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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, article id JME-17-0182Article 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.
    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)
  • 3.
    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.

  • 4.
    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
  • 5.
    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.

  • 6.
    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.

  • 7.
    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.

  • 8.
    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, ISSN 1932-6203, 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.

  • 9.
    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)
  • 10.
    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.

  • 11.
    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.

  • 12.
    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.

  • 13.
    Alenkvist, Ida
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gandasi, Nikhil R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Barg, Sebastian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Tengholm, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Activation-dependent translocation of Epac2 to granule docking sites at the beta cell plasma membrane2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no Suppl. 1, p. S210-S210Article in journal (Other academic)
  • 14.
    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)
  • 15.
    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)
  • 16.
    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.

  • 17.
    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
  • 18.
    Anthony, Lowell B.
    et al.
    Univ Kentucky, Markey Canc Ctr, Div Med Oncol, Lexington, KY 40536 USA..
    Pavel, Marianne E.
    Charite, Campus Virchow Klinikum, D-13353 Berlin, Germany..
    Hainsworth, John D.
    Sarah Cannon Res Inst, Nashville, TN USA..
    Kvols, Larry K.
    H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA..
    Segal, Scott
    Novartis Pharmaceut, E Hanover, NJ USA..
    Hoersch, Dieter
    Zentralklin Bad Berka GmbH, Klin Innere Med Gastroenterol & Endokrinol, Zentrum Neuroendokrine Tumore, Bad Berka, Germany..
    Van Cutsem, Eric
    Univ Hosp Gasthuisberg, Leuven, Belgium..
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Yao, James C.
    Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA..
    Impact of Previous Somatostatin Analogue Use on the Activity of Everolimus in Patients with Advanced Neuroendocrine Tumors: Analysis from the Phase III RADIANT-2 Trial2015In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 102, no 1-2, p. 18-25Article in journal (Refereed)
    Abstract [en]

    Background/Aims: The phase III placebo-controlled RADI-ANT-2 trial investigated the efficacy of everolimus plus octreotide long-acting repeatable (LAR) in patients with advanced neuroendocrine tumors (NET) associated with carcinoid syndrome. Here we report a secondary analysis based on the previous somatostatin analogue (SSA) exposure status of patients enrolled in RADIANT-2. Methods: Patients were randomly assigned to receive oral everolimus 10 mg/day plus octreotide LAR 30 mg intramuscularly (i.m.) or to receive matching placebo plus octreotide LAR 30 mg i.m. every 28 days. SSA treatment before study enrollment was permitted. Patient characteristics and progression-free survival (PFS) were analyzed by treatment arm and previous SSA exposure status. Results: Of the 429 patients enrolled in RADI-ANT-2, 339 were previously exposed to SSA (95% received octreotide); 173 of 339 patients were in the everolimus plus octreotide LAR arm. All patients had a protocol-specified history of secretory symptoms, but analysis by type showed that more patients who previously received SSA therapy had a history of flushing symptoms (77%), diarrhea (86%), or both (63%) compared with SSA-naive patients (62, 62, and 24%, respectively). Patients who received everolimus plus octreotide LAR had longer median PFS regardless of previous SSA exposure (with: PFS 14.3 months, 95% confidence interval, CI, 12.0-20.1; without: 25.2 months, 95% CI, 12.0-not reached) compared with patients who received placebo plus octreotide LAR (with: 11.1 months, 95% CI, 8.4-14.6; without: 13.6 months, 95% CI, 8.2-22.7). Conclusion: Everolimus in combination with octreotide improves PFS in patients with advanced NET associated with carcinoid syndrome, regardless of previous SSA exposure.

  • 19.
    Antonodimitrakis, Pantelis
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Wassberg, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Granberg, Dan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrin Oncology.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Eriksson, Barbro
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Streptozocin and 5-FU for the treatment of Pancreatic Neuroendocrine Tumors: Efficacy, Prognostic Factors and Toxicity2016In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 103, no 3-4, p. 345-353Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: In our center, the combination of streptozocin (STZ) and 5-fluorouracil (5-FU) has been used as the first-line treatment in the majority of patients with pancreatic neuroendocrine tumors (pNETs) over the past few decades. The objective of the current study was to assess the efficacy, prognostic factors and safety of the combination of STZ and 5-FU.

    PATIENTS AND METHODS: Medical records and radiological reports of 133 patients with pNETs who received the combination of STZ and 5-FU during the period 1981-2014 were retrospectively evaluated.

    RESULTS: Median survival from start of treatment was 51.9 months in the whole group. In the radiologically evaluable patients (n = 100) progression-free survival was 23 months. Complete response was reached in 3 patients (3%), partial response in 25 patients (25%), 64 patients (64%) had stable disease and 8 patients (8%) had progressive disease. In a multivariate analysis, surgery of the primary tumor and having a G3 tumor were significant positive and negative prognostic factors of survival from start of treatment, respectively. Having either a G3 tumor or stage IV tumor were significant prognostic factors for shorter progression-free survival. Chemotherapy had to be discontinued in 29 patients due to side-effects, of which kidney toxicity (mainly grade 1-2) was the most frequent.

    CONCLUSION: As shown in recent reports, the combination of STZ and 5-FU is effective in the treatment of pNETs in terms of survival and radiological response, and has an acceptable toxicity profile.

  • 20.
    Atabaki-Pasdar, Naeimeh
    et al.
    Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, SE-20502 Malmo, Sweden..
    Ohlsson, Mattias
    Lund Univ, Dept Astron & Theoret Phys, Computat Biol & Biol Phys Unit, Lund, Sweden..
    Shungin, Dmitry
    Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, SE-20502 Malmo, Sweden..
    Kurbasic, Azra
    Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, SE-20502 Malmo, Sweden..
    Ingelsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Pearson, Ewan R.
    Univ Dundee, Med Res Inst, Div Cardiovasc & Diabet Med, Dundee, Scotland..
    Ali, Ashfaq
    Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, SE-20502 Malmo, Sweden..
    Franks, Paul W.
    Lund Univ, Dept Clin Sci, Genet & Mol Epidemiol Unit, SE-20502 Malmo, Sweden.;Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.;Harvard Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA..
    Statistical power considerations in genotype-based recall randomized controlled trials2016In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 6, article id 37307Article in journal (Refereed)
    Abstract [en]

    Randomized controlled trials (RCT) are often underpowered for validating gene-treatment interactions. Using published data from the Diabetes Prevention Program (DPP), we examined power in conventional and genotype-based recall (GBR) trials. We calculated sample size and statistical power for genemetformin interactions (vs. placebo) using incidence rates, gene-drug interaction effect estimates and allele frequencies reported in the DPP for the rs8065082 SLC47A1 variant, a metformin transported encoding locus. We then calculated statistical power for interactions between genetic risk scores (GRS), metformin treatment and intensive lifestyle intervention (ILI) given a range of sampling frames, clinical trial sample sizes, interaction effect estimates, and allele frequencies; outcomes were type 2 diabetes incidence (time-to-event) and change in small LDL particles (continuous outcome). Thereafter, we compared two recruitment frameworks: GBR (participants recruited from the extremes of a GRS distribution) and conventional sampling (participants recruited without explicit emphasis on genetic characteristics). We further examined the influence of outcome measurement error on statistical power. Under most simulated scenarios, GBR trials have substantially higher power to observe gene-drug and gene-lifestyle interactions than same-sized conventional RCTs. GBR trials are becoming popular for validation of gene-treatment interactions; our analyses illustrate the strengths and weaknesses of this design.

  • 21. Bakhtadze, E
    et al.
    Borg, H
    Stenström, G
    Fernlund, P
    Arnqvist, H J
    Ekbom-Schnell, A
    Bolinder, J
    Eriksson, Jan W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Gudbjörnsdottir, S
    Nyström, L
    Groop, L C
    Sundkvist, G
    HLA-DQB1 genotypes, islet antibodies and beta cell function in the classification of recent-onset diabetes among young adults in the nationwide Diabetes Incidence Study in Sweden2006In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 49, no 8, p. 1785-1794Article in journal (Refereed)
    Abstract [en]

    AIMS/HYPOTHESIS: The World Health Organization considers an aetiological classification of diabetes to be essential. The aim of this study was to evaluate whether HLA-DQB1 genotypes facilitate the classification of diabetes as compared with assessment of islet antibodies by investigating young adult diabetic patients.

    SUBJECTS AND METHODS: Blood samples were available at diagnosis for 1,872 (90%) of the 2,077 young adult patients (aged 15-34 years old) over a 5-year period in the nationwide Diabetes Incidence Study in Sweden. Islet antibodies were measured at diagnosis in 1,869 patients, fasting plasma C-peptide (fpC-peptide) after diagnosis in 1,522, while HLA-DQB1 genotypes were determined in 1,743.

    RESULTS: Islet antibodies were found in 83% of patients clinically considered to have type 1 diabetes, 23% with type 2 diabetes and 45% with unclassifiable diabetes. After diagnosis, median fpC-peptide concentrations were markedly lower in patients with islet antibodies than in those without (0.24 vs 0.69 nmol/l, p<0.0001). Irrespective of clinical classification, patients with islet antibodies showed increased frequencies of at least one of the risk-associated HLA-DQB1 genotypes compared with patients without. Antibody-negative patients with risk-associated HLA-DQB1 genotypes had significantly lower median fpC-peptide concentrations than those without risk-associated genotypes (0.51 vs 0.74 nmol/l, p=0.0003).

    CONCLUSIONS/INTERPRETATION: Assessment of islet antibodies is necessary for the aetiological classification of diabetic patients. HLA-DQB1 genotyping does not improve the classification in patients with islet antibodies. However, in patients without islet antibodies, HLA-DQB1 genotyping together with C-peptide measurement may be of value in differentiating between idiopathic type 1 diabetes and type 2 diabetes.

  • 22.
    Banefelt, J.
    et al.
    Quantify Res, Stockholm, Sweden..
    Akesson, K.
    Lund Univ, Dept Orthopaed, Skane Univ Hosp, Malmo, Sweden..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Spangeus, A.
    Linkoping Univ, Dept Endocrinol, Dept Med & Hlth Sci, Linkoping, Sweden..
    Karlsson, L.
    Quantify Res, Stockholm, Sweden..
    Strom, O.
    Quantify Res, Stockholm, Sweden.;Karolinska Inst, Dept Learning Informat Management & Eth, Stockholm, Sweden..
    Ortsater, G.
    Quantify Res, Stockholm, Sweden..
    Libanati, C.
    UCB Pharma, Brussels, Belgium..
    Toth, E.
    UCB Pharma, Brussels, Belgium..
    Short-Term Fracture (Fx) Incidence And Risk Factors Following Fracture In A Swedish Database Study2017In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 28, p. S365-S365Article in journal (Other academic)
  • 23.
    Barazeghi, Elham
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Studies of epigenetic deregulation in parathyroid tumors and small intestinal neuroendocrine tumors2017Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Deregulation of the epigenome is associated with the initiation and progression of various types of human cancers. Here we investigated the level of 5-hydroxymethylcytosine (5hmC), expression and function of TET1 and TET2, and DNA methylation in parathyroid tumors and small intestinal neuroendocrine tumors (SI-NETs).

    In Paper I, an undetectable/very low level of 5hmC in parathyroid carcinomas (PCs) compared to parathyroid adenomas with positive staining, suggested that 5hmC may represent a novel biomarker for parathyroid malignancy. Immunohistochemistry revealed that increased tumor weight in adenomas was associated with a more aberrant staining pattern of 5hmC and TET1. A growth regulatory role of TET1 was demonstrated in parathyroid tumor cells.

    Paper II revealed that the expression of TET2 was also deregulated in PCs, and promoter hypermethylation was detected in PCs when compared to normal parathyroid tissues. 5-aza-2′-deoxycytidine treatment of a primary PC cell culture induced TET2 expression and further supported involvement of promoter hypermethylation in TET2 gene repression. TET2 knockout demonstrated a role for TET2 in cell growth and migration, and as a candidate tumor suppressor gene.

    In Paper III, variable levels of 5hmC, and aberrant expression of TET1 and TET2 were observed in SI-NETs. We demonstrated a growth regulatory role for TET1, and cytoplasmic expression with absent nuclear localization for TET2 in SI-NETs. In vitro experiments supported the involvement of exportin-1 in TET2 mislocalization, and suggested that KPT-330/selinexor, an orally bioavailable selective inhibitor of exportin-1 and nuclear export, with anti-cancer effects, could be further investigated as a therapeutic option in patients with SI-NETs.

    In Paper IV, DNA methylation was compared between SI-NET primary tumors and metastases by reduced representation bisulfite sequencing. Three differentially methylated regions (DMR) on chromosome 18 were detected and chosen for further analyses. The PTPRM gene, at 18p11, displayed low expression in SI-NETs with high levels of methylation in the presumed CpG island shores, and in the DMR rather than the promoter region or exon 1/intron 1 boundary. PTPRM overexpression resulted in inhibition of cell growth, proliferation, and induction of apoptosis in SI-NET cells, suggesting a role for PTPRM as an epigenetically deregulated candidate tumor suppressor gene in SI-NETs.  

    List of papers
    1. 5-Hydroxymethylcytosine discriminates between parathyroid adenoma and carcinoma
    Open this publication in new window or tab >>5-Hydroxymethylcytosine discriminates between parathyroid adenoma and carcinoma
    Show others...
    2016 (English)In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 8, article id 31Article in journal (Refereed) Published
    Abstract [en]

    Background: Primary hyperparathyroidism is characterized by enlarged parathyroid glands due to an adenoma (80-85 %) or multiglandular disease (similar to 15 %) causing hypersecretion of parathyroid hormone (PTH) and generally hypercalcemia. Parathyroid cancer is rare (<1-5 %). The epigenetic mark 5-hydroxymethylcytosine (5hmC) is reduced in various cancers, and this may involve reduced expression of the ten-eleven translocation 1 (TET1) enzyme. Here, we have performed novel experiments to determine the 5hmC level and TET1 protein expression in 43 parathyroid adenomas (PAs) and 17 parathyroid carcinomas (PCs) from patients who had local invasion or metastases and to address a potential growth regulatory role of TET1. Results: The global 5hmC level was determined by a semi-quantitative DNA immune-dot blot assay in a smaller number of tumors. The global 5hmC level was reduced in nine PCs and 15 PAs compared to four normal tissue samples (p < 0.05), and it was most severely reduced in the PCs. By immunohistochemistry, all 17 PCs stained negatively for 5hmC and TET1 showed negative or variably heterogeneous staining for the majority. All 43 PAs displayed positive 5hmC staining, and a similar aberrant staining pattern of 5hmC and TET1 was seen in about half of the PAs. Western blotting analysis of two PCs and nine PAs showed variable TET1 protein expression levels. A significantly higher tumor weight was associated to PAs displaying a more severe aberrant staining pattern of 5hmC and TET1. Overexpression of TET1 in a colony forming assay inhibited parathyroid tumor cell growth. Conclusions: 5hmC can discriminate between PAs and PCs. Whether 5hmC represents a novel marker for malignancy warrants further analysis in additional parathyroid tumor cohorts. The results support a growth regulatory role of TET1 in parathyroid tissue.

    Keywords
    5-hydroxymethylcytosine, 5hmC, Parathyroid cancer, Primary hyperparathyroidism, TET1
    National Category
    Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-282795 (URN)10.1186/s13148-016-0197-2 (DOI)000371782000002 ()26973719 (PubMedID)
    Funder
    Swedish Cancer Society
    Available from: 2016-04-14 Created: 2016-04-07 Last updated: 2017-11-30Bibliographically approved
    2. A role for TET2 in parathyroid carcinoma
    Open this publication in new window or tab >>A role for TET2 in parathyroid carcinoma
    Show others...
    2017 (English)In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 24, no 7, p. 329-338Article in journal (Refereed) Published
    Abstract [en]

    Primary hyperparathyroidism (pHPT) is rarely caused by parathyroid carcinoma (PC, <1-5% of pHPT cases). The TET proteins oxidize the epigenetic mark 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) and inactivation by mutation or epigenetic deregulation of TET1 and TET2 play important roles in various cancers. Recently, we found that 5hmC was severely reduced in all of the analyzed PCs and with deranged expression of TET1 for the majority of PCs. Here, we have examined the expression of the TET2 protein in 15 5hmC-negative PCs from patients who had local invasion or metastases. Cell growth and cell migratory roles for TET2 as well as epigenetic deregulated expression were addressed. Immunohistochemistry revealed very low/undetectable expression of TET2 in all PCs and verified for two PCs that were available for western blotting analysis. Knockdown of TET2 in the parathyroid cell line sHPT-1 resulted in increased cell growth and increased cell migration. DNA sequencing of TET2 in PCs revealed two common variants and no obvious inactivating mutations. Quantitative bisulfite pyrosequencing analysis of the TET2 promoter CpG island revealed higher CpG methylation level in the PCs compared to that in normal tissues and treatment of a PC primary cell culture with the DNA methylation inhibitor 5-aza-2'-deoxycytidine caused increased expression of the methylated TET2 gene. Hence, the data suggest that deregulated expression of TET2 by DNA hypermethylation may contribute to the aberrantly low level of 5hmC in PCs and further that TET2 plays a cell growth and cell migratory regulatory role and may constitute a parathyroid tumor suppressor gene.

    Keywords
    5-hydroxymethylcytosine, TET2, primary hyperparathyroidism, parathyroid carcinoma, promoter hypermethylation, tumor suppressor
    National Category
    Endocrinology and Diabetes Cancer and Oncology
    Identifiers
    urn:nbn:se:uu:diva-330022 (URN)10.1530/ERC-17-0009 (DOI)000404978400007 ()
    Funder
    Swedish Cancer Society
    Available from: 2017-10-09 Created: 2017-10-09 Last updated: 2018-04-03Bibliographically approved
    3. Decrease of 5-hydroxymethylcytosine and TET1 with nuclear exclusion of TET2 in small intestinal neuroendocrine tumors
    Open this publication in new window or tab >>Decrease of 5-hydroxymethylcytosine and TET1 with nuclear exclusion of TET2 in small intestinal neuroendocrine tumors
    Show others...
    (English)In: Article in journal (Refereed) Submitted
    National Category
    Cancer and Oncology Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-330575 (URN)
    Available from: 2017-10-03 Created: 2017-10-03 Last updated: 2017-10-04
    4. Reduced representation bisulfite sequencing of small intestinal neuroendocrine tumors identifies PTPRM as a novel candidate tumor suppressor gene
    Open this publication in new window or tab >>Reduced representation bisulfite sequencing of small intestinal neuroendocrine tumors identifies PTPRM as a novel candidate tumor suppressor gene
    Show others...
    (English)In: Article in journal (Refereed) Submitted
    National Category
    Cancer and Oncology Endocrinology and Diabetes
    Identifiers
    urn:nbn:se:uu:diva-330794 (URN)
    Available from: 2017-10-04 Created: 2017-10-04 Last updated: 2017-10-04
  • 24.
    Barazeghi, Elham
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Gill, Anthony J.
    Kolling Inst Med Res, Canc Diag & Pathol Res Grp, St Leonards, NSW, Australia..
    Sidhu, Stan
    Royal North Shore Hosp, Dept Surg, St Leonards, NSW, Australia.;Univ Sydney, Sydney, NSW, Australia..
    Norlen, Olov
    Uppsala Univ, Rudbeck Lab, Endocrine Unit, Dept Surg Sci, Uppsala, Sweden.;Royal North Shore Hosp, Dept Surg, St Leonards, NSW, Australia.;Univ Sydney, Sydney, NSW, Australia..
    Dina, Roberto
    Imperial Coll, Hammersmith Hosp, Dept Histopathol, London, England..
    Palazzo, F. Fausto
    Imperial Coll, Hammersmith Hosp, Dept Endocrine Surg, London, England..
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    A role for TET2 in parathyroid carcinoma2017In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 24, no 7, p. 329-338Article in journal (Refereed)
    Abstract [en]

    Primary hyperparathyroidism (pHPT) is rarely caused by parathyroid carcinoma (PC, <1-5% of pHPT cases). The TET proteins oxidize the epigenetic mark 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) and inactivation by mutation or epigenetic deregulation of TET1 and TET2 play important roles in various cancers. Recently, we found that 5hmC was severely reduced in all of the analyzed PCs and with deranged expression of TET1 for the majority of PCs. Here, we have examined the expression of the TET2 protein in 15 5hmC-negative PCs from patients who had local invasion or metastases. Cell growth and cell migratory roles for TET2 as well as epigenetic deregulated expression were addressed. Immunohistochemistry revealed very low/undetectable expression of TET2 in all PCs and verified for two PCs that were available for western blotting analysis. Knockdown of TET2 in the parathyroid cell line sHPT-1 resulted in increased cell growth and increased cell migration. DNA sequencing of TET2 in PCs revealed two common variants and no obvious inactivating mutations. Quantitative bisulfite pyrosequencing analysis of the TET2 promoter CpG island revealed higher CpG methylation level in the PCs compared to that in normal tissues and treatment of a PC primary cell culture with the DNA methylation inhibitor 5-aza-2'-deoxycytidine caused increased expression of the methylated TET2 gene. Hence, the data suggest that deregulated expression of TET2 by DNA hypermethylation may contribute to the aberrantly low level of 5hmC in PCs and further that TET2 plays a cell growth and cell migratory regulatory role and may constitute a parathyroid tumor suppressor gene.

  • 25.
    Barazeghi, Elham
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Marabita, Francesco
    Karolinska Institutet, Karolinska University Hospital.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Reduced representation bisulfite sequencing of small intestinal neuroendocrine tumors identifies PTPRM as a novel candidate tumor suppressor geneIn: Article in journal (Refereed)
  • 26.
    Barazeghi, Elham
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Prabhawa, Surendra
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Norlén, Olov
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Decrease of 5-hydroxymethylcytosine and TET1 with nuclear exclusion of TET2 in small intestinal neuroendocrine tumorsIn: Article in journal (Refereed)
  • 27. Barbu, Andrea R
    et al.
    Welsh, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gene Therapy2010In: Textbook of Diabetes / [ed] Richard I. G. Holt, Clive Cockram, Allan Flyvbjerg, Barry J. Goldstein, Wiley-Blackwell , 2010, 4th edition, p. 1064-1069Chapter in book (Other academic)
  • 28.
    Barbu, Andreea
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Persdotter Hedlund, Gabriella
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Lind, Jenny
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Carlsson, Carina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Pref-1 and adipokine expression inadipose tissues of GK And Zucker rats2009In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 299, no 2, p. 163-171Article in journal (Refereed)
    Abstract [en]

    In view of the central role of preadipocyte factor-1, adiponectin and leptin in white adipose tissue function, the aim of the present study was to analyze the mRNA expression of these proteins and of the inflammatory markers interleukin-6 and tumor necrosis factor-α in visceral and subcutaneous fat pads of rats with different metabolic disorders.

    We demonstrated highly divergent expression of preadipocyte factor-1, upregulated expression of adiponectin, interleukin-6 and TNF-α mRNA in adipose tissues of the diabetic Goto Kakizaki rat compared to the obese Zucker rat. This was correlated to an increased number of large adipocytes and serum levels of adiponectin. Furthermore, in all four strains studied (as above plus Wistar Furth and Zucker Lean), significant heterogeneity was evident in adipokine expression within specific adipose tissues previously defined as belonging to the visceral or subcutaneous fat depots.

    These results suggest that significantly increased levels of inflammation and redistribution of adipocyte size are mechanisms contributing to the development of type 2 diabetes in the GK rat.

  • 29.
    Barbu, Andreea R.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Bodin, Birgitta
    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.
    Jansson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Welsh, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    A perfusion protocol for highly efficient transduction of intact pancreatic islets of Langerhans2006In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 49, no 10, p. 2388-2391Article in journal (Refereed)
    Abstract [en]

    Successful gene transfer to pancreatic islets might be a powerful tool for dissecting the biological pathways involved in the functional impairment and destruction of beta cells in type 1 diabetes. In the long run, such an approach may also prove useful for promoting islet graft survival after transplantation in diabetic patients. However, efficient genetic modification of primary insulin-producing cells is limited by the specific compact structure of the pancreatic islet. We present here a whole-pancreas perfusion-based transduction procedure for genetic modification of intact pancreatic islets.

    We used flow cytometry analysis and confocal microscopy to evaluate the efficiency of in vitro and perfusion-based transduction protocols that use adenoviral and lentiviral vectors expressing green fluorescent protein. Islet cell viability was assessed by fluorescence microscopy and beta cell function was determined via glucose-stimulated insulin secretion.

    In intact rat and human pancreatic islets, adenoviral and lentiviral vectors mediated gene transfer to about 30% of cells, but they did not reach the inner cellular mass within the islet core. Using the whole-pancreas perfusion protocol, we demonstrate that at least in rodent models the centrally located insulin-producing cells can be transduced with high efficiency, while preserving the structural integrity of the islet. Moreover, islet cell viability and function are not impaired by this procedure.

    These results support the view that perfusion-based transduction protocols may significantly improve the yield of successfully engineered primary insulin-producing cells for diabetes research.

  • 30.
    Barg, Sebastian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Gucek, Alenka
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    How Kiss-and-Run Can Make Us Sick: SOX4 Puts a Break on the Pore2016In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 65, no 7, p. 1791-1793Article in journal (Other academic)
  • 31.
    Bell, Katy J. L.
    et al.
    Univ Sydney, Sydney Sch Publ Hlth, Sydney, NSW, Australia.
    Azizi, Lamiae
    Univ Sydney, Sch Math & Stat, Sydney, NSW, Australia.
    Nilsson, Peter M.
    Lund Univ, Dept Clin Sci, Univ Hosp, Malmö, Sweden.
    Hayen, Andrew
    UTS, Australian Ctr Publ & Populat Hlth Res, Sydney, NSW, Australia.
    Irwig, Les
    Univ Sydney, Sydney Sch Publ Hlth, Sydney, NSW, Australia.
    Östgren, Carl J.
    Linköping Univ, Dept Med & Hlth Sci, Linköping, Sweden.
    Sundström, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
    Prognostic impact of systolic blood pressure variability in people with diabetes2018In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 13, no 4, article id e0194084Article in journal (Refereed)
    Abstract [en]

    Objective: Blood pressure variability (BPV) has been associated with risk of cardiovascular events in observational studies, independently of mean BP levels. In states with higher autonomic imbalance, such as in diabetes, the importance of BP variability may theoretically be even greater. We aimed to investigate the incremental value of BPV for prediction of cardiovascular and all-cause mortality in patients with type 2 diabetes.

    Methods: We identified 9,855 patients without pre-existing cardiovascular disease who did not change BP-lowering treatment during the observation period from a Swedish primary health care cohort of patients with type 2 diabetes. BPV was summarized as the standard deviation (SD), coefficient of variation (CV), or variation independent of mean (VIM). Patients were followed for a median of 4 years and associations with cardiovascular and all-cause mortality were investigated using Cox proportional hazards models.

    Results: BPV was not associated with cardiovascular specific or all-cause mortality in the total sample. In patients who were not on BP-lowering drugs during the observation period (n = 2,949), variability measures were associated with all-cause mortality: hazard ratios were 1.05, 1.04 and 1.05 for 50% increases in SD, CV and VIM, respectively, adjusted for Framingham risk score risk factors, including mean BP. However, the addition of the variability measures in this subgroup only led to very minimal improvement in discrimination, indicating they may have limited clinical usefulness (change in C-statistic ranged from 0.000–0.003 in all models).

    Conclusions: Although BPV was independently associated with all-cause mortality in diabetes patients in primary care who did not have pre-existing cardiovascular disease or BP-lowering drugs, it may be of minimal clinical usefulness above and beyond that of other routinely measured predictors, including mean BP.

  • 32.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Brooks, Samantha J
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    O'Daly, Owen G
    Almèn, Markus S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Morell, Arvid
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Åberg, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Gingnell, Malin
    Uppsala University, Disciplinary Domain of Humanities and Social Sciences, Faculty of Social Sciences, Department of Psychology.
    Schultes, Bernd
    Hallschmid, Manfred
    Broman, Jan-Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Larsson, Elna-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Schiöth, Helgi B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Acute Sleep Deprivation Enhances the Brain's Response to Hedonic Food Stimuli: An fMRI Study2012In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 97, no 3, p. E443-447Article in journal (Refereed)
    Abstract [en]

    Context:

    There is growing recognition that a large number of individuals living in Western society are chronically sleep deprived. Sleep deprivation is associated with an increase in food consumption and appetite. However, the brain regions that are most susceptible to sleep deprivation-induced changes when processing food stimuli are unknown.

    Objective:

    Our objective was to examine brain activation after sleep and sleep deprivation in response to images of food.

    Intervention:

    Twelve normal-weight male subjects were examined on two sessions in a counterbalanced fashion: after one night of total sleep deprivation and one night of sleep. On the morning after either total sleep deprivation or sleep, neural activation was measured by functional magnetic resonance imaging in a block design alternating between high- and low-calorie food items. Hunger ratings and morning fasting plasma glucose concentrations were assessed before the scan, as were appetite ratings in response to food images after the scan.

    Main Outcome Measures:

    Compared with sleep, total sleep deprivation was associated with an increased activation in the right anterior cingulate cortex in response to food images, independent of calorie content and prescan hunger ratings. Relative to the postsleep condition, in the total sleep deprivation condition, the activation in the anterior cingulate cortex evoked by foods correlated positively with postscan subjective appetite ratings. Self-reported hunger after the nocturnal vigil was enhanced, but importantly, no change in fasting plasma glucose concentration was found.

    Conclusions:

    These results provide evidence that acute sleep loss enhances hedonic stimulus processing in the brain underlying the drive to consume food, independent of plasma glucose levels. These findings highlight a potentially important mechanism contributing to the growing levels of obesity in Western society.

  • 33.
    Benedict, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Vogel, Heike
    German Inst Human Nutr Potsdam Rehbrucke, Dept Expt Diabetol, Nuthetal, Germany.;German Ctr Diabet Res, Neuherberg, Germany..
    Jonas, Wenke
    German Inst Human Nutr Potsdam Rehbrucke, Dept Expt Diabetol, Nuthetal, Germany.;German Ctr Diabet Res, Neuherberg, Germany..
    Woting, Anni
    German Inst Human Nutr Potsdam Rehbrucke, Dept Gastrointestinal Microbiol, Arthur Scheunert Allee 114-116, D-14558 Nuthetal, Germany..
    Blaut, Michael
    German Inst Human Nutr Potsdam Rehbrucke, Dept Gastrointestinal Microbiol, Arthur Scheunert Allee 114-116, D-14558 Nuthetal, Germany..
    Schuermann, Annette
    German Inst Human Nutr Potsdam Rehbrucke, Dept Expt Diabetol, Nuthetal, Germany.;German Ctr Diabet Res, Neuherberg, Germany..
    Cedernaes, Jonathan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Gut microbiota and glucometabolic alterations in response to recurrent partial sleep deprivation in normal-weight young individuals2016In: Molecular Metabolism, ISSN 2212-8778, Vol. 5, no 12, p. 1175-1186Article in journal (Refereed)
    Abstract [en]

    Objective: Changes to the microbial community in the human gut have been proposed to promote metabolic disturbances that also occur after short periods of sleep loss (including insulin resistance). However, whether sleep loss affects the gut microbiota remains unknown. Methods: In a randomized within-subject crossover study utilizing a standardized in-lab protocol (with fixed meal times and exercise schedules), we studied nine normal-weight men at two occasions: after two nights of partial sleep deprivation (PSD; sleep opportunity 02: 45-07: 00 h), and after two nights of normal sleep (NS; sleep opportunity 22: 30-07: 00 h). Fecal samples were collected within 24 h before, and after two in-lab nights, of either NS or PSD. In addition, participants underwent an oral glucose tolerance test following each sleep intervention. Results: Microbiota composition analysis (V4 16S rRNA gene sequencing) revealed that after two days of PSD vs. after two days of NS, individuals exhibited an increased Firmicutes: Bacteroidetes ratio, higher abundances of the families Coriobacteriaceae and Erysipelotrichaceae, and lower abundance of Tenericutes (all P < 0.05) - previously all associated with metabolic perturbations in animal or human models. However, no PSD vs. NS effect on beta diversity or on fecal short-chain fatty acid concentrations was found. Fasting and postprandial insulin sensitivity decreased after PSD vs. NS (all P < 0.05). Discussion: Our findings demonstrate that short-term sleep loss induces subtle effects on human microbiota. To what extent the observed changes to the microbial community contribute to metabolic consequences of sleep loss warrants further investigations in larger and more prolonged sleep studies, to also assess how sleep loss impacts the microbiota in individuals who already are metabolically compromised. (C) 2016 The Author(s). Published by Elsevier GmbH.

  • 34. Benetou, V
    et al.
    Orfanos, P
    Feskanich, D
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Pettersson-Kymmer, U
    Ahmed, L A
    Peasey, A
    Wolk, A
    Brenner, H
    Bobak, M
    Wilsgaard, T
    Schöttker, B
    Saum, K-U
    Bellavia, A
    Grodstein, F
    Klinaki, E
    Valanou, E
    Papatesta, E-M
    Boffetta, P
    Trichopoulou, A
    Education, marital status, and risk of hip fractures in older men and women: the CHANCES project2015In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 26, no 6, p. 1733-1746Article in journal (Refereed)
    Abstract [en]

    The role of socioeconomic status in hip fracture incidence is unclear. In a diverse population of elderly, higher education was found to be associated with lower, whereas living alone, compared to being married/cohabiting, with higher hip fracture risk. Educational level and marital status may contribute to hip fracture risk.

    INTRODUCTION: The evidence on the association between socioeconomic status and hip fracture incidence is limited and inconsistent. We investigated the potential association of education and marital status with hip fracture incidence in older individuals from Europe and USA.

    METHODS: A total of 155,940 participants (79 % women) aged 60 years and older from seven cohorts were followed up accumulating 6456 incident hip fractures. Information on education and marital status was harmonized across cohorts. Hip fractures were ascertained through telephone interviews/questionnaires or through record linkage with registries. Associations were assessed through Cox proportional hazard regression adjusting for several factors. Summary estimates were derived using random effects models.

    RESULTS: Individuals with higher education, compared to those with low education, had lower hip fracture risk [hazard ratio (HR) = 0.84, 95 % confidence interval (CI) 0.72-0.95]. Respective HRs were 0.97 (95 % CI 0.82-1.13) for men and 0.75 (95 % CI 0.65-0.85) for women. Overall, individuals living alone, especially those aged 60-69 years, compared to those being married/cohabiting, tended to have a higher hip fracture risk (HR = 1.12, 95 % CI 1.02-1.22). There was no suggestion for heterogeneity across cohorts (P heterogeneity > 0.05).

    CONCLUSIONS: The combined data from >150,000 individuals 60 years and older suggest that higher education may contribute to lower hip fracture risk. Furthermore, this risk may be higher among individuals living alone, especially among the age group 60-69 years, when compared to those being married/cohabiting.

  • 35.
    Berglund, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Berne, Christian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Svärdsudd, Kurt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Clinical Epidemiology.
    Garmo, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Zethelius, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Geriatrics.
    Seasonal variations of insulin sensitivity from a euglycemic insulin clamp in elderly men2012In: Upsala Journal of Medical Sciences, ISSN 0300-9734, E-ISSN 2000-1967, Vol. 117, no 1, p. 35-40Article in journal (Refereed)
    Abstract [en]

    Introduction

    Seasonal variations in hemoglobin-A1c have been reported in diabetic patients, but the underlying mechanisms have not been elucidated.

    Aims

    To study if insulin sensitivity, insulin secretion, and fasting plasma glucose showed seasonal variations in a Swedish population-based cohort of elderly men.

    Methods

    Altogether 1117 men were investigated with a euglycemic insulin clamp and measurements of fasting plasma glucose and insulin secretion after an oral glucose tolerance test. Values were analyzed in linear regression models with an indicator variable for winter/summer season and outdoor temperature as predictors.

    Results

     During winter, insulin sensitivity (M/I, unit = 100 × mg × min-1 × kg-1/(mU × L-1)) was 11.0% lower (4.84 versus 5.44, P = 0.0003), incremental area under the insulin curve was 16.4% higher (1167 versus 1003 mU/L, P = 0.007). Fasting plasma glucose was, however, not statistically significantly different (5.80 versus 5.71 mmol/L, P = 0.28) compared to the summer season. There was an association between outdoor temperature and M/I (0.57 units increase (95% CI 0.29–0.82, P < 0.0001) per 10°C increase of outdoor temperature) independent of winter/summer season. Adjustment for life-style factors, type 2 diabetes, and medication did not alter these results.Read More:http://informahealthcare.com/doi/abs/10.3109/03009734.2011.628422

    Conclusions

    Insulin sensitivity showed seasonal variations with lower values during the winter and higher during the summer season. Inverse compensatory variations of insulin secretion resulted in only minor variations of fasting plasma glucose. Insulin sensitivity was associated with outdoor temperature. These phenomena should be further investigated in diabetic patients.

  • 36.
    Bergman, Åke
    et al.
    Swedish Toxicol Sci Res Ctr Swetox, Sodertalje, Sweden..
    Becher, Georg
    Norwegian Inst Publ Hlth, Oslo, Norway..
    Blumberg, Bruce
    Univ Calif Irvine, Irvine, CA USA..
    Bjerregaard, Poul
    Univ Southern Denmark, Odense, Denmark..
    Bornman, Riana
    Univ Pretoria, Sch Hlth Syst & Publ Hlth, ZA-0002 Pretoria, South Africa..
    Brandt, Ingvar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Environmental toxicology.
    Casey, Stephanie C.
    Univ Calif Irvine, Irvine, CA USA..
    Frouin, Heloise
    Vancouver Aquarium Marine Sci Ctr, Vancouver, BC, Canada..
    Giudice, Linda C.
    Univ Calif San Francisco, San Francisco, CA 94143 USA..
    Heindel, Jerrold J.
    Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA..
    Iguchi, Taisen
    Natl Inst Basic Biol, Okazaki, Aichi 444, Japan..
    Jobling, Susan
    Brunel Univ London, Uxbridge, Middx, England..
    Kidd, Karen A.
    Univ New Brunswick, New Brunswick, NJ USA..
    Kortenkamp, Andreas
    Brunel Univ London, Uxbridge, Middx, England..
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Muir, Derek
    Environm Canada, Burlington, ON L7R 4A6, Canada..
    Ochieng, Roseline
    Aga Khan Univ Hosp, Nairobi, Kenya..
    Ropstad, Erik
    Norwegian Univ Life Sci, Oslo, Norway..
    Ross, Peter S.
    Vancouver Aquarium Marine Sci Ctr, Vancouver, BC, Canada..
    Skakkebaek, Niels Erik
    Univ Copenhagen, Copenhagen Univ Hosp, Copenhagen, Denmark..
    Toppari, Jorma
    Univ Turku, Turku, Finland..
    Vandenberg, Laura N.
    Univ Massachusetts, Amherst, MA 01003 USA..
    Woodruff, Tracey J.
    Univ Calif San Francisco, San Francisco, CA 94143 USA..
    Zoeller, R. Thomas
    Univ Massachusetts, Amherst, MA 01003 USA..
    Manufacturing doubt about endocrine disrupter science - A rebuttal of industry-sponsored critical comments on the UNEP/WHO report "State of the Science of Endocrine Disrupting Chemicals 2012"2015In: Regulatory toxicology and pharmacology, ISSN 0273-2300, E-ISSN 1096-0295, Vol. 73, no 3, p. 1007-1017Article in journal (Other academic)
    Abstract [en]

    We present a detailed response to the critique of "State of the Science of Endocrine Disrupting Chemicals 2012" (UNEP/WHO, 2013) by financial stakeholders, authored by Lamb et al. (2014). Lamb et al.'s claim that UNEP/WHO (2013) does not provide a balanced perspective on endocrine disruption is based on incomplete and misleading quoting of the report through omission of qualifying statements and inaccurate description of study objectives, results and conclusions. Lamb et al. define extremely narrow standards for synthesizing evidence which are then used to dismiss the UNEP/WHO 2013 report as flawed. We show that Lamb et al. misuse conceptual frameworks for assessing causality, especially the Bradford Hill criteria, by ignoring the fundamental problems that exist with inferring causality from empirical observations. We conclude that Lamb et al.'s attempt of deconstructing the UNEP/WHO (2013) report is not particularly erudite and that their critique is not intended to be convincing to the scientific community, but to confuse the scientific data. Consequently, it promotes misinterpretation of the UNEP/WHO (2013) report by non-specialists, bureaucrats, politicians and other decision makers not intimately familiar with the topic of endocrine disruption and therefore susceptible to false generalizations of bias and subjectivity.

  • 37.
    Bhandage, Amol K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Korol, Sergiy V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology. Uppsala University.
    Shen, Qiujin
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Pei, Yu
    Karolinska Institute, Stockholm, Sweden.
    Deng, Qiaolin
    Karolinska Institute, Stockholm, Sweden.
    Espes, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    GABA Regulates Release of Inflammatory Cytokines From Peripheral Blood Mononuclear Cells and CD4+ T Cells and Is Immunosuppressive in Type 1 Diabetes2018In: EBioMedicine, ISSN 0360-0637, E-ISSN 2352-3964, Vol. 30, p. 283-294Article in journal (Refereed)
    Abstract [en]

    The neurotransmitter γ-aminobutyric acid (GABA) is an extracellular signaling molecule in the brain and in pancreatic islets. Here, we demonstrate that GABA regulates cytokine secretion from human peripheral blood mononuclear cells (PBMCs) and CD4+ T cells. In anti-CD3 stimulated PBMCs, GABA (100nM) inhibited release of 47 cytokines in cells from patients with type 1 diabetes (T1D), but only 16 cytokines in cells from nondiabetic (ND) individuals. CD4+ T cells from ND individuals were grouped into responder or non-responder T cells according to effects of GABA (100nM, 500nM) on the cell proliferation. In the responder T cells, GABA decreased proliferation, and inhibited secretion of 37 cytokines in a concentration-dependent manner. In the non-responder T cells, GABA modulated release of 8 cytokines. GABA concentrations in plasma from T1D patients and ND individuals were correlated with 10 cytokines where 7 were increased in plasma of T1D patients. GABA inhibited secretion of 5 of these cytokines from both T1D PBMCs and ND responder T cells. The results identify GABA as a potent regulator of both Th1- and Th2-type cytokine secretion from human PBMCs and CD4+ T cells where GABA generally decreases the secretion.

  • 38.
    Birkeland, Kare I.
    et al.
    Univ Oslo, Inst Clin Med.; Oslo Univ Hosp, Dept Transplantat Med..
    Jorgensen, Marit E.
    Steno Diabet Ctr Copenhagen.;Southern Denmark Univ, Natl Inst Publ Hlth..
    Carstensen, Bendix
    Steno Diabet Ctr Copenhagen..
    Persson, Frederik
    Steno Diabet Ctr Copenhagen..
    Gulseth, Hanne L.
    Oslo Univ Hosp, Dept Endocrinol Morbid Obes & Prevent Med..
    Thuresson, Marcus
    Statisticon AB..
    Fenici, Peter
    AstraZeneca..
    Nathanson, David
    Karolinska Inst, Dept Clin Sci & Educ..
    Nyström, Thomas
    Karolinska Inst, Dept Clin Sci & Educ..
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Bodegard, Johan
    AstraZeneca Nord Baltic, Med Dept..
    Norhammar, Anna
    Karolinska Inst, Södersjukhuset, Dept Med.;Capio St Görans Hosp.
    Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic): A Multinational Observational Analysis2017In: The Lancet Diabetes and Endocrinology, ISSN 2213-8587, E-ISSN 2213-8595, Vol. 5, no 9, p. 709-717Article in journal (Refereed)
    Abstract [en]

    Background In patients with type 2 diabetes and a high cardiovascular risk profile, the sodium-glucose co-transporter-2 (SGLT2) inhibitors empagliflozin and canagliflozin have been shown to lower cardiovascular morbidity and mortality. Using real-world data from clinical practice, we aimed to compare cardiovascular mortality and morbidity in new users of SGLT2 inhibitors versus new users of other glucose-lowering drugs, in a population with a broad cardiovascular risk profile. Methods CVD-REAL Nordic was an observational analysis of individual patient-level data from the Prescribed Drug Registers, Cause of Death Registers, and National Patient Registers in Denmark, Norway, and Sweden. All patients who filled a prescription for glucose-lowering drugs between 2012 and 2015 were included and followed up until Dec 31, 2015. Patients were divided into new users of SGLT2 inhibitors and new users of other glucose-lowering drugs. Each SGLT2 inhibitor user was matched with three users of other glucose-lowering drugs by use of propensity scores. Hazard ratios (HRs) were estimated by country (Cox survival model) and weighted averages were calculated. Cardiovascular outcomes investigated were cardiovascular mortality, major adverse cardiovascular events (cardiovascular mortality, myocardial infarction, and ischaemic or haemorrhagic stroke), hospital events for heart failure (inpatient or outpatient visit with a primary diagnosis of heart failure), non-fatal myocardial infarction, non-fatal stroke, and atrial fibrillation. We also assessed incidence of severe hypoglycaemia. Findings Matched SGLT2 inhibitor (n=22 830) and other glucose-lowering drug (n=68 490) groups were well balanced at baseline, with a mean follow-up of 0.9 (SD 4.1) years (80 669 patient-years) and mean age of 61 (12.0) years; 40% (36 362 of 91 320) were women and prevalence of cardiovascular disease was 25% (22 686 of 91 320). 94% of the total SGLT2 inhibitor exposure time was for use of dapagliflozin, with 5% for empagliflozin, and 1% for canagliflozin. Compared with other glucose-lowering drugs, use of SGLT2 inhibitors was associated with decreased risk of cardiovascular mortality (HR 0.53 [95% CI 0.40-0.71]), major adverse cardiovascular events (0.78 [0.69-0.87]), and hospital events for heart failure (0.70 [0.61-0.81]; p<0.0001 for all). We did not identify significant differences between use of SGLT2 inhibitors and use of other glucose-lowering drugs for non-fatal myocardial infarction, non-fatal stroke, or atrial fibrillation. Compared with other glucose-lowering drugs, use of SGLT2 inhibitors was associated with a decreased risk of severe hypoglycaemia (HR 0.76 [0.65-0.90]; p=0.001). For cardiovascular mortality, the differences were similar for the 25% of individuals with cardiovascular disease at baseline and those without (HR 0.60 [0.42-0.85] vs 0.55 [0.34-0.90]), while for major adverse cardiovascular events the HR in the group with cardiovascular disease at baseline was 0.70 (0.59-0.83) versus 0.90 (0.76-1.07) in the group without. Interpretation In a population of patients with type 2 diabetes and a broad cardiovascular risk profile, SGLT2 inhibitor use was associated with reduced cardiovascular disease and cardiovascular mortality compared with use of other glucose-lowering drugs-a finding consistent with the results of clinical trials in patients at high cardiovascular risk.

  • 39.
    Biskup, Izabela
    et al.
    Swedish Univ Agr Sci, BioCtr, Dept Food Sci, Uppsala, Sweden.;Wroclaw Med Univ, Dept Pharmacognosy, Wroclaw, Poland..
    Kyro, Cecilie
    Danish Canc Soc, Res Ctr, Copenhagen, Denmark..
    Marklund, Matti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Olsen, Anja
    Danish Canc Soc, Res Ctr, Copenhagen, Denmark..
    van Dam, Rob M.
    Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore.;Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore, Singapore.;Natl Univ Hlth Syst, Singapore, Singapore.;Harvard Univ, Harvard TH Chan Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA..
    Tjonneland, Anne
    Danish Canc Soc, Res Ctr, Copenhagen, Denmark..
    Overvad, Kim
    Aarhus Univ, Dept Publ Hlth, Epidemiol Sect, Aarhus, Denmark..
    Lindahl, Bernt
    Umea Univ, Dept Publ Hlth, Umea, Sweden.;Umea Univ, Dept Clin Med, Umea, Sweden..
    Johansson, Ingegerd
    Umea Univ, Dept Odontol & Cariol, Umea, Sweden..
    Landberg, Rikard
    Swedish Univ Agr Sci, BioCtr, Dept Food Sci, Uppsala, Sweden.;Karolinska Inst, Inst Environm Med, Nutr Epidemiol Unit, Stockholm, Sweden..
    Plasma alkylresorcinols, biomarkers of whole-grain wheat and rye intake, and risk of type 2 diabetes in Scandinavian men and women2016In: American Journal of Clinical Nutrition, ISSN 0002-9165, E-ISSN 1938-3207, Vol. 104, no 1, p. 88-96Article in journal (Refereed)
    Abstract [en]

    Background: Studies that use dietary biomarkers to investigate the association between whole-grain intake and the risk of developing type 2 diabetes (T2D) are lacking. Objective: We examined the association between plasma total alkylresorcinols and the alkylresorcinol C17:0-to-C21:0 ratio, biomarkers of whole-grain wheat and rye intake and relative whole grain rye over whole-grain wheat intake, respectively, and the risk of T2D among Scandinavian men and women. Design: A nested case-control study was established within the Northern Sweden Health and Disease Study and the Danish Diet, Cancer and Health cohort. Alkylresorcinol concentrations and the ratios of C17:0 to C21:0 were determined in plasma samples from 931 case-control pairs. ORs for T2D were calculated for plasma total alkylresorcinol concentration or C17:0-to-C21:0 ratio in quartiles with the use of conditional logistic regression that was adjusted for potential confounders. Additional analyses with whole-grain wheat and rye intake estimated from food-frequency questionnaires (FFQs) as exposures were also performed. Results: The plasma total alkylresorcinol concentration was not associated with T2D risk (OR: 1.34; 95% CI: 0.95, 1.88) for the highest compared with the lowest quartiles in multivariable adjusted models. However, the C17:0-to-C21:0 ratio was associated with a lower diabetes risk (OR: 0.54; 95% CI: 0.37, 0.78). Analyses with whole-grain intake estimated from FFQs yielded similar results. Conclusions: Total whole-grain wheat and rye intake, reflected by alkylresorcinols in plasma, was not associated with a lower risk of T2D in a population with high whole-grain intake. In contrast, the proportion of whole-grain rye to whole-grain wheat intake, indicated by the plasma C17:0-to-C21:0 ratio, was inversely associated with T2D. This suggests that whole-grain intake dominated by rye may be favorable for T2D prevention.

  • 40.
    Bjermo, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Dietary Fatty Acids and Inflammation: Observational and Interventional Studies2011Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Dietary fat quality influences the risk of type 2 diabetes and cardiovascular disease. A low-grade inflammation is suggested to contribute to the disease development, often accompanied by obesity. Whereas n-3 polyunsaturated fatty acids (PUFA) have been considered anti-inflammatory, n-6 PUFA have been proposed to act pro-inflammatory. Saturated fatty acids (SFA) act pro-inflammatory in vitro.

    This thesis aimed to investigate effects of different fatty acids on low-grade inflammation in observational and interventional studies. In Paper I and II, fatty acid composition in serum cholesterol esters was used as objective marker of dietary fat quality and related to serum C-reactive protein (CRP) and other circulating inflammatory markers in two population-based cohorts, conducted in middle-aged men and elderly men and women, respectively. In Paper III and IV, the impact of diets differing in fat quality on inflammation and oxidative stress was investigated in randomised controlled studies, in subjects with metabolic syndrome and abdominal obesity.

    In Paper I and II, a low proportion of linoleic acid (18:2 n-6) in serum was associated with higher CRP concentrations, indicating that a low intake of vegetable fats may be related to low-grade inflammation. High CRP concentrations were also associated with high proportions of palmitoleic (16:1) and oleic (18:1) acids and high stearoyl coenzymeA desaturase index, possibly reflecting altered fat metabolism and/or high SFA intake in this population. When comparing two high-fat diets rich in either saturated or monounsaturated fat, and two low-fat diets with or without long-chain n-3 PUFA supplementation during 12 weeks (Paper III), no differences in inflammation or oxidative stress markers were observed. Moreover, a 10-week intervention (Paper IV) with high linoleic acid intake showed no adverse effects on inflammation or oxidative stress. Instead, interleukin-1 receptor antagonist and tumor necrosis factor receptor-2 decreased after linoleic acid intake compared with a diet high in SFA.

    The results in this thesis indicate that dietary n-6 PUFA found in vegetable fats is associated with lower inflammation marker levels, and to some extent reduces systemic inflammation when compared with SFA. Supplementation of n-3 PUFA did not exert any systemic anti-inflammatory effects, maybe due to a relatively low dose.

    List of papers
    1. Serum fatty acid composition and indices of stearoyl-CoA desaturase activity are associated with systemic inflammation: longitudinal analyses in middle-aged men
    Open this publication in new window or tab >>Serum fatty acid composition and indices of stearoyl-CoA desaturase activity are associated with systemic inflammation: longitudinal analyses in middle-aged men
    2008 (English)In: British Journal of Nutrition, ISSN 0007-1145, E-ISSN 1475-2662, Vol. 99, no 6, p. 1186-1189Article in journal (Refereed) Published
    Abstract [en]

    Altered fatty acid (FA) composition is related to insulin resistance and CVD. One possible mediator may be inflammation, but longitudinal data relating FA composition to inflammation taking insulin resistance into account are limited. We investigated the long-term association between FA composition and C-reactive protein (CRP) concentrations in a large population-based cohort study in 767 men followed for 20 years. The association between FA composition in serum cholesteryl esters at age 50 and CRP concentrations at age 70 was investigated using linear regression. In addition, desaturase activities (stearoyl-CoA desaturase-1 (SCD-1), Delta 5- and Delta 6-desaturase) were estimated using FA product-to-precursor ratios. Insulin resistance was measured directly at follow-up by euglycaemic clamp. After adjusting for confounders (smoking, physical activity, alcohol intake, obesity and erythrocyte sedimentation rate) CRP concentrations were inversely associated with the proportion of 18:2n-6 (P=0.002) and positively associated with 16:1n-7 (P=0.008), 18: 1n-9 (P=0.0003), 20:5n-3 (P=0.04) and estimated SCD-1 (P=0.005) and Delta 6-desaturase (P=0.02) activities. After adding insulin resistance to the model, 18: 1n-9, 18:2n-6 and SCD-1 remained significant predictors of CRP. A FA composition indicating low intake of 18:2n-6, high intake of SFA and high SCD-1 activity is, in a Swedish population of middle-aged men, associated with CRP concentrations 20 years later, even independently of obesity and insulin resistance.

    Keywords
    C-reactive protein, fatty acids, SCD-1, inflammation
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-17694 (URN)10.1017/S0007114507871674 (DOI)000255955500006 ()18062827 (PubMedID)
    Available from: 2008-08-15 Created: 2008-08-15 Last updated: 2018-02-22Bibliographically approved
    2. Relationships between serum fatty acid composition and multiple markers of inflammation and endothelial function in an elderly population
    Open this publication in new window or tab >>Relationships between serum fatty acid composition and multiple markers of inflammation and endothelial function in an elderly population
    Show others...
    2009 (English)In: Atherosclerosis, ISSN 0021-9150, E-ISSN 1879-1484, Vol. 203, no 1, p. 298-303Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND: Fatty acid (FA) composition in serum has been associated with C-reactive protein (CRP), but associations with other markers of inflammation and endothelial function, e.g. adhesion molecules are unknown. We recently suggested a possible role of the lipogenic enzyme stearoyl coenzymeA desaturase-1 (SCD-1) in inflammation. This study investigates the associations between serum FA composition, including SCD-1 index, and various inflammatory and endothelial function markers. METHODS: 264 Swedish men and women aged 70 years participated in this cross-sectional population-based study. FA composition was measured in serum cholesteryl esters and was correlated to inflammatory markers (CRP, interleukin [IL]-2, IL-6, IL-8, tumor necrosis factor [TNF]-alpha, vascular cellular adhesion molecule [VCAM]-1, intercellular adhesion molecule [ICAM]-1, E-selectin, P-selectin, L-selectin, interferon-gamma, and monocyte chemoattractant protein [MCP]-1), using linear regression analysis. SCD-1 activity was estimated by FA product-to-precursor ratio (16:1/16:0). RESULTS: Serum FA composition was significantly associated with CRP and E-selectin but not with other inflammatory markers. After adjusting for BMI, smoking, physical activity, alcohol consumption and lipid-lowering therapy, the proportion of palmitoleic acid and SCD-1 index were positively correlated with CRP concentrations (P=0.003 and P=0.001, respectively). CONCLUSION: A FA composition reflecting high intake of saturated fat and a high SCD-1 index is independently related to CRP concentrations, but not to other markers of inflammation and endothelial function in this population of elderly men and women. Given the absent association between FA composition and the other markers, CRP may be the preferable marker to use when investigating potential relationships between FAs and low-grade inflammation.

    Keywords
    Fatty acids, Inflammation, Endothelial function, SCD-1, C-reactive protein, Adhesion molecules
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-103687 (URN)10.1016/j.atherosclerosis.2008.06.020 (DOI)000264510700045 ()18687433 (PubMedID)
    Available from: 2009-05-20 Created: 2009-05-20 Last updated: 2017-12-13Bibliographically approved
    3. Effects of dietary fat modification on oxidative stress and inflammatory markers in the LIPGENE study
    Open this publication in new window or tab >>Effects of dietary fat modification on oxidative stress and inflammatory markers in the LIPGENE study
    Show others...
    2010 (English)In: British Journal of Nutrition, ISSN 0007-1145, E-ISSN 1475-2662, Vol. 104, no 9, p. 1357-1362Article in journal (Refereed) Published
    Abstract [en]

    Subjects with the metabolic syndrome (MetS) have enhanced oxidative stress and inflammation. Dietary fat quality has been proposed to be implicated in these conditions. We investigated the impact of four diets distinct in fat quantity and quality on 8-iso-PGF2α (a major F2-isoprostane and oxidative stress indicator), 15-keto-13,14-dihydro-PGF2α (15-keto-dihydro-PGF2α, a major PGF2α metabolite and marker of cyclooxygenase-mediated inflammation) and C-reactive protein (CRP). In a 12-week parallel multicentre dietary intervention study (LIPGENE), 417 volunteers with the MetS were randomly assigned to one of the four diets: two high-fat diets (38 % energy (%E)) rich in SFA or MUFA and two low-fat high-complex carbohydrate diets (28 %E) with (LFHCC n-3) or without (LFHCC) 1·24 g/d of very long chain n-3 fatty acid supplementation. Urinary levels of 8-iso-PGF2α and 15-keto-dihydro-PGF2α were determined by RIA and adjusted for urinary creatinine levels. Serum concentration of CRP was measured by ELISA. Neither concentrations of 8-iso-PGF2α and 15-keto-dihydro-PGF2α nor those of CRP differed between diet groups at baseline (P>0·07) or at the end of the study (P>0·44). Also, no differences in changes of the markers were observed between the diet groups (8-iso-PGF2α, P = 0·83; 15-keto-dihydro-PGF2α, P = 0·45; and CRP, P = 0·97). In conclusion, a 12-week dietary fat modification did not affect the investigated markers of oxidative stress and inflammation among subjects with the MetS in the LIPGENE study.

    Keywords
    Dietary fat; Oxidative stress; Inflammation; Metabolic syndrome; LIPGENE study
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-133408 (URN)10.1017/S000711451000228X (DOI)000284015300012 ()20569506 (PubMedID)
    Available from: 2010-11-09 Created: 2010-11-09 Last updated: 2017-12-12Bibliographically approved
    4. Dietary fat modification and liver fat content in abdominal obesity
    Open this publication in new window or tab >>Dietary fat modification and liver fat content in abdominal obesity
    Show others...
    (English)Manuscript (preprint) (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-156073 (URN)
    Available from: 2011-08-02 Created: 2011-07-11 Last updated: 2011-11-10
  • 41. Bjornsdottir, Sigridur
    et al.
    Oksnes, Marianne
    Isaksson, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Methlie, Paal
    Nilsen, Roy M.
    Hustad, Steinar
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Hulting, Anna-Lena
    Husebye, Eystein S.
    Lovas, Kristian
    Nystrom, Thomas
    Bensing, Sophie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Autoimmunity.
    Circadian hormone profiles and insulin sensitivity in patients with Addison's disease: a comparison of continuous subcutaneous hydrocortisone infusion with conventional glucocorticoid replacement therapy2015In: Clinical Endocrinology, ISSN 0300-0664, E-ISSN 1365-2265, Vol. 83, no 1, p. 28-35Article in journal (Refereed)
    Abstract [en]

    ContextConventional glucocorticoid replacement therapy in patients with Addison's disease (AD) is unphysiological with possible adverse effects on mortality, morbidity and quality of life. The diurnal cortisol profile can likely be restored by continuous subcutaneous hydrocortisone infusion (CSHI). ObjectiveThe aim of this study was to compare circadian hormone rhythms and insulin sensitivity in conventional thrice-daily regimen of glucocorticoid replacement therapy with CSHI treatment in patients with AD. Design and settingAn open, randomized, two-period, 12-week crossover multicentre trial in Norway and Sweden. PatientsTen Norwegian patients were admitted for 24-h sampling of hormone profiles. Fifteen Swedish patients underwent euglycaemic-hyperinsulinaemic clamp. InterventionThrice-daily regimen of oral hydrocortisone (OHC) and CSHI treatment. Main outcome measureWe measured the circadian rhythm of cortisol, adrenocorticotropic hormone (ACTH), growth hormone (GH), insulin-like growth factor-1, (IGF-1), IGF-binding protein-3 (IGFBP-3), glucose, insulin and triglycerides during OHC and CSHI treatment. Euglycaemic-hyperinsulinaemic clamp was used to assess insulin sensitivity. ResultsContinuous subcutaneous hydrocortisone infusion provided a more physiological circadian cortisol curve including a late-night cortisol surge. ACTH levels showed a near normal circadian variation for CSHI. CSHI prevented a continuous decrease in glucose during the night. No difference in insulin sensitivity was observed between the two treatment arms. ConclusionContinuous subcutaneous hydrocortisone infusion replacement re-established a circadian cortisol rhythm and normalized the ACTH levels. Patients with CSHI replacement had a more stable night-time glucose level compared with OHC without compromising insulin sensitivity. Thus, restoring night-time cortisol levels might be advantageous for patients with AD.

  • 42.
    Björk, Anne
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences.
    Mellström, Dan
    Ohlsson, Claes
    Karlsson, Magnus
    ljunggren, Östen
    Kindmark, Andreas
    Johansson, Gunnar
    POLYMORPHIC VARIATIONS IN THE GENE FOR CYP2R1 IS ASSOCIATED WITH CIRCULATING LEVELS OF 25OHD3, BUT NOT WITH CALCIUM – PHOSPHATE CONCENTRATIONS (MROS SWEDEN)Manuscript (preprint) (Other academic)
  • 43. Björk, Anne
    et al.
    Ribom, Eva
    Johansson, Gunnar
    Scragg, Robert
    Mellström, Dan
    Grundberg, Elin
    Ohlsson, Claes
    Karlsson, Magnus
    Ljunggren, Östen
    Kindmark, Andreas
    Genetic variation in the vitamin D receptor gene is not associated with measures of muscle strength, physical performance, or falls in elderly men. Data from MrOS Sweden.Manuscript (preprint) (Other academic)
  • 44.
    Björk, Anne
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Ribom, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Johansson, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Family Medicine and Preventive Medicine.
    Scragg, Robert
    Section of Epidemiology & Biostatistics, School of Population Health, University of Auckland, Auckland, New Zeeland.
    Mellström, Dan
    Geriatric Medicine, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg Sweden. Centre for Bone and Arthritis Research at the Sahlgrenska Academy, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
    Grundberg, Elin
    Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, McGill University, Montreal, Quebec, Canada.
    Ohlsson, Claes
    Geriatric Medicine, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, University of Gothenburg, Gothenburg Sweden. Centre for Bone and Arthritis Research at the Sahlgrenska Academy, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
    Karlsson, Magnus
    Department of Clinical Sciences and Orthopedic Surgery, Lund University, Skåne University Hospital, Malmö..
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Genetic variation in the vitamin D receptor gene is not associated with measures of muscle strength, physical performance, or falls in elderly men. Data from MrOS Sweden.Manuscript (preprint) (Other academic)
  • 45.
    Björklund, Peyman
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Krajisnik, Tijana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Åkerström, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Westin, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Larsson, Tobias E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Internal Medicine.
    Type I membrane Klotho expression is decreased and inversely correlated to serum calcium in primary hyperparathyroidism2008In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 93, no 10, p. 4152-4157Article in journal (Refereed)
    Abstract [en]

    Context: The type I membrane protein Klotho was recently shownto mediate PTH secretion in parathyroid cells in response tolow extracellular calcium. In contrast, Klotho inhibits PTHsecretion indirectly through the action of fibroblast growthfactor-23. Abnormal Klotho expression in parathyroid disordersremains to be elucidated.

    Objective: The aim of the study was to determine: 1) Klothoexpression in parathyroid adenomas from patients with primaryhyperparathyroidism (pHPT) compared to normal tissue; and 2)its relation to the serum calcium and PTH levels.

    Design: Surgically removed parathyroid glands (n = 40) and fournormal parathyroid tissue specimens were analyzed for KlothomRNA and protein levels by quantitative real-time PCR and immunohistochemistry.In vitro effects of calcium on Klotho mRNA expression were studiedin bovine parathyroid cells.

    Results: Klotho mRNA levels were significantly decreased (n= 23) or undetectable (n = 17) in parathyroid adenomas comparedto normal tissues (P < 0.001). Reduced Klotho protein expressionwas confirmed by immunohistochemistry. Klotho mRNA levels wereinversely correlated to serum calcium (r = –0.97; P <0.0001), and calcium dose-dependently decreased Klotho mRNAexpression in normal parathyroid cells in vitro (P < 0.01).Serum calcium was the only significant marker of Klotho expressionin multivariate analysis with calcium, phosphate, PTH, and adenomaweight as independent variables.

    Conclusions: Parathyroid Klotho expression is decreased or undetectablein pHPT. We provide evidence that 1) serum calcium is stronglyassociated with parathyroid Klotho expression in pHPT; and 2)abnormal PTH secretion in hypercalcemic pHPT subjects is mediatedby Klotho-independent mechanisms.

  • 46.
    Blixt, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    The bank vole (Myodes glareolus) – a novel animal model for the study of diabetes mellitus2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The bank vole (Microtus arvalis) develops glucose intolerance both when kept in captivity and in the wild state. Glucose intolerant bank voles kept in captivity exhibited polydipsia, polyuria, hyperglycemia, hyperinsulinemia, islet autoantibodies and a markedly changed islet structure resembling so–called hydropic degeneration. Islets showing hydropic degeneration have reduced β–cell mass. However, the relative islet size to total pancreas area was not changed.

    Pancreatic islet isolated from glucose intolerant bank voles had an altered islet function showing signs of being exposed to an increased functional demand on their β–cells. Also, islets from male bank voles seem more affected than the islets from females. Islets isolated from glucose tolerant male bank voles cultured for 5 days at 28 mM glucose did not reveal any change in insulin gene expression or insulin biosynthesis rate. However, islets from female bank voles displayed a glucose concentration dependent response. This suggests that there is gender difference in that, islets of female more easily than islets of males adapt to elevated glucose concentration. Furthermore, islets isolated from glucose tolerant males had reduced insulin gene expression after exposure to proinflammatory cytokines for 48 hrs. This effect seemed to be NO-independent since only a minor elevation of nitrite accumulation in the medium was seen, and the use of iNOS inhibitor could not counteract the cytokine effect. The observed response seen in bank vole islets upon exposure to various glucose concentrations or proinflammatory cytokines is similar to those seen in studies of human islets. The bank vole may therefore represent a novel animal model for the study of diabetes. An unresolved issue is the role of the Ljungan virus which is found in the bank vole colony.

    Bank voles developing glucose intolerance display features of both human type 1 and type 2 diabetes, where environmental factors seems to play an important role as determinant. Our findings suggest that bank voles bred in the laboratory may develop more of a type 2 diabetes. However, bank voles caught in nature instead may rather develop a type 1 form of the disease.

    List of papers
    1. Characterization of β-cell function of pancreatic islets isolated from bank voles developing glucose intolerance/diabetes: an animal model showing features of both type 1 and type 2 diabetes mellitus, and a possible role of the Ljungan virus
    Open this publication in new window or tab >>Characterization of β-cell function of pancreatic islets isolated from bank voles developing glucose intolerance/diabetes: an animal model showing features of both type 1 and type 2 diabetes mellitus, and a possible role of the Ljungan virus
    2007 (English)In: General and Comparative Endocrinology, ISSN 0016-6480, E-ISSN 1095-6840, Vol. 154, no 1-3, p. 41-47Article in journal (Refereed) Published
    Abstract [en]

    Bank voles (Clethrionomys glareolus) kept in captivity develop diabetes mellitus to a significant extent. Also in wild bank voles, elevated blood glucose has been observed. A newly isolated picornavirus named Ljungan virus (LV) has been found in the pancreas of these bank voles. Moreover, LV infection in combination with environmental factors may cause glucose intolerance/diabetes (GINT/D) in normal mice. The aim of the present study was to investigate the functional characteristics of pancreatic islets, isolated from bank voles, bred in the laboratory but considered LV infected. About 20% of all males and females were classified as GINT/D following a glucose tolerance test. Of these animals the majority had become diabetic by 20 weeks of age, with a tendency towards an earlier onset in the males. GINT/D animals had increased serum insulin levels. Islets were tested on the day of isolation (day 0) and after 1 week of culture for their insulin content and their capacity to synthesize (pro)insulin, secrete insulin and metabolize glucose. Functional differences could be observed between normal and GINT/D animals as well as between genders. An elevated basal insulin secretion was observed on day 0 indicating β-cell dysfunction among islets isolated from diabetic males. In vitro culture could reverse some functional changes. The increased serum insulin level and the increased basal islet insulin secretion may suggest that the animals had developed a type 2 diabetes-like condition. It is likely that the putative stress imposed in the laboratory, maybe in combination with LV infection, can lead to an increased functional demand on the β-cells.

    Keywords
    Bank vole, Clethrionomys glareolus, Diabetes mellitus, Insulin release, Ljungan virus, Pancreatic islets
    National Category
    Medical and Health Sciences
    Research subject
    Medical Cell Biology
    Identifiers
    urn:nbn:se:uu:diva-17170 (URN)10.1016/j.ygcen.2007.06.019 (DOI)000249641100006 ()17686482 (PubMedID)
    Available from: 2008-06-17 Created: 2008-06-17 Last updated: 2017-12-08Bibliographically approved
    2. Suppression of bank vole pancreatic islet function by proinflammatory cytokines
    Open this publication in new window or tab >>Suppression of bank vole pancreatic islet function by proinflammatory cytokines
    2009 (English)In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 305, no 1-2, p. 1-5Article in journal (Refereed) Published
    Abstract [en]

    Bank voles kept in captivity may develop diabetes. We recently characterized beta-cell function of pancreatic islets from normal and glucose intolerant/diabetic bank voles. These animals had features of both human type 1 and type 2 diabetes. Cytokines may impair β-cell function in both types of diabetes. Presently, we studied how pancreatic islets isolated from normal, i.e. glucose tolerant bank voles are affected by proinflammatory cytokines in vitro. Islets were exposed to hIL-1β (25U/ml) alone or in combination with hTNF-α (1000U/ml)+mIFN-γ (1000U/ml) for 48h, whereupon islet functions were assessed. Cytokines markedly reduced insulin gene expression and the (pro)insulin biosynthesis rate, which was accompanied by a profound depletion of the islet insulin content. The cytokines did not affect the culture medium insulin accumulation and the glucose oxidation rate, but caused a modest increase in medium nitrite, an indicator of nitric oxide (NO) generation. Cytokine-induced decrease in islet insulin content was not prevented by the preferential inducible NO synthase inhibitor aminoguanidine. These findings suggest that the reduction in islet insulin content is not attributed to enhanced exocytosis or related to altered glucose metabolism, but is rather due to a decline in insulin production. The suppressive effects of islet functions elicited by cytokines seem to be mediated by an NO-independent mechanism. In relation to previous studies on cytokine effects on islets from various species, the bank vole islets show a pattern which more resembles human islets than rat or murine islets.

    Keywords
    Bank vole, pancreatic islet, proinflammatory cytokines, interleukin-1β, tumor necrosis factor-α, interferon-γ
    National Category
    Medical and Health Sciences
    Research subject
    Medical Cell Biology
    Identifiers
    urn:nbn:se:uu:diva-122700 (URN)10.1016/j.mce.2009.02.010 (DOI)000266750200001 ()19433255 (PubMedID)
    Available from: 2010-04-16 Created: 2010-04-16 Last updated: 2017-12-12Bibliographically approved
    3. Pancreatic islets of bank vole show signs of dysfunction after prolonged exposure to high glucose in vitro.
    Open this publication in new window or tab >>Pancreatic islets of bank vole show signs of dysfunction after prolonged exposure to high glucose in vitro.
    (English)Manuscript (preprint) (Other academic)
    Keywords
    Bank vole, pancreatic islet, glucose culture, diabetes mellitus
    National Category
    Endocrinology and Diabetes Endocrinology and Diabetes
    Research subject
    Medical Cell Biology
    Identifiers
    urn:nbn:se:uu:diva-122713 (URN)
    Available from: 2010-04-16 Created: 2010-04-16 Last updated: 2010-05-12
    4. Morphologic investigation of the endocrine pancreas in diabetic bank voles indicates a type 2 diabetes profile.
    Open this publication in new window or tab >>Morphologic investigation of the endocrine pancreas in diabetic bank voles indicates a type 2 diabetes profile.
    (English)Manuscript (preprint) (Other academic)
    Keywords
    Bank vole, hydropic degeneration, pancreatic islet, hyperinsulinemia, diabetes mellitus
    National Category
    Endocrinology and Diabetes Endocrinology and Diabetes
    Research subject
    Medical Cell Biology
    Identifiers
    urn:nbn:se:uu:diva-122714 (URN)
    Available from: 2010-04-16 Created: 2010-04-16 Last updated: 2010-05-12
  • 47.
    Blixt, Martin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Niklasson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sandler, Stellan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Morphologic investigation of the endocrine pancreas in diabetic bank voles indicates a type 2 diabetes profile.Manuscript (preprint) (Other academic)
  • 48.
    Blixt, Martin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Niklasson, Bo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Sandler, Stellan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Pancreatic islets of bank vole show signs of dysfunction after prolonged exposure to high glucose in vitro.Manuscript (preprint) (Other academic)
  • 49.
    Bodegard, J.
    et al.
    AstraZeneca, Sodertalje, Sweden..
    Nathanson, D.
    Karolinska Inst, Dept Clin Sci & Educa, Stockholm, Sweden..
    Nystrom, T.
    Karolinska Inst, Stockholm, Sweden..
    Thuresson, M.
    Statisticon AB, Uppsala, Sweden..
    Norhammar, A.
    Karolinska Inst, Dept Med, Stockholm, Sweden..
    Eriksson, Jan W.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Second-line treatment with sulfonylurea compared to DPP4 inhibitors demonstrated associations with earlier treatment intensification with insulin2015In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, no Suppl. 1, p. S189-S189Article in journal (Other academic)
  • 50. Bodei, Lisa
    et al.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Kidd, Mark
    Prasad, Vikas
    Modlin, Irvin M
    The Status of Neuroendocrine Tumor Imaging: From Darkness to Light?2015In: Neuroendocrinology, ISSN 0028-3835, E-ISSN 1423-0194, Vol. 101, no 1, p. 1-17Article in journal (Refereed)
    Abstract [en]

    Diagnostic imaging plays a pivotal role in the diagnosis, staging, treatment selection and follow-up for neuroendocrine tumors. The available diagnostic strategies are morphologic imaging, including computed tomography, magnetic resonance imaging (MRI) and ultrasound techniques, and molecular imaging, including scintigraphy with 111In-pentetreotide and positron emission tomography with 68Ga-DOTA-peptides, 18F-DOPA and 11C-5-HTP. A combination of anatomic and functional techniques is routinely performed to optimize sensitivity and specificity. The introduction of diffusion-weighted MRI and dynamic contrast-enhanced techniques represents a promising advance in radiologic imaging, whereas new receptor-binding peptides, including somatostatin agonists and antagonists, represent the recent most favorable innovation in molecular imaging. Future development includes the short-term validation of these techniques, but in extension also a more comprehensive multilevel integration of biologic information pertaining to a specific tumor and patient, possibly encompassing genomic considerations, currently evolving as a new entity denoted ‘precision medicine'. The ideal is a diagnostic sequence that captures the global status of an individual's tumor and encompasses a multidimensional characterization of tumor location, metabolic performance and target identification. To date, advances in imagery have focused on increasing resolution, discrimination and functional characterization. In the future, the fusion of imagery with the parallel analysis of biological and genomic information has the potential to considerably amplify diagnosis.

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