as reflected in heart rate variability. No significant differences in symptom of hypoglycemia were observed.

    Conclusions/interpretation: Short-term exposure to a GLP-1 receptor agonist does not seem to impact the counter-regulatory hormonal and metabolic responses in post-GBP subjects during hypoglycemic conditions, suggesting that the improvement in symptomatic hypoglycemia post-GBP seen following treatment with GLP-1 receptor agonists may be mediated by mechanism not directly involved in counter-regulation.

    Place, publisher, year, edition, pages
    BIOSCIENTIFICA LTD, 2019
    National Category
    Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-390513 (URN)10.1530/EJE-19-0171 (DOI)000472835100013 ()31176298 (PubMedID)
    Funder
    Swedish Diabetes AssociationErnfors FoundationEXODIAB - Excellence of Diabetes Research in Sweden
    Available from: 2019-08-12 Created: 2019-08-12 Last updated: 2023-12-14Bibliographically approved
    2. Effects of Gastric Bypass Surgery on the Brain: Simultaneous Assessment of Glucose Uptake, Blood Flow, Neural Activity, and Cognitive Function During Normo- and Hypoglycemia
    Open this publication in new window or tab >>Effects of Gastric Bypass Surgery on the Brain: Simultaneous Assessment of Glucose Uptake, Blood Flow, Neural Activity, and Cognitive Function During Normo- and Hypoglycemia
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    2021 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 70, no 6, p. 1265-1277Article in journal (Refereed) Published
    Abstract [en]

    While Roux-en-Y gastric bypass (RYGB) surgery in obese individuals typically improves glycemic control and prevents diabetes, it also frequently causes asymptomatic hypoglycemia. Previous work showed attenuated counterregulatory responses following RYGB. The underlying mechanisms as well as the clinical consequences are unclear. In this study, 11 subjects without diabetes with severe obesity were investigated pre- and post-RYGB during hyperinsulinemic normo-hypoglycemic clamps. Assessments were made of hormones, cognitive function, cerebral blood flow by arterial spin labeling, brain glucose metabolism by F-18-fluorodeoxyglucose (FDG) positron emission tomography, and activation of brain networks by functional MRI. Post- versus presurgery, we found a general increase of cerebral blood flow but a decrease of total brain FDG uptake during normoglycemia. During hypoglycemia, there was a marked increase in total brain FDG uptake, and this was similar for post- and presurgery, whereas hypothalamic FDG uptake was reduced during hypoglycemia. During hypoglycemia, attenuated responses of counterregulatory hormones and improvements in cognitive function were seen postsurgery. In early hypoglycemia, there was increased activation post- versus presurgery of neural networks in brain regions implicated in glucose regulation, such as the thalamus and hypothalamus. The results suggest adaptive responses of the brain that contribute to lowering of glycemia following RYGB, and the underlying mechanisms should be further elucidated.

    Place, publisher, year, edition, pages
    American Diabetes Association, 2021
    National Category
    Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-452976 (URN)10.2337/db20-1172 (DOI)000671940300008 ()33674408 (PubMedID)
    Note

    K.E.A. and M.H.L. contributed equally.

    Available from: 2021-09-15 Created: 2021-09-15 Last updated: 2023-12-14Bibliographically approved
    3. Time Course of Metabolic, Neuroendocrine, and Adipose Effects During 2 Years of Follow-up After Gastric Bypass in Patients With Type 2 Diabetes
    Open this publication in new window or tab >>Time Course of Metabolic, Neuroendocrine, and Adipose Effects During 2 Years of Follow-up After Gastric Bypass in Patients With Type 2 Diabetes
    Show others...
    2021 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 106, no 10Article in journal (Refereed) Published
    Abstract [en]

    Context: Roux-en-Y gastric bypass surgery (RYGB) markedly improves glycemia in patients with type 2 diabetes (T2D), but underlying mechanisms and changes over time are incompletely understood.

    Objective: Integrated assessment of neuroendocrine and metabolic changes over time in T2D patients undergoing RYGB.

    Design and Setting: Follow-up of single-center randomized study.

    Patients: Thirteen patients with obesity and T2D compared to 22 healthy subjects. Interventions: Blood chemistry, adipose biopsies, and heart rate variability were obtained before and 4, 24, and 104 weeks post-RYGB.

    Results: After RYGB, glucose-lowering drugs were discontinued and hemoglobin A1c fell from mean 55 to 41 mmol/mol by 104 weeks (P<0.001). At 4 weeks, morning cortisol (P<0.05) and adrenocorticotropin (P=0.09) were reduced by 20%. Parasympathetic nerve activity (heart rate variability derived) increased at 4 weeks (P<0.05) and peaked at 24 weeks (P<0.01). C-reactive protein (CRP) and white blood cells were rapidly reduced (P<0.01). At 104 weeks, basal and insulin-stimulated adipocyte glucose uptake increased by 3-fold vs baseline and expression of genes involved in glucose transport, fatty acid oxidation, and adipogenesis was upregulated (P<0.01). Adipocyte volume was reduced by 4 weeks and more markedly at 104 weeks, by about 40% vs baseline (P<0.01).

    Conclusions: We propose this order of events: (1) rapid glucose lowering (days); (2) attenuated cortisol axis activity and inflammation and increased parasympathetic tone (weeks); and (3) body fat and weight loss, increased adipose glucose uptake, and whole-body insulin sensitivity (months-years; similar to healthy controls). Thus, neuroendocrine pathways can partly mediate early glycemic improvement after RYGB, and adipose factors may promote long-term insulin sensitivity and normoglycemia.

    Place, publisher, year, edition, pages
    Endocrine SocietyThe Endocrine Society, 2021
    Keywords
    T2D, RYGB, neuroendocrine changes, adipose effects
    National Category
    Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-457938 (URN)10.1210/clinem/dgab398 (DOI)000705200500042 ()34086911 (PubMedID)
    Funder
    Diabetesfonden, DIA2019-490Ernfors FoundationEXODIAB - Excellence of Diabetes Research in SwedenNovo Nordisk, NNF20OC0063864
    Available from: 2021-11-08 Created: 2021-11-08 Last updated: 2024-01-15Bibliographically approved
    4. Effects of acute GLP-1 receptor activation on the glycemic and neurohormonal responses to meal test after gastric bypass
    Open this publication in new window or tab >>Effects of acute GLP-1 receptor activation on the glycemic and neurohormonal responses to meal test after gastric bypass
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Keywords
    Roux-en Y gastric bypass, post-bariatric hypoglycaemia, GLP-1 analogue, hypoglycaemia counterregulation, cortisol
    National Category
    Endocrinology and Diabetes
    Research subject
    Medical Science
    Identifiers
    urn:nbn:se:uu:diva-517680 (URN)
    Available from: 2023-12-13 Created: 2023-12-13 Last updated: 2023-12-14
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  • 39.
    Almby, Kristina E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Abrahamsson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Lundqvist, Martin H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Hammar, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Thombare, Ketan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Panagiotou, Amalia
    Uppsala Univ Hosp, Dept Internal Med, Uppsala, Sweden.
    Karlsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Wiklund, Urban
    Umea Univ, Dept Radiat Sci, Biomed Engn, Umea, Sweden.
    Eriksson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Effects of GLP-1 on counter-regulatory responses during hypoglycemia after GBP surgery2019In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 181, no 2, p. 161-171Article in journal (Refereed)
    Abstract [en]

    Objectives: The aim of the study was to explore the role of GLP-1 receptor activation on the counter-regulation and symptoms of hypoglycemia in subjects who have undergone gastric bypass surgery (GBP).

    Design: Experimental hyperinsulinemic-hypoglycemic clamp study.

    Methods: Twelve post-GBP subjects participated in a randomized cross-over study with two hyperinsulinemic, hypoglycemic clamps (glucose nadir 2.7 mmol/L) performed on separate days with concomitant infusions of the GLP-1 analog exenatide or with saline, respectively. Continuous measurements of metabolites and counter-regulatory hormones as well as assessments of heart rate variability and symptoms of hypoglycemia were performed throughout the clamps.

    Results: No effect of GLP-1 receptor activation on counter-regulatory hormones (glucagon, catecholamines, cortisol, GH) or glucose infusion rate was seen, but we found indications of a downregulation of the sympathetic relative to the parasympathetic nerve activity, as reflected in heart rate variability. No significant differences in symptom of hypoglycemia were observed.

    Conclusions/interpretation: Short-term exposure to a GLP-1 receptor agonist does not seem to impact the counter-regulatory hormonal and metabolic responses in post-GBP subjects during hypoglycemic conditions, suggesting that the improvement in symptomatic hypoglycemia post-GBP seen following treatment with GLP-1 receptor agonists may be mediated by mechanism not directly involved in counter-regulation.

  • 40.
    Almby, Kristina E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Katsogiannos, Petros
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Pereira, Maria J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Karlsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Wiklund, Urban
    Umeå Univ, Dept Radiat Sci, Umeå, Sweden..
    Kamble, Prasad G.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Eriksson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Time Course of Metabolic, Neuroendocrine, and Adipose Effects During 2 Years of Follow-up After Gastric Bypass in Patients With Type 2 Diabetes2021In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 106, no 10Article in journal (Refereed)
    Abstract [en]

    Context: Roux-en-Y gastric bypass surgery (RYGB) markedly improves glycemia in patients with type 2 diabetes (T2D), but underlying mechanisms and changes over time are incompletely understood.

    Objective: Integrated assessment of neuroendocrine and metabolic changes over time in T2D patients undergoing RYGB.

    Design and Setting: Follow-up of single-center randomized study.

    Patients: Thirteen patients with obesity and T2D compared to 22 healthy subjects. Interventions: Blood chemistry, adipose biopsies, and heart rate variability were obtained before and 4, 24, and 104 weeks post-RYGB.

    Results: After RYGB, glucose-lowering drugs were discontinued and hemoglobin A1c fell from mean 55 to 41 mmol/mol by 104 weeks (P<0.001). At 4 weeks, morning cortisol (P<0.05) and adrenocorticotropin (P=0.09) were reduced by 20%. Parasympathetic nerve activity (heart rate variability derived) increased at 4 weeks (P<0.05) and peaked at 24 weeks (P<0.01). C-reactive protein (CRP) and white blood cells were rapidly reduced (P<0.01). At 104 weeks, basal and insulin-stimulated adipocyte glucose uptake increased by 3-fold vs baseline and expression of genes involved in glucose transport, fatty acid oxidation, and adipogenesis was upregulated (P<0.01). Adipocyte volume was reduced by 4 weeks and more markedly at 104 weeks, by about 40% vs baseline (P<0.01).

    Conclusions: We propose this order of events: (1) rapid glucose lowering (days); (2) attenuated cortisol axis activity and inflammation and increased parasympathetic tone (weeks); and (3) body fat and weight loss, increased adipose glucose uptake, and whole-body insulin sensitivity (months-years; similar to healthy controls). Thus, neuroendocrine pathways can partly mediate early glycemic improvement after RYGB, and adipose factors may promote long-term insulin sensitivity and normoglycemia.

    Download full text (pdf)
    fulltext
  • 41.
    Almby, Kristina E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Lundqvist, Martin H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Abrahamsson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Kvernby, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Fahlström, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Pereira, Maria J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Gingnell, Malin
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Cervenka: Psychiatry.
    Karlsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Fanni, Giovanni
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Wiklund, Urban
    Umeå Univ, Dept Radiat Sci, Umeå, Sweden..
    Haller, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Univ Geneva, Fac Med, Geneva, Switzerland..
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wikström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Eriksson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Effects of Gastric Bypass Surgery on the Brain: Simultaneous Assessment of Glucose Uptake, Blood Flow, Neural Activity, and Cognitive Function During Normo- and Hypoglycemia2021In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 70, no 6, p. 1265-1277Article in journal (Refereed)
    Abstract [en]

    While Roux-en-Y gastric bypass (RYGB) surgery in obese individuals typically improves glycemic control and prevents diabetes, it also frequently causes asymptomatic hypoglycemia. Previous work showed attenuated counterregulatory responses following RYGB. The underlying mechanisms as well as the clinical consequences are unclear. In this study, 11 subjects without diabetes with severe obesity were investigated pre- and post-RYGB during hyperinsulinemic normo-hypoglycemic clamps. Assessments were made of hormones, cognitive function, cerebral blood flow by arterial spin labeling, brain glucose metabolism by F-18-fluorodeoxyglucose (FDG) positron emission tomography, and activation of brain networks by functional MRI. Post- versus presurgery, we found a general increase of cerebral blood flow but a decrease of total brain FDG uptake during normoglycemia. During hypoglycemia, there was a marked increase in total brain FDG uptake, and this was similar for post- and presurgery, whereas hypothalamic FDG uptake was reduced during hypoglycemia. During hypoglycemia, attenuated responses of counterregulatory hormones and improvements in cognitive function were seen postsurgery. In early hypoglycemia, there was increased activation post- versus presurgery of neural networks in brain regions implicated in glucose regulation, such as the thalamus and hypothalamus. The results suggest adaptive responses of the brain that contribute to lowering of glycemia following RYGB, and the underlying mechanisms should be further elucidated.

  • 42.
    Almby, Kristina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Wiklund, Urban
    Department of Radiation Sciences, Radiation Physics, Biomedical Engineering, Umeå University.
    Lundqvist, Martin H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Pereira, Maria J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Abrahamsson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Effects of acute GLP-1 receptor activation on the glycemic and neurohormonal responses to meal test after gastric bypassManuscript (preprint) (Other academic)
  • 43.
    Almeamar, Hussein
    et al.
    St Vincents Univ Hosp, ENETS Ctr Excellence, Natl Ctr Neuroendocrine Tumours, Dublin, Ireland..
    Cullen, Lisa
    St Vincents Univ Hosp, ENETS Ctr Excellence, Natl Ctr Neuroendocrine Tumours, Dublin, Ireland..
    Murphy, David J.
    St Vincents Univ Hosp, Dept Radiol, Dublin, Ireland.;UCD Sch Med, Dublin, Ireland..
    Crowley, Rachel K.
    St Vincents Univ Hosp, ENETS Ctr Excellence, Natl Ctr Neuroendocrine Tumours, Dublin, Ireland.;UCD Sch Med, Dublin, Ireland..
    Toumpanakis, Christos
    Royal Free Hosp, ENETS Ctr Excellence, London, England..
    Welin, Staffan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    O'Shea, Donal
    St Vincents Univ Hosp, ENETS Ctr Excellence, Natl Ctr Neuroendocrine Tumours, Dublin, Ireland.;UCD Sch Med, Dublin, Ireland..
    O'Toole, Dermot
    St Vincents Univ Hosp, ENETS Ctr Excellence, Natl Ctr Neuroendocrine Tumours, Dublin, Ireland.;Trinity Coll Dublin, Dept Clin Med, Dublin, Ireland..
    Real-world efficacy of lutetium peptide receptor radionuclide therapy in patients with neuroendocrine tumours2022In: Journal of neuroendocrinology, ISSN 0953-8194, E-ISSN 1365-2826, Vol. 34, no 6, article id e13138Article in journal (Refereed)
    Abstract [en]

    Lutetium peptide receptor radio nuclide therapy (Lu-PRRT) is an effective treatment for progressive, metastatic, somatostatin-receptor-positive, well-differentiated neuroendocrine tumours (WD-NETs). Here, we report a single centre experience of real-world efficacy, long-term side effects, and challenges of this treatment. This was a retrospective analysis. All patients linked with our centre who had Lu-PRRT were included. Clinicopathological data were analysed using descriptive statistics, Kaplan-Meier, and Cox regression. A total of 45 patients had Lu-PRRT, of those 30 (67%) were males, and 13 (29%) were more than 65 years old. The primary site was small intestine in 30 (67%) patients, pancreas in seven (16%) patients, and lung in three (7%) patients. The tumor was grade 1 in 15 (35%) patients, grade 2 in 22 (48%) patients, and grade 3 in six (13%) patients. A total of 41 (91%) patients had liver metastasis, and 20 (44%) patients had carcinoid syndrome. Lu-PRRT was the second-line therapy in all patients. Krenning's score was 4 in 36 (80%) patients and 3 in nine (20%) patients. The median waiting time to start Lu-PRRT therapy was 87 days. The median follow-up was 41 months. A total of 23 (51%) patients had a partial response, 18 (40%) patients had stable disease, and four (9%) patients had progression. None of the patients had a complete response. The median progression-free survival (PFS) was 38 months (95% CI: 25.8-50.1). The median overall survival (OS) was not reached. Nine patients died during follow-up (death from any cause). Prior treatment with targeted therapies or high dose somatostatin analogues were negative predictors of Lu-PRRT outcome (p-values of < .001 and < .045, respectively). There were two serious haematological toxicities, one patient developed acute myeloid leukaemia (AML), and the other developed chronic myeloid leukaemia (CML). Lu-PRRT is an effective second-line treatment for metastatic WD-NETs. The effect of targeted therapies on Lu-PRRT outcome was significant and needs to be clarified in further studies.

  • 44.
    Almgren, Malin
    et al.
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Mol Med, Stockholm, Sweden.;Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden..
    Atkinson, Richard
    Obetech Obes Res Ctr, Richmond, VA USA.;Virginia Commonwealth Univ, Richmond, VA USA..
    He, Jia
    Obetech Obes Res Ctr, Richmond, VA USA.;Virginia Commonwealth Univ, Richmond, VA USA..
    Hilding, Agneta
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Hagman, Emilia
    Karolinska Inst, Dept Clin Sci Intervent & Technol, Div Pediat, Stockholm, Sweden..
    Wolk, Alicja
    Karolinska Inst, Inst Environm Med, Div Nutr Epidemiol, S-10401 Stockholm, Sweden..
    Thorell, Anders
    Ersta Hosp, Dept Surg, Stockholm, Sweden..
    Marcus, Claude
    Karolinska Inst, Dept Clin Sci Intervent & Technol, Div Pediat, Stockholm, Sweden..
    Naslund, Erik
    Karolinska Inst, Dept Clin Sci, Danderyd Hosp, Div Surg, Stockholm, Sweden..
    Ostenson, Claes-Goran
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Schalling, Martin
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Mol Med, Stockholm, Sweden..
    Lavebratt, Catharina
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Ctr Mol Med, Stockholm, Sweden..
    Adenovirus-36 Is Associated with Obesity in Children and Adults in Sweden as Determined by Rapid ELISA2012In: PLOS ONE, E-ISSN 1932-6203, Vol. 7, no 7, article id e41652Article in journal (Refereed)
    Abstract [en]

    Background: Experimental and natural human adenovirus-36 (Adv36) infection of multiple animal species results in obesity through increasing adipogenesis and lipid accumulation in adipocytes. Presence of Adv36 antibodies detected by serum neutralization assay has previously been associated with obesity in children and adults living in the USA, South Korea and Italy, whereas no association with adult obesity was detected in Belgium/the Netherlands nor among USA military personnel. Adv36 infection has also been shown to reduce blood lipid levels, increase glucose uptake by adipose tissue and skeletal muscle biopsies, and to associate with improved glycemic control in non-diabetic individuals. Principal Findings: Using a novel ELISA, 1946 clinically well-characterized individuals including 424 children and 1522 nondiabetic adults, and 89 anonymous blood donors, residing in central Sweden representing the population in Stockholm area, were studied for the presence of antibodies against Adv36 in serum. The prevalence of Adv36 positivity in lean individuals increased from similar to 7% in 1992-1998 to 15-20% in 2002-2009, which paralleled the increase in obesity prevalence. We found that Adv36-positive serology was associated with pediatric obesity and with severe obesity in females compared to lean and overweight/mildly obese individuals, with a 1.5 to 2-fold Adv36 positivity increase in cases. Moreover, Adv36 positivity was less common among females and males on antilipid pharmacological treatment or with high blood triglyceride level. Insulin sensitivity, measured as lower HOMA-IR, showed a higher point estimate in Adv36-positive obese females and males, although it was not statistically significant (p = 0.08). Conclusion: Using a novel ELISA we show that Adv36 infection is associated with pediatric obesity, severe obesity in adult females and lower risk of high blood lipid levels in non-diabetic Swedish individuals.

  • 45.
    Al-Shamkhi, Nasrin
    et al.
    Örebro Univ Hosp, Dept Internal Med, Örebro, Sweden.;Örebro Univ, Fac Med & Hlth, Sch Med Sci, Örebro, Sweden.;Uppsala Univ Hosp, Dept Endocrinol & Diabetol, Uppsala, Sweden.;Akadem Sjukhuset, Endokrin & Diabetesmottagningen, S-75185 Uppsala, Sweden..
    Berinder, Katarina
    Karolinska Univ Hosp, Dept Endocrinol, Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Borg, Henrik
    Lund Univ, Skane Univ Hosp, Dept Endocrinol, Lund, Sweden..
    Burman, Pia
    Lund Univ, Skane Univ Hosp, Dept Endocrinol, Malmö, Sweden..
    Dahlqvist, Per
    Umeå Univ, Dept Publ Hlth & Clin Med, Umeå, Sweden..
    Hoybye, Charlotte
    Karolinska Univ Hosp, Dept Endocrinol, Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Olsson, Daniel S.
    Sahlgrens Univ Hosp, Dept Endocrinol, Gothenburg, Sweden.;Univ Gothenburg, Inst Med, Dept Internal Med & Clin Nutr, Sahlgrenska Acad, Gothenburg, Sweden.;AstraZeneca, BioPharmaceut R&D, Cardiovasc Renal & Metab CVRM, Gothenburg, Sweden..
    Ragnarsson, Oskar
    Sahlgrens Univ Hosp, Dept Endocrinol, Gothenburg, Sweden.;Univ Gothenburg, Inst Med, Dept Internal Med & Clin Nutr, Sahlgrenska Acad, Gothenburg, Sweden.;Univ Gothenburg, Wallenberg Ctr Mol & Translat Med, Gothenburg, Sweden..
    Ekman, Bertil
    Linköping Univ, Dept Endocrinol Linköping & Norrköping, Linköping, Sweden.;Linköping Univ, Dept Hlth Med & Caring Sci, Linköping, Sweden..
    Edén Engström, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Pituitary function before and after surgery for nonfunctioning pituitary adenomas-data from the Swedish Pituitary Register2023In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 189, no 2, p. 217-224Article in journal (Refereed)
    Abstract [en]

    Objective: Data on pre- and postoperative pituitary function in nonfunctioning pituitary adenomas (NFPA) are not consistent. We aimed to investigate pituitary function before and up to 5 years after transsphenoidal surgery with emphasis on the hypothalamic-pituitary-adrenal axis (HPA).

    Design and methods: Data from the Swedish Pituitary Register was used to analyze anterior pituitary function in 838 patients with NFPA diagnosed between 1991 and 2014. Patients who were reoperated or had received radiotherapy were excluded.

    Results: Preoperative ACTH, TSH, LH/FSH, and GH deficiencies were reported in 31% (236/755), 39% (300/769), 51% (378/742), and 28% (170/604) of the patients, respectively. Preoperative median tumor volume was 5.0 (2.4-9.0) cm(3). Among patients with preoperative, 1 year and 5 years postoperative data on the HPA axis (n = 428), 125 (29%) were ACTH-deficient preoperatively. One year postoperatively, 26% (32/125) of them had recovered ACTH function while 23% (70/303) patients had developed new ACTH deficiency. Thus, 1 year postoperatively, 163 (38%) patients were ACTH-deficient (P < .001 vs. preoperatively). No further increase was seen 5 years postoperatively (36%, P = .096). At 1 year postoperatively, recoveries in the TSH and LH/FSH axes were reported in 14% (33/241) and 15% (46/310), respectively, and new deficiencies in 22% (88/403) and 29% (83/288), respectively.

    Conclusions: Adrenocorticotrophic hormone deficiency increased significantly at 1 year postoperatively. Even though not significant, some patients recovered from or developed new deficiency between 1 and 5 years postoperatively. This pattern was seen in all axes. Our study emphasizes that continuous individual evaluations are needed during longer follow-up of patients operated for NFPA.

    Download full text (pdf)
    fulltext
  • 46.
    Alskar, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Karlsson, Mats O.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Kjellsson, Maria C.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
    Interspecies scaling of dynamic glucose and insulin using a mathematical model approach2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no Suppl. 1, p. S306-S307Article in journal (Other academic)
  • 47.
    Amin, Kawa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Lung- allergy- and sleep research.
    Levels of cytokines and GADA in type I and II diabetic patients2020In: Primary Care Diabetes, ISSN 1751-9918, E-ISSN 1878-0210, Vol. 14, no 1, p. 61-67Article in journal (Refereed)
    Abstract [en]

    AbstractBACKGROUND:

    Diabetes Mellitus is described as a group of metabolic diseases in which the patient has higher blood glucose levels due to many causes. These include a defect in insulin secretion and failure of the body's cells to respond to the hormone. Cytokines and autoantibodies have a critical role in the pathogenesis of diabetes, especially type I.

    AIM OF THE STUDY:

    The aim of this study was to measure the serum levels of interleukin-1 beta (IL-1 β), interleukin-3 (IL-3), interferon-gamma (INF- γ), and glutamic acid decarboxylase autoantibody (GADA) in patients with type I and type II diabetes mellitus.

    MATERIAL AND METHODS:

    In this cross-sectional study, serum samples were taken from 250 individuals, including 100 samples from patients with type II diabetes mellitus, 100 samples from healthy controls, and 50 samples from patients with type I diabetes mellitus. Five milliliters of venous blood were taken from each individual and the samples were analyzed for cytokines (IL-1 β, IL-3, and INF- γ) and GABA using ELISA.

    RESULTS:

    In the study, we found that the serum levels of IL-1 β were significantly higher in the healthy control group compared to the patients with type I and type II diabetes mellitus. The levels of IL-3 and INF- γ were significantly higher in type II diabetes mellitus, while GABA serum levels were higher in type I diabetes mellitus.

    CONCLUSION:

    Our data showed that GADA is an important autoantibody, not only in type I but also in type II diabetes mellitus and can probably be used in the future for diagnosis of this disease. There was also a close association of GADA with systemic immunoregulation in type I and II diabetes mellitus. The relation of cytokines (IL-1 β, IL-3, and INF- γ) and GADA in patients with diabetes will also increase our understanding for the immunology of diabetes mellitus and to propose specific treatment on the basis of our findings. Our data also include correlation between age and the level of cytokines and GADA with different conclusion for each parameter.

  • 48.
    Anagandula, Mahesh
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hyöty, Heikki
    University of Tampere, School of Medicine, Tampere, Finland ,Fimlab Ltd, Pirkanmaa Hospital District, Finland.
    Frisk, Gun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Enterovirus-induced changes in explanted human islet of Langerhans resemble findings in islets of fulminant and conventional type 1 diabetesManuscript (preprint) (Other academic)
    Abstract [en]

    Hypothesis: Fulminant Type 1 diabetes is a unique subtype of T1D, mostly reported in the Japanese population, which is characterized by extensive beta cell death already at onset, often without any insulitis. Enterovirus (EV) infections are associated with the etiology of both fulminant and conventional T1D. However the causative mechanism is not known for any of these diseases. EVs capability to cause lytic vs non-lytic infection in explanted human islets may have implications on the pathogenesis of these two types of T1D.

    Aim: To study the effect of infection of explanted human pancreatic islets with lytic (CBV-1) and non-lytic (CBV-4) Coxsackie B virus strains on cytopathic effect/islet disintegration and to what extent genes involved in viral sensing, antiviral defense and encoding of islet auto-antigens are affected by the viral replication. Also, to compare these findings with the findings reported in fulminant and conventional T1D.

    Methods: Degree of cytopathic effect/islet disintegration was studied and viral replication was measured. Genes involved in viral sensing (NOD2, TLR7 and TLR4), antiviral pathways (OAS2, MX1, PKR, and IRF7), genes coding for known islet auto antigens (GAD65, ZNT8) and the islet hormones, insulin and glucagon, were studied. Mock-infected explanted islet served as controls.

    Results: All CBV strains replicated in the explanted islets but only the CBV-1 strains caused cytopathic effect/islet cell disintegration. Infection with all CBV strains resulted in the induction of genes encoding OAS2 and MX1. In contrast, mRNA expression levels of the gene encoding insulin was reduced. The gene encoding PKR was induced by one of the lytic strains (CBV-1-11) and also by the non-lytic CBV4 strain, while the mRNA expression levels of genes encoding glucagon, NOD2, TLR7, TLR4, MCL1, GAD65 and ZNT8 were not significantly affected.

  • 49.
    Andersson Svärd, Agnes
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Biology Education Centre.
    Peripheral blood cell HLA class II gene expression in children at genetic risk for type 1 diabetes and coeliac disease2015Independent thesis Advanced level (professional degree), 20 credits / 30 HE creditsStudent thesis
    Download full text (pdf)
    AAS_2015
  • 50.
    Annebäck, Matilda
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hedberg, Jakob
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Almquist, Martin
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Risk of Permanent Hypoparathyroidism After Total Thyroidectomy for Benign Disease: A Nationwide Population-based Cohort Study From Sweden2021In: Annals of Surgery, ISSN 0003-4932, E-ISSN 1528-1140, Vol. 274, no 6, p. e1202-e1208Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate the prevalence and risk factors for permanent hypoparathyroidism after total thyroidectomy for benign disease in a population-based setting with data independent of input of complication data.

    SUMMARY OF BACKGROUND DATA: The reported rate of permanent hypoparathyroidism is highly variable and mostly rely on reported complication data from national or institutional registries.

    METHODS: All patients who underwent total thyroidectomy in Sweden from 2005 to 2015 were identified through Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal Surgery and the Swedish National Patient Register. Patients were matched to outcome data from the Swedish Prescribed Drug Register. Permanent hypoparathyroidism was defined as treatment with calcium and/or active vitamin D more than 1 year after surgery.

    RESULTS: Seven thousand eight hundred fifty-two patients were included and 938 (12.5%) developed permanent hypoparathyroidism. The risk was lower in patients registered in the quality register (11.0% vs 16%, P < 0.001). In a multivariable analysis there was a higher risk of permanent hypoparathyroidism in patients with parathyroid autotransplantation [Odds ratio (OR) 1.72; 95% confidence interval 1.47-2.01], center-volume <100 thyroidectomies per year (OR 1.22; 1.03-1.44), age above 60 year (OR 1.64; 1.36-1.98) and female sex (OR 1.27; 1.05-1.54). Reported data from the quality register only identified 178 of all 938 patients with permanent hypoparathyroidism.

    CONCLUSION: The risk of permanent hypoparathyroidism after total thyroidectomy was high and associated with parathyroid autotransplantation, higher age, female sex and surgery at a low volume center. Reported follow-up data might underestimate the rate of permanent hypoparathyroidism.

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