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  • 1. Abraham-Nordling, Mirna
    et al.
    Byström, Kristina
    Törring, Ove
    Lantz, Mikael
    Berg, Gertrud
    Calissendorff, Jan
    Nyström, Helena Filipsson
    Jansson, Svante
    Jörneskog, Gun
    Karlsson, F Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nyström, Ernst
    Ohrling, Hans
    Orn, Thomas
    Hallengren, Bengt
    Wallin, Göran
    Incidence of hyperthyroidism in Sweden2011In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 165, no 6, p. 899-905Article in journal (Refereed)
    Abstract [en]

    Introduction The incidence of hyperthyroidism has been reported in various countries to be 23-93/100 000 inhabitants per year. This extended study has evaluated the incidence for ∼40% of the Swedish population of 9 million inhabitants. Sweden is considered to be iodine sufficient country. Methods All patients including children, who were newly diagnosed with overt hyperthyroidism in the years 2003-2005, were prospectively registered in a multicenter study. The inclusion criteria are as follows: clinical symptoms and/or signs of hyperthyroidism with plasma TSH concentration below 0.2 mIE/l and increased plasma levels of free/total triiodothyronine and/or free/total thyroxine. Patients with relapse of hyperthyroidism or thyroiditis were not included. The diagnosis of Graves' disease (GD), toxic multinodular goiter (TMNG) and solitary toxic adenoma (STA), smoking, initial treatment, occurrence of thyroid-associated eye symptoms/signs, and demographic data were registered. Results A total of 2916 patients were diagnosed with de novo hyperthyroidism showing the total incidence of 27.6/100 000 inhabitants per year. The incidence of GD was 21.0/100 000 and toxic nodular goiter (TNG=STA+TMNG) occurred in 692 patients, corresponding to an annual incidence of 6.5/100 000. The incidence was higher in women compared with men (4.2:1). Seventy-five percent of the patients were diagnosed with GD, in whom thyroid-associated eye symptoms/signs occurred during diagnosis in every fifth patient. Geographical differences were observed. Conclusion The incidence of hyperthyroidism in Sweden is in a lower range compared with international reports. Seventy-five percent of patients with hyperthyroidism had GD and 20% of them had thyroid-associated eye symptoms/signs during diagnosis. The observed geographical differences require further studies.

  • 2.
    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.
    GLP1 analogs as treatment of postprandial hypoglycemia following gastric bypass surgery: a potential new indication?2013In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 169, no 6, p. 885-889Article in journal (Refereed)
    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.

  • 3.
    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.

  • 4. Abrams, Pascale
    et al.
    Boquete, Hugo
    Fideleff, Hugo
    Feldt-Rasmussen, Ulla
    Jonsson, J
    Koltowska-Häggström, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Wilton, Patrick
    Abs, Roger
    GH replacement in hypopituitarism improves lipid profile and quality of life independently of changes in obesity variables2008In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 159, no 6, p. 825-832Article in journal (Refereed)
    Abstract [en]

    Objective: GH deficiency (GHD) in adults is characterized by elevated body mass index (BMI), increased waist girth (WG) and increased fat mass (FM). Information about how these indicators of obesity affect the lipid profile and quality of life (QoL) of GHD subjects is scarce. It is also unclear how changes in these indicators brought about by GH replacement influence lipids and QoL. Design and methods: Adult GHD Subjects from the Pfizer International Metabolic Database were grouped according to BMI (n = 291 with BMI < 25 kg/m(2), n = 372 with BMI 25-30 kg/m(2), n = 279 with BMI > 30 kg/m(2)), WG (n = 508 with normal WG, n = 434 with increased WG) and FM (n = 357) and according to changes in these variables after 1 year of GH replacement. Serum IGF-1 concentrations, lipid concentrations and QoL using the QoL Assessment of GHD in Adults questionnaire were assessed at baseline and after 1 year of treatment. Results: At baseline, total and low-density lipoprotein (LDL) cholesterol were similarly elevated in the BMI and WG groups, but high-density lipoprotein (HDL) cholesterol decreased and triglycerides increased with increasing BMI and WG. QoL was progressively poorer with increasing BMI and WG. After 1 year of GH replacement, total and LDL cholesterol and QoL improved in all BMI, WG and FM groups. Conclusions: Variables of obesity adversely affect the already unfavourable lipid profile in GHD Subjects by decreasing HDL cholesterol, but do not counteract the positive effect of GH replacement on LDL cholesterol. Similarly, QoL is influenced by obesity, but responds equally well to GH treatment independent of BMI, WG and FM.

  • 5. Abs, Roger
    et al.
    Feldt-Rasmussen, Ulla
    Mattsson, Anders F
    Monson, John P
    Bengtsson, Bengt-Ake
    Goth, M I
    Wilton, Patrick
    Koltowska-Häggström, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Determinants of cardiovascular risk in 2589 hypopituitary GH-deficient adults - a KIMS database analysis.2006In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 155, no 1, p. 79-90Article in journal (Refereed)
    Abstract [en]

    Objective: The aim of the present study was to clarify the relationship between GH deficiency (GHD) andsome cardiovascular risk factors and to analyse the effect of GH replacement therapy in a large numberof patients over a prolonged period of time.Design: Data for analysis were retrieved from KIMS (Pfizer International Metabolic Database). Serumconcentrations of total cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein(LDL)-cholesterol and triglycerides were obtained from 2589 patients at baseline and from 1206patients after 1 and 2 years of GH replacement therapy. Body mass index (BMI), waist and hip, restingblood pressure and body composition were also measured.Results: At baseline, the unfavourable effects of GHD were most obvious in the lipid profiledemonstrating elevated mean total and LDL-cholesterol, in the increased waist circumference and theelevated BMI. The cholesterol concentration, BMI and body composition were significantly adverselyaffected by a number of factors, including age, sex and the use of anti-epileptic drugs. The therapeuticeffect of GH was essentially uniform across the whole population. GH replacement reduced significantlythe mean total and LDL-cholesterol, the waist circumference and the fat mass and was maintainedduring 2 years.Conclusions: This analysis of a large number of patients confirmed that GHD adults present with anincreased cardiovascular risk. The sustained improvement of the adverse lipid profile and bodycomposition suggests that GH replacement therapy may reduce the risk of cardiovascular disease andthe premature mortality seen in hypopituitary patients with untreated GHD.

  • 6.
    Almby, Kristina E.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Abrahamsson, Niclas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Lundqvist, Martin H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Hammar, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular epidemiology.
    Thombare, Ketan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Panagiotou, Amalia
    Uppsala Univ Hosp, Dept Internal Med, Uppsala, Sweden.
    Karlsson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Sundbom, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Wiklund, Urban
    Umea Univ, Dept Radiat Sci, Biomed Engn, Umea, Sweden.
    Eriksson, Jan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Effects of GLP-1 on counter-regulatory responses during hypoglycemia after GBP surgery2019In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 181, no 2, p. 161-171Article in journal (Refereed)
    Abstract [en]

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

    Design: Experimental hyperinsulinemic-hypoglycemic clamp study.

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

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

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

  • 7.
    Al-Shamkhi, Nasrin
    et al.
    Örebro Univ Hosp, Dept Internal Med, Örebro, Sweden.;Örebro Univ, Fac Med & Hlth, Sch Med Sci, Örebro, Sweden.;Uppsala Univ Hosp, Dept Endocrinol & Diabetol, Uppsala, Sweden.;Akadem Sjukhuset, Endokrin & Diabetesmottagningen, S-75185 Uppsala, Sweden..
    Berinder, Katarina
    Karolinska Univ Hosp, Dept Endocrinol, Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Borg, Henrik
    Lund Univ, Skane Univ Hosp, Dept Endocrinol, Lund, Sweden..
    Burman, Pia
    Lund Univ, Skane Univ Hosp, Dept Endocrinol, Malmö, Sweden..
    Dahlqvist, Per
    Umeå Univ, Dept Publ Hlth & Clin Med, Umeå, Sweden..
    Hoybye, Charlotte
    Karolinska Univ Hosp, Dept Endocrinol, Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden..
    Olsson, Daniel S.
    Sahlgrens Univ Hosp, Dept Endocrinol, Gothenburg, Sweden.;Univ Gothenburg, Inst Med, Dept Internal Med & Clin Nutr, Sahlgrenska Acad, Gothenburg, Sweden.;AstraZeneca, BioPharmaceut R&D, Cardiovasc Renal & Metab CVRM, Gothenburg, Sweden..
    Ragnarsson, Oskar
    Sahlgrens Univ Hosp, Dept Endocrinol, Gothenburg, Sweden.;Univ Gothenburg, Inst Med, Dept Internal Med & Clin Nutr, Sahlgrenska Acad, Gothenburg, Sweden.;Univ Gothenburg, Wallenberg Ctr Mol & Translat Med, Gothenburg, Sweden..
    Ekman, Bertil
    Linköping Univ, Dept Endocrinol Linköping & Norrköping, Linköping, Sweden.;Linköping Univ, Dept Hlth Med & Caring Sci, Linköping, Sweden..
    Edén Engström, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Pituitary function before and after surgery for nonfunctioning pituitary adenomas-data from the Swedish Pituitary Register2023In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 189, no 2, p. 217-224Article in journal (Refereed)
    Abstract [en]

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

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

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

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

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  • 8.
    Arnardottir, Steinunn
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism. Uppsala Univ Hosp, Dept Endocrinol & Diabet, Uppsala, Sweden..
    Järås, Jacob
    Reg Canc Ctr RCC Stockholm Gotland, Stockholm, Sweden..
    Burman, Pia
    Lund Univ, Skanes Univ Hosp, Dept Endocrinol, Malmö, Sweden..
    Berinder, Katarina
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Endocrinol, Stockholm, Sweden..
    Dahlqvist, Per
    Umeå Univ, Dept Publ Hlth & Clin Med, Umeå, Sweden..
    Erfurth, Eva Marie
    Lund Univ, Skanes Univ Hosp, Dept Endocrinol, Malmö, Sweden..
    Höybye, Charlotte
    Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Endocrinol, Stockholm, Sweden..
    Larsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism. Uppsala Univ Hosp, Dept Endocrinol & Diabet, Uppsala, Sweden..
    Ragnarsson, Oskar
    Univ Gothenburg, Inst Med, Dept Internal Med & Clin Nutr, Sahlgrenska Acad, Gothenburg, Sweden.;Sahlgrens Univ Hosp, Dept Endocrinol, Gothenburg, Sweden..
    Ekman, Bertil
    Linköping Univ, Dept Endocrinol Linköping, Dept Internal Med Norrköping, Dept Hlth Med & Caring Sci, Linköping, Sweden..
    Edén Engström, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism. Uppsala Univ Hosp, Dept Endocrinol & Diabet, Uppsala, Sweden..
    Long-term outcomes of patients with acromegaly: a report from the Swedish Pituitary Register2022In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 186, no 3, p. 329-339Article in journal (Refereed)
    Abstract [en]

    Objective: To describe the treatment and long-term outcomes of patients with acromegaly from all healthcare regions in Sweden.

    Design and methods: Analysis of prospectively reported data from the Swedish Pituitary Register of 698 patients (51% females) with acromegaly diagnosed from 1991 to 2011. The latest clinical follow-up date was December 2012, while mortality data were collected for 28.5 years until June 2019.

    Results: The annual incidence was 3.7/million; 71% of patients had a macroadenoma, 18% had visual field defects, and 25% had at least one pituitary hormone deficiency. Eighty-two percent had pituitary surgery, 10% radiotherapy, and 39% medical treatment. At the 5- and 10-year follow-ups, insulin-like growth factor 1 levels were within the reference range in 69 and 78% of patients, respectively. In linear regression, the proportion of patients with biochemical control including adjuvant therapy at 10 years follow-up increased over time by 1.23% per year. The standardized mortality ratio (SMR) (95% CI) for all patients was 1.29 (1.11-1.49). For patients with biochemical control at the latest follow-up, SMR was not increased, neither among patients diagnosed between 1991 and 2000, SMR: 1.06 (0.85-1.33) nor between 2001 and2011, SMR: 0.87 (0.61-1.24). In contrast, non-controlled patients at the latest follow-up from both decades had elevated SMR, 1.90 (1.33-2.72) and 1.98 (1.24-3.14), respectively.

    Conclusions: The proportion of patients with biochemical control increased over time. Patients with biochemically controlled acromegaly have normal life expectancy, while non-controlled patients still have increased mortality. The high rate of macroadenomas and unchanged age at diagnosis illustrates the need for improvements in the management of patients with acromegaly.

  • 9.
    Backman, Samuel
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Bajic, Duska
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Crona, Joakim
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Experimental Surgery.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Whole genome sequencing of apparently mutation-negative MEN1 patients2020In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 182, no 1, p. 35-45Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE:Multiple Endocrine Neoplasia type 1 (MEN1) is an autosomal dominant syndrome usually caused by loss-of-function mutations in the MEN1-gene. However, a minority of patients who fulfill the criteria for MEN1 are not found to harbor MEN1-mutations. Besides, some of these individuals, present with a subtly different phenotype suggestive of sporadic disease. The aim of the present study was to investigate the genetic architecture of mutation-negative MEN1. DESIGN:Fourteen patients with a clinical diagnosis (n=13) or suspicion (n=1) of MEN1 who had negative genetic screening of the MEN1 gene were included. METHODS:Constitutional DNA from the included patients, as well as tumor DNA from six of the patients, was subjected to whole genome sequencing. Constitutional variants were filtered against population databases and somatic variants were studied under a tumor-suppressor model. RESULTS:Three patients carried pathogenic variants (two splice-site variants, one missense variant) in MEN1 that had not been detected during routine clinical sequencing, one patient carried a pathogenic variant in CASR and one patient carried a gross deletion on chromosome 1q which included the CDC73 gene. Analysis of matched tumor DNA from six patients without mutations did not detect any recurrent genes fulfilling Knudson's two-hit model. CONCLUSION:These results highlight the possibility of germline mutations being missed in routine screening, the importance of considering phenocopies in atypical or mutation-negative cases. The absence of apparent disease-causing mutations suggests that a fraction of MEN1 mutation negative MEN1 cases may be due to the chance occurrence of several endocrine tumors in one patient.

  • 10. Barner, C.
    et al.
    Petersson, M.
    Engström, Britt Edén
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Höybye, C.
    Effects on insulin sensitivity and body composition of combination therapy with GH and IGF1 in GH deficient adults with type 2 diabetes2012In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 167, no 5, p. 697-703Article in journal (Refereed)
    Abstract [en]

    Objective: The aim of this trial was to evaluate the effect on insulin sensitivity and body composition of combination therapy with GH and IGF1 in adults with GH deficiency (GHD) and diabetes. Design, patients and methods: A 6-month randomised placebo-controlled pilot study. Fourteen adults with GHD and type 2 diabetes were included. All received rhGH (0.15 mg/day for 1 month and 0.3 mg/day for 5 months) and were randomised to rhIGF1 (15 μg/kg per day for 1 month and 30 μg/kg per day for 5 months) or placebo. Insulin sensitivity was evaluated with euglycaemic hyperinsulinaemic clamp and body composition by computed tomography of abdominal and thigh fat, as well as bioimpedance. Results: Twelve patients completed the study. They were overweight and obese; at baseline, insulin sensitivity (M-value) was low. IGF1 and IGF1 SDS increased in both groups, with the highest increase in the GH and IGF1 group. Positive changes in M-value by +1.4 mg/kg per min, in subcutaneous abdominal fat by -60.5 ml and in fat-free mass by +4.4% were seen in the GH and IGF1 group. Corresponding values in the GH and placebo-treated group were -1.5 mg/kg per min, +23 ml and -0.04% respectively (P=0.02, P=0.04 and P=0.03 for delta values between groups). No safety issues occurred. Conclusions: Combined GH and IGF1 treatment resulted in positive, but rather small effects, and might be a treatment option in a few selected patients.

  • 11. Bennet, Anna M
    et al.
    Brismar, Kerstin
    Hallqvist, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy.
    Reuterwall, Christina
    De Faire, Ulf
    The risk of myocardial infarction is enhanced by a synergistic interaction between serum insulin and smoking.2002In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 147, no 5, p. 641-7Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To evaluate the relationship between levels of serum insulin, the homeostasis model assessment (HOMA) and IGF-binding protein-1 (IGFBP-1) as factors related to myocardial infarction (MI) risk, and their interaction with lifestyle-related risk factors.

    DESIGN: The Stockholm epidemiology programme (SHEEP), a case-control study, consisting of 749 first-time MI cases (510 men, 239 women) and 1101 healthy controls (705 men, 396 women) was used.

    METHODS: The risk of developing MI was assessed by calculating odds ratios (OR) and synergistic interactions (SI) between serum insulin, IGFBP-1, HOMA and other variables related to MI risk (including smoking) in men and women.

    RESULTS: Subjects with elevated levels of insulin and HOMA (>75th percentile) had increased MI risks when compared with individuals with low levels. ORs for elevated insulin and HOMA (adjusted for age and residential area) for men: insulin 1.6 (95% confidence interval (CI) 1.3-2.1) and HOMA 1.5 (95% CI 1.1-1.9) and for women: insulin 2.1 (95% CI 1.5-2.9) and HOMA 1.9 (95% CI 1.3-2.8). Women with low levels of IGFBP-1 (<10th percentile) showed a tendency towards elevated MI risk even if this was not statistically significant (OR 1.5 (95% CI 0.9-2.6)). Smokers with high levels of serum insulin had greatly increased MI risk (OR for men: 4.7 (95% CI 3.0-7.2) and OR for women: 8.1 (95% CI 4.5-14.8)). SI scores based upon these interactions were statistically significant.

    CONCLUSIONS: These results might have preventive cardiovascular implications as they clearly suggest that subjects with insulin resistance are particularly susceptible to the hazards of smoking.

  • 12.
    Boe, Anette S.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bredholt, Geir
    Knappskog, Per M.
    Hjelmervik, Trond Ove
    Mellgren, Gunnar
    Winqvist, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Husebye, Eystein S.
    Autoantibodies against 21-hydroxylase and side-chain cleavage enzyme in autoimmune Addison's disease are mainly immunoglobulin G12004In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 150, no 1, p. 49-56Article in journal (Other academic)
    Abstract [en]

    OBJECTIVE: Immunoglobulin G (IgG) antibodies to the steroidogenic enzymes 21-hydroxylase (21OH) and side-chain cleavage enzyme (SCC) are important diagnostic markers for autoimmune Addison's disease and autoimmune polyendocrine syndromes (APS) types I and II. The characterization of autoantibody (IgG) subclasses may reveal information on how tIssue destruction takes place; therefore, IgG subtypes of anti-21OH and anti-SCC antibodies from sera of patients with Addison's disease, APS I and APS II were determined using recombinant 21OH and SCC. METHODS: SCC(51-521) and his-SCC(51-521) were expressed by pET-scc in the Escherichia coli strain BL21 Star (DE3) and inclusion bodies were purified. Full-length, human 21OH fused to an N-terminal 6x histidine affinity tag was expressed in insect cells by using the baculovirus expression system bac-to-bac. Western blots were used to investigate the IgG subtype(s) of the autoantibodies against 21OH and SCC in patients and healthy blood donors. RESULTS: All anti-SCC positive sera (n=10) contained autoantibodies of the IgG1 subclass, while four out of ten also contained IgG3. All anti-21OH positive sera (n=16) had autoantibodies exclusively against IgG1. Sera from 20 healthy subjects did not show any reactivity against 21OH or SCC. CONCLUSIONS: The finding of a predominating IgG1 response against 21OH and SCC may suggest that T helper (Th) cells of the Th1 subclass are involved in destruction of the adrenal cortex in patients with autoimmune Addison's disease.

  • 13.
    Burman, Pia
    et al.
    Lund Univ, Skane Univ Hosp Malmo, Dept Endocrinol, S-20502 Malmo, Sweden..
    Edén-Engström, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Ekman, Bertil
    Linkoping Univ, Dept Endocrinol, Linkoping, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Karlsson, Anders F.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Schwarcz, Erik
    Univ Orebro, Fac Med & Hlth, Dept Internal Med, SE-70182 Orebro, Sweden..
    Wahlberg, Jeanette
    Linkoping Univ, Dept Endocrinol, Linkoping, Sweden.;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden..
    Limited value of cabergoline in Cushing's disease: a prospective study of a 6-week treatment in 20 patients2016In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 174, no 1, p. 17-24Article in journal (Refereed)
    Abstract [en]

    Context and objective: The role of cabergoline in Cushing's disease (CD) remains controversial. The experience is limited to case reports and few open studies that report the effects determined after >= 1 month of treatment. In prolactinomas and dopamine-responsive GH-secreting tumours, effects of cabergoline are seen within days or weeks. Here, we searched for short-term effects of cabergoline in CD. Design: Twenty patients (19 naive and one recurrent) were included in a prospective study. Cabergoline was administered in increasing doses of 0.5-5 mg/week over 6 weeks. Methods: Urinary free cortisol (UFC) 24 h, morning cortisol and ACTH, and salivary cortisol at 0800, 1600 and 2300 h were determined once weekly throughout. Diurnal curves (six samples) of serum cortisol were measured at start and end. Results: At study end, the median cabergoline dose was 5 mg, range 2.5-5 mg/week. The prolactin levels, markers of compliance, were suppressed in all patients. During the treatment, hypercortisolism varied, gradual and dose-dependent reductions were not seen. Five patients had a >50% decrease of UFC, three had a >50% rise of UFC. Salivary cortisol at 2300 h showed a congruent >50% change with UFC in two of the five cases with decreased UFC, and in one of the three cases with increased UFC. One patient with decreases in both UFC and 2300 h salivary cortisol also had a reduction in diurnal serum cortisol during the course of the study. Conclusions: Cabergoline seems to be of little value in the management of CD. Only one patient had a response-like pattern. Given the known variability of disease activity in CD, this might represent a chance finding.

  • 14. Burman, Pia
    et al.
    Lethagen, ÅsaLinda
    Ivancev, Krasnodar
    Johansson, Leif
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Radiology.
    Dual bronchial carcinoids and Cushing's syndrome with a paradoxical response to dexamethasone and a false positive outcome of inferior petrosal sinus sampling2008In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 159, no 4, p. 483-8Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Establishing the cause of Cushing's syndrome (CS) can be a considerable challenge, in particular in ectopic adrenocorticotropic hormone (ACTH) syndrome, and often requires a combination of biochemical tests and imaging procedures. SUBJECT: A 27-year-old man presented with signs of CS. P-ACTH levels were three times above the upper limit of normal (ULN) and free urinary cortisol around 2000 nmol/24 h. The work-up showed remarkable results. RESULTS: A 2-day low-dose dexamethasone suppression test demonstrated paradoxical increases in cortisol. Sampling from the bilateral inferior petrosal sinus sampling (BIPSS) showed a central to peripheral ACTH ratio of 4.7 after corticotrophin-releasing hormone (CRH) stimulation, i.e. indicated pituitary disease, but magnetic resonance imaging of the pituitary was normal. Computed tomography (CT) scan of the lungs showed two oval-shaped masses, 1.3 x 1.8 and 1.3 x 2 cm, in the middle lobe. Both were positive at somatostatin receptor scintigraphy, compatible with tumors or inflammatory lesions. Subsequently, (11)C-5-hydroxytryptophan-PET showed distinct uptake in the tumors but not elsewhere. Two carcinoids situated 3 cm apart, both staining for ACTH, were removed at surgery. CONCLUSION: This unique case with dual bronchial carcinoids inducing hypercortisolism illustrates the problems with identifying the source of ACTH in CS. Possibly, an abnormal regulation of ACTH production in response to dexamethasone, or steroid-induced tumor necrosis, explains the paradoxical outcome at dexamethasone suppression, and the false positive result at BIPSS reflects an unusual sensitivity of the pituitary corticotrophs to CRH in this patient. The work-up illustrates the great value of (11)C-5-hydroxytryptophan-PET as a diagnostic procedure when other investigations have produced ambiguous results.

  • 15. Burén, Jonas
    et al.
    Liu, Hui-Xia
    Jensen, Jørgen
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    Dexamethasone impairs insulin signalling and glucose transport by depletion of insulin receptor substrate-1, phosphatidylinositol 3-kinase and protein kinase B in primary cultured rat adipocytes.2002In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 146, no 3, p. 419-29Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Glucocorticoid excess leads to insulin resistance. This study explores the effects of glucocorticoids on the glucose transport system and insulin signalling in rat adipocytes. The interaction between glucocorticoids and high levels of insulin and glucose is also addressed.

    DESIGN AND METHODS: Isolated rat adipocytes were cultured for 24 h at different glucose concentrations (5 and 15 mmol/l) with or without the glucocorticoid analogue dexamethasone (0.3 micromol/l) and insulin (10(4) microU/ml). After the culture period, the cells were washed and then basal and insulin-stimulated glucose uptake, insulin binding and lipolysis as well as cellular content of insulin signalling proteins (insulin receptor substrate-1 (IRS-1), IRS-2, phosphatidylinositol 3-kinase (PI3-K) and protein kinase B (PKB)) and glucose transporter isoform GLUT4 were measured.

    RESULTS: Dexamethasone in the medium markedly decreased both basal and insulin-stimulated glucose uptake at both 5 and 15 mmol/l glucose (by approximately 40-50%, P<0.001 and P<0.05 respectively). Combined long-term treatment with insulin and dexamethasone exerted additive effects in decreasing basal, and to a lesser extent insulin-stimulated, glucose uptake capacity (P<0.05) compared with dexamethasone alone, but this was seen only at high glucose (15 mmol/l). Insulin binding was decreased (by approximately 40%, P<0.05) in dexamethasone-treated cells independently of surrounding glucose concentration. Following dexamethasone treatment a approximately 75% decrease (P<0.001) in IRS-1 expression and an increase in IRS-2 (by approximately 150%, P<0.001) was shown. Dexamethasone also induced a subtle decrease in PI3-K (by approximately 20%, P<0.01) and a substantial decrease in PKB content (by approximately 45%, P<0.001). Insulin-stimulated PKB phosphorylation was decreased (by approximately 40%, P<0.01) in dexamethasone-treated cells. Dexamethasone did not alter the amount of total cellular membrane-associated GLUT4 protein. The effects of dexamethasone per se on glucose transport and insulin signalling proteins were mainly unaffected by the surrounding glucose and insulin levels. Dexamethasone increased the basal lipolytic rate (approximately 4-fold, P<0.05), but did not alter the antilipolytic effect of insulin.

    CONCLUSIONS: These results suggest that glucocorticoids, independently of the surrounding glucose and insulin concentration, impair glucose transport capacity in fat cells. This is not due to alterations in GLUT4 abundance. Instead dexamethasone-induced insulin resistance may be mediated via reduced cellular content of IRS-1 and PKB accompanied by a parallel reduction in insulin-stimulated activation of PKB.

  • 16. Burén, Jonas
    et al.
    Liu, Hui-Xia
    Lauritz, Johan
    Eriksson, Jan W
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology, Diabetes and Metabolism.
    High glucose and insulin in combination cause insulin receptor substrate-1 and -2 depletion and protein kinase B desensitisation in primary cultured rat adipocytes: possible implications for insulin resistance in type 2 diabetes.2003In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 148, no 1, p. 157-67Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: The purpose of this study was to investigate the cellular effects of long-term exposure to high insulin and glucose levels on glucose transport and insulin signalling proteins.

    DESIGN AND METHODS: Rat adipocytes were cultured for 24 h in different glucose concentrations with 10(4) microU/ml of insulin or without insulin. After washing, (125)I-insulin binding, basal and acutely insulin-stimulated d-[(14)C]glucose uptake, and insulin signalling proteins and glucose transporter 4 (GLUT4) were assessed.

    RESULTS: High glucose (15 and 25 mmol/l) for 24 h induced a decrease in basal and insulin-stimulated glucose uptake compared with control cells incubated in low glucose (5 or 10 mmol/l). Twenty-four hours of insulin treatment decreased insulin binding capacity by approximately 40%, and shifted the dose-response curve for insulin's acute effect on glucose uptake 2- to 3-fold to the right. Twenty-four hours of insulin treatment reduced basal and insulin-stimulated glucose uptake only in the presence of high glucose (by approximately 30-50%). At high glucose, insulin receptor substrate-1 (IRS-1) expression was downregulated by approximately 20-50%, whereas IRS-2 was strongly upregulated by glucose levels of 10 mmol/l or more (by 100-400%). Insulin treatment amplified the suppression of IRS-1 when combined with high glucose and also IRS-2 expression was almost abolished. Twenty-four hours of treatment with high glucose or insulin, alone or in combination, shifted the dose-response curve for insulin's effect to acutely phosphorylate protein kinase B (PKB) to the right. Fifteen mmol/l glucose increased GLUT4 in cellular membranes (by approximately 140%) compared with 5 mmol/l but this was prevented by a high insulin concentration.

    CONCLUSIONS: Long-term exposure to high glucose per se decreases IRS-1 but increases IRS-2 content in rat adipocytes and it impairs glucose transport capacity. Treatment with high insulin downregulates insulin binding capacity and, when combined with high glucose, it produces a marked depletion of IRS-1 and -2 content together with an impaired sensitivity to insulin stimulation of PKB activity. These mechanisms may potentially contribute to insulin resistance in type 2 diabetes.

  • 17.
    Bäcklund, Nils
    et al.
    Umeå Univ, Dept Publ Hlth & Clin Med, Umeå, Sweden.
    Brattsand, Göran
    Umeå Univ, Dept Med Biosci, Clin Chem, Umeå, Sweden.
    Israelsson, Marlen
    Umeå Univ, Dept Med Biosci, Clin Chem, Umeå, Sweden.
    Ragnarsson, Oskar
    Univ Gothenburg, Inst Med, Dept Internal Med & Clin Nutr, Sahlgrenska Acad, Gothenburg, Sweden; Sahlgrens Univ Hosp, Dept Endocrinol, Gothenburg, Sweden.
    Burman, Pia
    Lund Univ, Skåne Univ Hosp, Dept Endocrinol, Malmö, Sweden.
    Edén Engström, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Høybye, Charlotte
    Karolinska Inst, Patient Area Endocrinol & Nephrol Inflammat & Inf, Dept Mol Med & Surg, Stockholm, Sweden; Karolinska Univ Hosp, Stockholm, Sweden.
    Berinder, Katarina
    Karolinska Inst, Patient Area Endocrinol & Nephrol Inflammat & Inf, Dept Mol Med & Surg, Stockholm, Sweden; Karolinska Univ Hosp, Stockholm, Sweden.
    Wahlberg, Jeanette
    Linköping Univ, Dept Med & Hlth Sci, Dept Endocrinol, Linköping, Sweden.
    Olsson, Tommy
    Umeå Univ, Dept Publ Hlth & Clin Med, Umeå, Sweden.
    Dahlqvist, Per
    Umeå Univ, Dept Publ Hlth & Clin Med, Umeå, Sweden.
    Reference intervals of salivary cortisol and cortisone and their diagnostic accuracy in Cushing's syndrome2020In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 182, no 6, p. 569-582Article in journal (Refereed)
    Abstract [en]

    Objective: The challenge of diagnosing Cushing's syndrome (CS) calls for high precision biochemical screening. This study aimed to establish robust reference intervals for, and compare the diagnostic accuracy of, salivary cortisol and cortisone in late-night samples and after a low-dose (1 mg) dexamethasone suppression test (DST).

    Design and methods: Saliva samples were collected at 08:00 and 23:00 h, and at 08: 00 h, after a DST, from 22 patients with CS and from 155 adult reference subjects. We also collected samples at 20:00 and 22:00 h from 78 of the reference subjects. Salivary cortisol and cortisone were analysed with liquid chromatography-tandem mass spectrometry. The reference intervals were calculated as the 2.5th and 97.5th percentiles of the reference population measurements. Diagnostic accuracies of different tests were compared, based on areas under the receiver-operating characteristic curves.

    Results: The upper reference limits of salivary cortisol and cortisone at 23: 00 h were 3.6 nmol/L and 13.5 nmol/L, respectively. Using these reference limits, CS was detected wit h a sensitivity (95% CI) of 90% (70-99%) and specificity of 96% (91-98%) for cortisol, and a 100% (84-100%) sensitivity and 95% (90-98%) specificity for cortisone. After DST, cortisol and cortisone upper reference limits were 0.79 nmol/L and 3.5 nmol/L, respectively. CS was detected with 95% (75-100%) sensitivity and 96% (92-99%) specificity with cortisol, and 100% (83-100%) sensitivity and 94% (89-97%) specificity with cortisone. No differences in salivary cortisol or cortisone levels were found between samples collected at 22:00 and 23:00 h.

    Conclusion: Salivary cortisol and cortisone in late-night samples and after DST showed high accuracy for diagnosing CS, salivary cortisone being slightly, but significantly better.

  • 18. Ciganoka, Darja
    et al.
    Balcere, Inga
    Kapa, Ivo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Peculis, Raitis
    Valtere, Andra
    Nikitina-Zake, Liene
    Lase, Ieva
    Schiöth, Helgi B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Pirags, Valdis
    Klovins, Janis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
    Identification of somatostatin receptor type 5 gene polymorphisms associated with acromegaly2011In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 165, no 4, p. 517-525Article in journal (Refereed)
    Abstract [en]

    Objective: The aim of this study was to characterize the genetic variance of somatostatin receptor 5 (SSTR5) and investigate the possible correlation of such variants with acromegaly risk and different disease characteristics. Design and methods: The SSTR5 gene coding region and 2000 bp upstream region was sequenced in 48 patients with acromegaly and 96 control subjects. Further, three single nucleotide polymorphisms (SNPs) were analyzed in the same group of acromegaly patients and in an additional group of 475 age- and sex-matched controls. Results: In total, 19 SNPs were identified in the SSTR5 gene locus by direct sequencing. Three SNPs (rs34037914, rs169068, and rs642249) were significantly associated with the presence of acromegaly using the initial controls. The allele frequencies were significantly (P<0.01) different between the acromegaly patients and the additional large control group. rs34037914 and rs642249 remained significantly associated with acromegaly after Bonferroni correction and permutation tests (odds ratio (OR) = 3.38; 95% confidence interval (CI), 1.78-6.42; P=0.00016 and OR=2.41; 95% CI, 1.41-4.13; P=0.0014 respectively). Haplotype reconstruction revealed two possible risk haplotypes determined by rs34037914 (633T) and rs642249 (1044A) alleles. Both haplotypes were found in significantly higher frequency in acromegaly patients compared with controls (P=0.001). In addition, the 663T allele was significantly associated with a younger age of acromegaly diagnosis (unstandardized regression coefficient beta=-10.4; P=0.002), increased body mass index (beta=4.1; P=0.004), higher number of adenoma resection (P<0.001) and lack of observable tumor shrinkage after somatostatin analog treatment (P=0.014). Conclusions: Our results demonstrate a previously undetected strong association of two SSTR5 SNPs with acromegaly. The data also suggest a possible involvement of SSTR5 variants in decreased suppression of GH production and increased tumor proliferation.

  • 19.
    Crona, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Baudin, Eric
    Univ Paris Saclay, Dept Imagerie, Serv Oncol Endocrinienne, Gustave Roussy, Villejuif, France..
    Terzolo, Massimo
    Univ Turin, Dept Clin & Biol Sci, San Luigi Hosp, Orbassano, Italy..
    Chrisoulidou, Alexandra
    Theagenio Canc Hosp, Dept Endocrinol, Thessaloniki, Greece..
    Angelousi, Anna
    Natl & Kapodistrian Univ Athens, Laiko Hosp, Dept Internal Med 1, Unit Endocrinol, Athens, Greece..
    Ronchi, Cristina L.
    Univ Birmingham, Inst Metab & Syst Res, Birmingham, W Midlands, England.;Univ Hosp Wurzburg, Div Endocrinol & Diabet, Wurzburg, Germany..
    Oliveira, Cristina Lamas
    Complejo Hosp Univ Albacete, Endocrinol Dept, Albacete, Spain..
    van Dijkum, Els J. M. Nieveen
    Univ Amsterdam, Canc Ctr Amsterdam, Dept Surg, Amsterdam UMC, Amsterdam, Netherlands..
    Ceccato, Filippo
    Univ Hosp Padova, Dept Med DIMED, Endocrinol Unit, Padua, Italy..
    Borson-Chazot, Francoise
    Univ Claude Bernard Lyon 1, Hosp Civils Lyon, Federat Endocrinol, Lyon, France..
    Reimondo, Giuseppe
    Univ Turin, San Luigi Gonzaga Hosp, Dept Clin & Biol Sci, Internal Med, Turin, Italy..
    Tiberi, Guido A. M.
    Univ Brescia, Dept Clin & Expt Sci, Surg Clin, ASST Spedali Civili, Brescia, Italy..
    Ettaieb, Hester
    Maxima Med Ctr, Div Endocrinol, Dept Internal Med, Eindhoven, Netherlands..
    Kiriakopoulos, Andreas
    Natl & Kapodistrian Univ Athens, Surg Clin 5, Evgenid Hosp, Sch Med, Athens, Greece..
    Letizia, Canu
    Univ Florence, Dept Expt & Clin Biomed Sci, Florence, Italy..
    Kastelan, Darko
    Univ Hosp Ctr Zagreb, Dept Endocrinol, Zagreb, Croatia..
    Osher, Esthr
    Tel Aviv Univ, Tel Aviv Sourasky Med Ctr Israel, Inst Endocrinol Metab & Hypertens, Sackler Fac Med, Tel Aviv, Israel..
    Yiannakopoulou, Eugenia
    Univ West Attica, Dept Biomed Sci, Fac Hlth Sci, Athens, Greece..
    Arnaldi, Giorgio
    Polytech Univ Marche, Dept Clin & Mol Sci, Div Endocrinol, Ancona, Italy..
    Assie, Guillaume
    Univ Paris, CNRS, Inst Cochin, INSERM, Paris, France.;Hop Cochin, AP HP, Endocrinol, Paris, France..
    Paiva, Isabel
    Ctr Hosp & Univ Coimbra, Dept Endocrinol Diabet & Metab, Coimbra, Portugal..
    Bourdeau, Isabelle
    Ctr Hosp Univ Montreal CHUM, Dept Med, Res Ctr, Div Endocrinol, Montreal, PQ, Canada..
    Newell-Price, John
    Univ Sheffield, Dept Oncol & Metab, Med Sch, Sheffield, S Yorkshire, England..
    Nowak, Karolina M.
    Bielanski Hosp, Ctr Postgrad Med Educ, Dept Endocrinol, Warsaw, Poland..
    Romero, M. Tous
    Hosp Univ Virgen Macarena, UGC Endocrinol & Nutr, Seville, Spain..
    De Martino, Maria Cristina
    Univ Federico II Napoli, Dipartimento Med Clin & Chirurg, Sez Endocrinol, Naples, Italy..
    Bugalho, Maria Joao
    CHULN, Serv Endocrinol Diabet & Metabol, Lisbon, Portugal.;Univ Lisbon, Fac Med, Lisbon, Portugal..
    Sherlock, Mark
    Beaumont Hosp, Dept Endocrinol, Dublin, Ireland.;Royal Coll Surgeons Ireland, Dublin, Ireland..
    Vantyghem, Marie-Christine
    Lille Univ Hosp, Endocrinol Diabetol Metab & Nutr Dept, Lille, France..
    Dennedy, Michael Conall
    Natl Univ Ireland, Dept Endocrinol & Diabet Mellitus, Dept Med, Clin Sci Inst, Galway, Ireland..
    Loli, Paula
    Osped Niguarda Ca Granda, Endocrinol, Naples, Italy..
    Rodien, Patrice
    CHU Angers, Serv Endocrinol Diabetol & Nutr, Angers 9, France..
    Feelders, Richard
    Erasmus MC, Div Endocrinol, Dept Internal Med, Rotterdam, Netherlands..
    de Krijger, Ronald
    Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands.;Univ Med Ctr, Dept Pathol, Utrecht, Netherlands..
    Van Slycke, Sam
    OLV Hosp Aalst, Gen & Endocrine Surg, Aalst, Belgium..
    Aylwin, Simon
    Kings Coll Hosp London, London, England..
    Morelli, Valentina
    Osped Maggiore Policlin, Endocrinol Unit, Fdn IRCCS Ca Granda, Milan, Italy..
    Vroonen, Laurent
    Ctr Hosp Univ Liege, Dept Endocrinol, Liege, Belgium..
    Shafigullina, Zulfiya
    North Western Med Univ, Endocrinol Dept, St Petersburg, Russia..
    Bancos, Irina
    Mayo Clin, Div Endocrinol Diabet Metab & Nutr, Rochester, MN USA..
    Trofimiuk-Mueldner, Malgorzata
    Jagiellonian Univ Med Coll, Dept Endocrinol, Krakow, Poland..
    Quinkler, Marcus
    Endocrinol Charlottenburg, Berlin, Germany..
    Luconi, Michaela
    Univ Florence, Dept Expt & Clin Biomed Sci, Florence, Italy..
    Kroiss, Matthias
    Univ Hosp Wurzburg, Div Endocrinol & Diabet, Wurzburg, Germany.;Univ Wurzburg, Comprehens Canc Ctr Mainfranken, Wurzburg, Germany..
    Naruse, Mitsuhide
    Ijinkai Takeda Gen Hosp, Endocrine Ctr, Kyoto, Japan.;NHO Kyoto Med Ctr, Clin Res Inst Endocrinol & Metab, Kyoto, Japan..
    Igaz, Peter
    Semmelweis Univ, Dept Internal Med 2, Budapest, Hungary.;Hungarian Acad Sci, MTA SE Mol Med Res Grp, Budapest, Hungary.;Semmelweis Univ, Budapest, Hungary..
    Mihai, Radu
    Univ Oxford, Dept Endocrine Surg, Churchill Canc Ctr, Oxford, England..
    Della Casa, Silvia
    Catholic Univ, Endocrinol Dept, Gemelli Polyclin Fdn, Rome, Italy..
    Berruti, Alfredo
    Univ Brescia, Dept Med & Surg Specialties, Radiol Sci & Publ Hlth, Med Oncol,ASST Spedali Civili, Brescia, Italy..
    Fassnacht, Martin
    Univ Hosp Wurzburg, Div Endocrinol & Diabet, Wurzburg, Germany.;Univ Wurzburg, Comprehens Canc Ctr Mainfranken, Wurzburg, Germany..
    Beuschlein, Felix
    Univ Spital Zurich, Klin Endokrinol Diabetol & Klin Ernahrung, Zurich, Switzerland.;Klinikum Univ Munchen, Deptr Endocrinol, Med Klin & Poliklin 4, Munich, Germany..
    ENSAT registry-based randomized clinical trials for adrenocortical carcinoma2021In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 184, no 2, p. R51-R59Article, review/survey (Refereed)
    Abstract [en]

    Adrenocortical carcinoma (ACC) is an orphan disease lacking effective systemic treatment options. The low incidence of the disease and high cost of clinical trials are major obstacles in the search for improved treatment strategies. As a novel approach, registry-based clinical trials have been introduced in clinical research, so allowing for significant cost reduction, but without compromising scientific benefit. Herein, we describe how the European Network for the Study of Adrenal Tumours (ENSAT) could transform its current registry into one fit for a clinical trial infrastructure. The rationale to perform randomized registry-based trials in ACC is outlined including an analysis of relevant limitations and challenges. We summarize a survey on this concept among ENSAT members who expressed a strong interest in the concept and rated its scientific potential as high. Legal aspects, including ethical approval of registry-based randomization were identified as potential obstacles. Finally, we describe three potential randomized registry-based clinical trials in an adjuvant setting and for advanced disease with a high potential to be executed within the framework of an advanced ENSAT registry. Thus we, therefore, provide the basis for future registry-based trials for ACC patients. This could ultimately provide proof-of-principle of how to perform more effective randomized trials for an orphan disease.

  • 20.
    Crona, Joakim
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Skogseid, Britt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Tumor Biology.
    Genetics of neuroendocrine tumors2016In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 174, no 6, p. R275-R290Article, review/survey (Refereed)
    Abstract [en]

    Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms, arising from neuroendocrine cells that are dispersed throughout the body. Around 20% of NETs occur in the context of a genetic syndrome. Today there are at least ten recognized NET syndromes. This includes the classical syndromes: multiple endocrine neoplasias types 1 and 2, and von Hippel-Lindau and neurofibromatosis type 1. Additional susceptibility genes associated with a smaller fraction of NETs have also been identified. Recognizing genetic susceptibility has proved essential both to provide genetic counseling and to give the best preventive care. In this review we will also discuss the knowledge of somatic genetic alterations in NETs. At least 24 genes have been implicated as drivers of neuroendocrine tumorigenesis, and the overall rates of genomic instability are relatively low. Genetic intra-tumoral, as well as inter-tumoral heterogeneity in the same patient, have also been identified. Together these data point towards the common pathways in NET evolution, separating early from late disease drivers. Although knowledge of specific mutations in NETs has limited impact on actual patient management, we predict that in the near future genomic profiling of tumors will be included in the clinical arsenal for diagnostics, prognostics and therapeutic decisions.

  • 21.
    Cui, Tao
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Tsolakis, Apostolos V
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Li, Su-Chen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Cunningham, Janet L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Lind, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Öberg, Kjell
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Giandomenico, Valeria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Olfactory receptor 51E1 protein as a potential novel tissue biomarker for small intestine neuroendocrine carcinomas2013In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 168, no 2, p. 253-261Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Late diagnosis hinders proper management of small intestine neuroendocrine carcinoma (SI-NEC) patients. The olfactory receptor, family 51, subfamily E, member 1 (OR51E1) has been reported as a potential novel SI-NEC marker, without protein expression recognition. Thus, we further studied whether the encoded protein may be a novel SI-NEC clinical biomarker.

    DESIGN: OR51E1 coding sequence was cloned using total RNA from SI-NEC patient specimens. Quantitative real-time PCR analysis explored OR51E1 expression in laser capture microdissected SI-NEC cells and adjacent microenvironment cells. Moreover, immunohistochemistry investigated OR51E1 protein expression on operation and biopsy material from primary SI-NECs, mesentery, and liver metastases from 70 patients. Furthermore, double immunofluorescence studies explored the potential co-localization of the vesicular monoamine transporter 1 (SLC18A1, generally referred to as VMAT1) and OR51E1 in the neoplastic cells and in the intestinal mucosa adjacent to the tumor.

    RESULTS: OR51E1 coding sequence analysis showed absence of mutation in SI-NEC patients at different stages of disease. OR51E1 expression was higher in microdissected SI-NEC cells than in the adjacent microenvironment cells. Furthermore, both membranous and cytoplasmic OR51E1 immunostaining patterns were detected in both primary SI-NECs and metastases. Briefly, 18/43 primary tumors, 7/28 mesentery metastases, and 6/18 liver metastases were 'positive' for OR51E1 in more than 50% of the tumor cells. In addition, co-localization studies showed that OR51E1 was expressed in >50% of the VMAT1 immunoreactive tumor cells and of the enterochromaffin cells in the intestinal mucosa adjacent to the tumor.

    CONCLUSION: OR51E1 protein is a potential novel clinical tissue biomarker for SI-NECs. Moreover, we suggest its potential therapeutic molecular target development using solid tumor radioimmunotherapy.

  • 22.
    Cunningham, Janet L.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Janson, Eva Tiensuu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine Oncology.
    Agarwal, Smriti
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Grimelius, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Tachykinins in endocrine tumors and the carcinoid syndrome2008In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 159, no 3, p. 275-282Article in journal (Refereed)
    Abstract [en]

    Objective

    A new antibody, active against the common tachykinin (TK) C-terminal. was used to study TK expression in patients with endocrine tumors and a possible association between plasma-TK levels and symptoms of diarrhea and flush in patients with metastasizing ileocecal serotonin-producing carcinoid tumors (MSPCs).

    Method

    TK, serotonin and chromogranin A (CgA) immunoreactivity (IR) was studied by immunohistochemistry in tissue samples from 33 midgut carcinoids and 72 other endocrine tumors. Circulating TK (P-TK) and urinary-5 hydroxyindoleacetic acid (U-5HIAA) concentrations were measured in 42 patients with MSPCs before treatment and related to symptoms in patients with the carcinoid syndrome. Circulating CgA concentrations were also measured in 39 out of the 42 patients.

    Results

    All MSPCs displayed serotonin and strong TK expression. TK-IR was also seen in all serotonin-producing lung and appendix carcinoids. None of the other tumors examined contained TK-IR cells. Concentrations of P-TK, P-CgA, and U-5HIAA were elevated in patients experiencing daily episodes of either flush or diarrhea, when compared with patients experiencing occasional or none of these symptoms. In a Spearman partial rank test, the correlation of P-TK with daily diarrhea was independent of both U-5HIAA and CgA levels.

    Conclusion

    We found that TK synthesis occurs in serotonin-IR tumors and that P-TK levels are significantly correlated with symptoms of flush and diarrhea in patients with MSPCs. This is. to our knowledge, the first report demonstrating an independent correlation of P-TKs with carcinoid diarrhea, a symptom that is customarily regarded as serotonin mediated. Further investigations may present opportunities for new therapeutic possibilities.

  • 23.
    Cunningham, Janet L.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Tsolakis, Apostolos V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jacobson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Janson, Eva Tiensuu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Connective tissue growth factor expression in endocrine tumors is associated with high stromal expression of alpha-smooth muscle actin2010In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 163, no 4, p. 691-697Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE

    Complications due to fibrosis development are common in patients with well-differentiated endocrine carcinomas in the small intestine (ileal carcinoids). Connective tissue growth factor (CTGF) expression in ileal carcinoids may be related to this fibrosis development. This study aimed to examine CTGF expression in relation to local myofibroblast differentiation in a large series of ileal carcinoids and in different types of endocrine tumors.

    METHODS

     Immunoreactivity (IR) for CTGF and α-smooth muscle actin (α-SMA), a marker for myofibroblasts, was compared in serial tumor tissue sections from 42 patients with ileal carcinoids and from 80 patients with other endocrine tumors. Western blot was performed on an additional 21 patients with ileal carcinoids.

    RESULTS

    CTGF IR was present in >50% of tumor cells in all 42 ileal carcinoids and in 2 out of 14 endocrine pancreatic tumors, 4 out of 6 rectal carcinoids, and 1 out of 5 lung carcinoids. Tumors with abundant CTGF expression also displayed α-SMA IR in stromal fibroblast-like cells, whereas other endocrine tumors displayed less or no CTGF and α-SMA IR. Protein bands corresponding to full-length CTGF (36-42 kDa) were detected in protein lysates from ileal carcinoids.

    CONCLUSION

    CTGF is uniquely prevalent in ileal carcinoids when compared with most other endocrine tumor types. Immunoreactive cells are adjacent areas with increased fibrovascular stroma that express α-SMA. This supports a potential role for CTGF in myofibroblast-mediated fibrosis associated with ileal carcinoids, and indicates that CTGF should be investigated as a target for future therapy.

  • 24. Dogra, Prerna
    et al.
    Sundin, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Molecular Imaging, Uppsala University Hospital.
    Juhlin, C. Christofer
    Calissendorff, Jan
    Falhammar, Henrik
    Bancos, Irina
    Rare benign adrenal lesions2023In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 188, no 4, p. 407-420Article in journal (Refereed)
    Abstract [en]

    While most benign lesions of the adrenal glands represent either an adrenocortical adenoma or a myelolipoma, the advent and frequent use of high-resolution radiological investigations have led to relatively increased incidental discovery of rare adrenal lesions, specifically benign adrenal cysts, adrenal ganglioneuromas, adrenal schwannomas, adrenal hemorrhage, and adrenal calcifications. Radiological characteristics of the different rare benign adrenal lesions could vary from distinct to indeterminate. Though typically nonfunctional, these rare lesions require evaluation for adrenal hormone excess, as they may phenotypically appear similar to pheochromocytoma or adrenocortical carcinoma and could sometimes be associated with or conceal an underlying functional adrenal tumor. In this review, we discuss the various rare benign adrenal lesions, emphasizing a practical perspective.

  • 25.
    Eriksson, Jan W
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Visvanathar, Robin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Kullberg, Joel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Antaros Medical, Mölndal, Sweden.
    Strand, Robin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Skrtic, Stanko
    Innovation Strategies & External Liaison, Pharmaceutical Technologies & Development, AstraZeneca, Gothenburg, Sweden;Institute of Medicine at Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden .
    Ekström, Simon
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lubberink, Mark
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Lundqvist, Martin H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Katsogiannos, Petros
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Pereira, Maria J.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical diabetology and metabolism.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology. Antaros Medical, Mölndal, Sweden .
    Tissue-specific glucose partitioning and fat content in prediabetes and type 2 diabetes: whole-body PET/MRI during hyperinsulinemia2021In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 184, no 6, p. 879-889Article in journal (Refereed)
    Abstract [en]

    Objective: To obtain direct quantifications of glucose turnover, volumes and fat content of several tissues in the development of type 2 diabetes (T2D) using a novel integrated approach for whole-body imaging.

    Design and methods: Hyperinsulinemic-euglycemic clamps and simultaneous whole-body integrated [18F]FDG-PET/MRI with automated analyses were performed in control (n = 12), prediabetes (n = 16) and T2D (n = 13) subjects matched for age, sex and BMI.

    Results: Whole-body glucose uptake (Rd) was reduced by approximately 25% in T2D vs control subjects, and partitioning to brain was increased from 3.8% of total Rd in controls to 7.1% in T2D. In liver, subcutaneous AT, thigh muscle, total tissue glucose metabolic rates (MRglu) and their % of total Rd were reduced in T2D compared to control subjects. The prediabetes group had intermediate findings. Total MRglu in heart, visceral AT, gluteus and calf muscle was similar across groups. Whole-body insulin sensitivity assessed as glucose infusion rate correlated with liver MRglu but inversely with brain MRglu. Liver fat content correlated with MRglu in brain but inversely with MRglu in other tissues. Calf muscle fat was inversely associated with MRglu only in the same muscle group.

    Conclusions: This integrated imaging approach provides detailed quantification of tissue-specific glucose metabolism. During T2D development, insulin-stimulated glucose disposal is impaired and increasingly shifted away from muscle, liver and fat toward the brain. Altered glucose handling in the brain and liver fat accumulation may aggravate insulin resistance in several organs.

  • 26.
    Espes, Daniel
    et al.
    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.
    Lau, Joey
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    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.
    Towards the clinical translation of stem cell therapy for type 1 diabetes2017In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 177, no 4, p. R159-R168Article, review/survey (Refereed)
    Abstract [en]

    Insulin-producing cells derived from human embryonic stem cells (hESCs) or induced pluripotent stem cells (iPSCs) have for long been a promising, but elusive treatment far from clinical translation into type 1 diabetes therapy. However, the field is now on the verge of moving such insulin-producing cells into clinical trials. Although stem cell therapies provide great opportunities, there are also potential risks such as teratoma formation associated with the treatment. Many considerations are needed on how to proceed with clinical translation, including whether to use hESCs or iPSCs, and whether encapsulation of tissue will be needed. This review aims to give an overview of the current knowledge of stem cell therapy outcomes in animal models of type 1 diabetes and a proposed road map towards the clinical setting with special focus on the potential risks and hurdles which needs to be considered. From a clinical point of view, transplantation of insulin-producing cells derived from stem cells must be performed without immune suppression in order to be an attractive treatment option. Although costly and highly labour intensive, patient-derived iPSCs would be the only solution, if not clinically successful encapsulation or tolerance induction protocols are introduced.

  • 27.
    Feldt-Rasmussen, Ulla
    et al.
    Department of Medical Endocrinology, Rigshospitalet, National University Hospital, Copenhagen University, Denmark.
    Brabant, Georg
    Department of Endocrinology, Christie Hospital, Manchester, UK.
    Maiter, Dominique
    Department of Endocrinology and Nutrition, University Hospital Saint‐Luc, Brussels, Belgium.
    Jonsson, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Toogood, Andy
    Department of Endocrinology, University Hospital Birmingham NHS Foundation Trust, UK.
    Koltowska-Haggstrom, Maria
    Pfizer, Inc., Sollentuna, Sweden.
    Rasmussen, Aase Krogh
    Department of Medical Endocrinology, PE 2132, Rigshospitalet, National University Hospital, Copenhagen University, Denmark.
    Buchfelder, Michael
    Department of Neurosurgery, University of Erlangen Nuernberg, Germany.
    Saller, Bernhard
    Endocrine Care, Pfizer, Inc., Tadworth, UK.
    Biller, Beverly M. K.
    Neuroendocrine Unit, Harvard Medical School, Massachusetts General Hospital, Boston, USA.
    Response to GH treatment in adult GH deficiency is predicted by gender, age, and IGF1 SDS but not by stimulated GH-peak2013In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 168, no 5, p. 733-743Article in journal (Refereed)
    Abstract [en]

    Objective: We studied whether the severity of GH deficiency (GHD) defined as i) GH-peak on stimulation tests (insulin tolerance test (ITT), arginine, and glucagon), ii) number of additional pituitary deficits, or iii) baseline IGF1 SDS could impact the response to GH treatment. We further explored whether iv) IGF1 SDS after 24 months of GH replacement or v) Delta IGF1 SDS from baseline to 24 months was related to the phenotypic response to GH treatment. Design, patients, and measurements: The patient cohort (n=1752; 50% women) was obtained from KIMS (Pfizer International Metabolic Database). The patients were divided into three groups of approximately equal size (tertiles) according to the stimulated GH-peak values and baseline IGF1 SDS and were studied at baseline, 12, and 24 months of GH therapy. Results: Lower baseline IGF1 SDS predicted better response in weight, BMI, total cholesterol, and triglycerides, while IGF1 SDS after 24 months was associated with reduction in waist/hip ratio, total cholesterol, and improved quality of life (QoL). Age-correlated negatively with the response in body weight, BMI, waist, IGF1 SDS, and total and LDL-cholesterol. Response in weight and BMI was greater in men than in women, whereas women showed greater improvement in QoL than men. Patients with more severe GHD as assessed by lower GH-peaks and more pituitary hormone deficiencies had a greater increase in IGF1 SDS. The increase in IGF1 SDS was associated with a reduction in waist/hip ratio and an increase in weight, BMI, and triglycerides. There was no correlation with other lipids, blood pressure, or glucose. Conclusion: Our findings indicate that baseline and 24 months, IGF1 and its degree of increase during GH replacement were more important than stimulated peak GH to predict the phenotypic response.

  • 28. Gardner, Chris J.
    et al.
    Mattsson, Anders F.
    Daousi, Christina
    Korbonits, Marta
    Koltowska-Häggström, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Cuthbertson, Daniel J.
    GH deficiency after traumatic brain injury: improvement in quality of life with GH therapy: analysis of the KIMS database2015In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 172, no 4, p. 371-381Article in journal (Refereed)
    Abstract [en]

    Objective: Prevalence of GH deficiency (GHD) caused by traumatic brain injury (TBI) is highly variable. Short-term studies show improvement in quality of life (QoL) during GH replacement (GHR), but long-term data are lacking. The aim of this study was to analyse the clinical characteristics of post-traumatic hypopituitarism and the QoL effects of long-term GHR. Design/methods: Pfizer International Metabolic Database patients with GHD caused by TBI and by non-functioning pituitary adenoma (NFPA) were compared regarding: clinical characteristics at baseline and 1-year of GHR, and QoL response up to 8-years of GHR (QoL-AGHDA total scores and dimensions) in relationship with country-specific norms. Results: TBI patients compared with NFPA patients were younger, diagnosed with GHD 2.4 years later after primary disease onset (P<0.0001), had a higher incidence of isolated GHD, higher GH peak, a more favourable metabolic profile and worse QoL, were shorter by 0.9 cm (1.8 cm when corrected for age and gender; P=0.004) and received higher GH dose (mean difference: 0.04 mg/day P=0.006). In TBI patients, 1-year improvement in QoL was greater than in NFPA (change in QoL-AGHDA score 5.0 vs 3.5, respectively, P=0.04) and was sustained over 8 years. In TBI patients, socialisation normalised after 1 year of GHR, self-confidence and tenseness after 6 years and no normalisation of tiredness and memory was observed. Conclusion: Compared with NFPA, TBI patients presented biochemically with less severe hypopituitarism and worse QoL scores. GHR achieved clinically relevant, long-term benefit in QoL.

  • 29.
    Grundberg, Elin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Brändström, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ribom, Eva L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Genetic variation in the human vitamin D receptor is associated with muscle strength, fat mass and body weight in Swedish women2004In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 150, no 3, p. 323-328Article in journal (Refereed)
    Abstract [en]

    Objective: Bone mineral density (BMD) is under strong genetic control and a number of candidategenes have been associated with BMD. Both muscle strength and body weight are considered to beimportant predictors of BMD but far less is known about the genes affecting muscle strength andfat mass. The purpose of this study was to investigate the poly adenosine (A) repeat and the BsmISNP in the vitamin D receptor (VDR) in relation to muscle strength and body composition in healthywomen.

    Design: A population-based study of 175 healthy women aged 20–39 years was used.

    Methods: The polymorphic regions in the VDR gene (the poly A repeat and the BsmI SNP) were amplifiedby PCR. Body mass measurements (fat mass, lean mass, body weight and body mass index) andmuscle strength (quadriceps, hamstring and grip strength) were evaluated.

    Results: Individuals with shorter poly A repeat, ss and/or absence of the linked BsmI restriction site(BB) have higher hamstring strength (ss vs LL, P ¼ 0.02), body weight (ss vs LL, P ¼ 0.049) andfat mass (ss vs LL, P ¼ 0.04) compared with women with a longer poly A repeat (LL) and/or thepresence of the linked BsmI restriction site (bb).

    Conclusions: Genetic variation in the VDR is correlated with muscle strength, fat mass and bodyweight in premenopausal women. Further functional studies on the poly A microsatellite areneeded to elucidate whether this is the functionally relevant locus or if the polymorphism is in linkagedisequilibrium with a functional variant in a closely situated gene further downstream of the VDR30UTR.

  • 30.
    Gulseth, Hanne L.
    et al.
    Univ Oslo, Oslo Univ Hosp, Dept Endocrinol Morbid Obes & Prevent Med, Oslo, Norway;Univ Oslo, Fac Med, Oslo, Norway;Univ Oslo, Fac Med, Inst Basic Med Sci, Dept Nutr, Oslo, Norway;Norwegian Inst Publ Hlth, Dept Chron Dis & Ageing, Oslo, Norway.
    Gjelstad, Ingrid M. F.
    Univ Oslo, Oslo Univ Hosp, Dept Endocrinol Morbid Obes & Prevent Med, Oslo, Norway;Univ Oslo, Fac Med, Oslo, Norway;Univ Oslo, Fac Med, Inst Basic Med Sci, Dept Nutr, Oslo, Norway.
    Tiereny, Audrey C.
    Univ Coll Dublin, UCD Conway Inst, Nutrigen Res Grp, Dublin, Ireland;Univ Coll Dublin, UCD Inst Food & Hlth, Sch Publ Hlth Physiotherapy & Sports Sci, Dublin, Ireland;Univ Limerick, Sch Allied Hlth, Limerick, Ireland;La Trobe Univ, Sch Allied Hlth, Melbourne, Vic, Australia.
    McCarthy, Danielle
    Univ Reading, Dept Food Biosci, Hugh Sinclair Unit Human Nutr, Reading, Berks, England;Queens Univ Belfast, Northern Ireland Technol Ctr, Inst Global Food Secur, Belfast, Antrim, North Ireland.
    Lovegrove, Julie A.
    Univ Reading, Dept Food Biosci, Hugh Sinclair Unit Human Nutr, Reading, Berks, England;Univ Reading, Inst Cardiovasc & Metab Res, Reading, Berks, England.
    Defoort, Catherine
    Aix Marseille Univ, INSERM, INRA, C2VN, Marseille, France.
    Blaak, Ellen E.
    Maastricht Univ, Med Ctr, Sch Nutr Toxicol & Metab, NUTRIM, Maastricht, Netherlands.
    Lopez-Miranda, Jose
    Univ Cordoba, Hosp Univ Reina Sofia, Inst Maimonides Invest Biomed Cordoba IMIBIC, Lipids & Atherosclerosis Res Unit, Madrid, Spain;Inst Salud Carlos III, CIBER Fisiopatol Obesidad & Nutr CIBEROBN, Madrid, Spain.
    Dembinska-Kiec, Aldona
    Jagiellonian Univ, Dept Clin Biochem, Med Coll, Krakow, Poland.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Roche, Helen M.
    Univ Coll Dublin, UCD Conway Inst, Nutrigen Res Grp, Dublin, Ireland;Univ Coll Dublin, UCD Inst Food & Hlth, Sch Publ Hlth Physiotherapy & Sports Sci, Dublin, Ireland.
    Drevon, Christian A.
    Univ Oslo, Fac Med, Inst Basic Med Sci, Dept Nutr, Oslo, Norway.
    Birkeland, Kare, I
    Univ Oslo, Oslo Univ Hosp, Dept Endocrinol Morbid Obes & Prevent Med, Oslo, Norway;Univ Oslo, Fac Med, Oslo, Norway;Univ Oslo, Fac Med, Inst Clin Med, Oslo, Norway.
    Effects of dietary fat on insulin secretion in subjects with the metabolic syndrome2019In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 180, no 5, p. 321-328Article in journal (Refereed)
    Abstract [en]

    Objective: Impaired insulin secretion and action contribute to the development of type 2 diabetes. Dietary fat modification may improve insulin sensitivity, whereas the effect on insulin secretion is unclear. We investigated the effect of dietary fat modification on insulin secretion in subjects with the metabolic syndrome.

    Design: In a 12-week pan-European parallel, randomized controlled dietary intervention trial (LIPGENE), 486 subjects were assigned to four isoenergetic diets: high-fat diets rich in saturated fat (HSFA) or monounsaturated fat (HMUFA) or low-fat, high-complex carbohydrate diets with (LFHCC n-3) or without (LFHCC control) 1.2 g/day of n-3 PUFA supplementation. Insulin secretion was estimated as acute insulin response to glucose (AIRg) and disposition index (DI), modeled from an intravenous glucose tolerance test.

    Results: There were no overall effect of the dietary intervention on AIRg and DI in the total cohort, in neither the highfat nor LFHCC groups. We observed significant diet*fasting glucose category interactions for AIRg (P = 0.021) and DI (P = 0.001) in the high-fat groups. In subjects with normal fasting glucose and preserved first phase insulin secretion, the HMUFA diet increased, whereas the HSFA diet reduced AIRg (P = 0.015) and DI (P = 0.010).

    Conclusions: The effects of dietary fat modification on insulin secretion were minor, and only evident in normoglycemic subjects. In this case, the HMUFA diet improved AIRg and DI, as compared to the HSFA diet.

  • 31. Gustafsson, Stefan
    et al.
    Lind, Lars
    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.
    Venge, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Flyvbjerg, Allan
    Söderberg, Stefan
    Ingelsson, Erik
    Adiponectin and cardiac geometry and function in elderly: results from two community-based cohort studies2010In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 162, no 3, p. 543-550Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Several smaller studies have indicated that adiponectin might be associated with left ventricular (LV) mass and function, but community-based studies with adequate sample size and adjustment for potential confounders are lacking. Our objective was to investigate such associations in two large community-based studies of elderly. DESIGN: Cross-sectional. METHODS: We evaluated cross-sectional relations between serum adiponectin and echocardiographic measures of cardiac geometry and function (LV mass index, LV relative wall thickness, LV end-diastolic diameter, left atrial diameter, ejection fraction, LV isovolumic relaxation time, and E/A ratio) in 954 70-year-old participants (50% women) of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), and in 427 71-year-old men from the Uppsala Longitudinal Study of Adult Men (ULSAM). RESULTS: In models adjusted for age, sex, body mass index, systolic blood pressure, antihypertensive treatment, antidiabetic treatment, lipid-lowering medication, fasting blood glucose, total cholesterol, high-density lipoprotein cholesterol, creatinine, and smoking, adiponectin was inversely associated with ejection fraction in men (beta, -1.62; 95% confidence interval (CI), -2.50, -0.75 in PIVUS; beta, -1.35; 95% CI, -2.41, -0.29 in ULSAM), but not in women. After additional adjustment for N-terminal pro-brain natriuretic peptide (NT-proBNP), the association between adiponectin and ejection fraction was attenuated (beta, -0.98; 95% CI, -1.86, -0.10 in PIVUS; beta, -0.75; 95% CI, -1.84, 0.35 in ULSAM). CONCLUSIONS: Serum adiponectin concentrations were associated with ejection fraction in men, and these associations were partially attenuated by NT-proBNP. Our results imply that adiponectin may be associated with systolic function through pathways that involve natriuretic peptides.

  • 32.
    Hagström, Emil
    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 Surgical Sciences, Endocrine Surgery.
    Lundgren, Ewa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Rastad, Jonas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Metabolic abnormalities in patients with normocalcemic hyperparathyroidism detected at a population-based screening2006In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 155, no 1, p. 33-39Article in journal (Refereed)
    Abstract [en]

    Objective: Dyslipidemia, hypertension, diabetes mellitus and also primary hyperparathyroidism (pHPT)are associated with an increased risk of cardiovascular diseases. Metabolic abnormalities in mild pHPThave been reported, but never in cases with normal calcium and high parathyroid hormone (PTH)levels, i.e. suffering from ‘normocalcemic pHPT’. Our aim was to explore the occurrence of thesemetabolic abnormalities in individuals with normocalcemic pHPT identified in a population-basedscreening, and the effects of parathyroidectomy vs conservative treatment on metabolic variables.Design and methods: A population-based screening of 5202 post-menopausal women identified 30patients with normal calcium, inappropriately high PTH and normal creatinine. A 5-year follow-upincluded 15 parathyroidectomized (PTx) and nine conservatively followed cases, in a non-randomizedsetting, together with age-matched controls. Biochemical variables and body mass index (BMI) wereinvestigated.Results: At study entry, cases had higher calcium, PTH, glucose, low-density lipoprotein (LDL)/highdensitylipoprotein (HDL)-cholesterol, very low-density lipoprotein (VLDL)-cholesterol, total triglycerides,and BMI compared to controls (PZ!0.0001–0.035). The cases had a lower HDL-cholesterolvalue (PZ0.013) and one third of the cases had hypertriglyceridemia. During follow-up, the PTx casesdecreased in calcium, PTH, LDL/HDL-cholesterol, total and LDL-cholesterol (PZ0.0076–0.022).Investigated biochemical variables remained adverse in conservatively followed cases during follow-upexcept a decreased LDL-cholesterol value. All surgically treated patients had parathyroid adenoma.Conclusions: Cases with normocalcemic pHPT have increased proatherogenic lipoprotein levels, BMIand glucose levels compared to age-matched controls. Parathyroidectomy has positive effects on someof these variables and reverses them to the same level as the controls, while conservative treatmentfails to normalize the investigated metabolic variables.

  • 33. Hoybye, Charlotte
    et al.
    Jönsson, Peter
    Monson, John P.
    Koltowska-Häggström, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hána, Václav
    Geffner, Mitchell
    Abs, Roger
    Impact of the primary aetiology upon the clinical outcome of adults with childhood-onset GH deficiency2007In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 157, no 5, p. 589-596Article in journal (Refereed)
    Abstract [en]

    Objective: The impact of the aetiology of childhood-onset GH deficiency (CO-GHD) on the clinical presentation during adulthood and the response to GH replacement has been poorly defined. Our study aims to characterize CO-GHD in adults due to different aetiologies and evaluate the effect of 2 years of GH replacement therapy.

    Design and methods: Data from 353 adults with CO-GHD from Pfizer International Metabolic Database KIMS were retrospectively grouped according to GHD aetiology: non-organic disorder (n=147), organic pituitary disease (n=159), and brain tumour (n=47). Extent of pituitary dysfunction, IGF-I concentration, lipid concentrations and quality-of-life (QoL) were assessed at baseline and after 2 years of GH replacement.

    Results: GHD was diagnosed at a later age in the organic pituitary group than in the other groups, resulting in a shorter duration of GH treatment during childhood. However, the final height was greater in the organic pituitary group. Panhypopituitarism was most common in the non-organic disorder and in the organic pituitary groups, while isolated GHD was more prominent in the brain tumour group. Serum IGF-I levels were the lowest in the non-organic group. QoL was the poorest in the brain tumour group. Lipid profile and QoL improved significantly during GH replacement.

    Conclusion: The adverse consequences of CO-GHD in adulthood vary between aetiologies, but improve similarly with GH treatment. It is, therefore, important to consider retesting all patients with CO-GHD in early adulthood and, if persistent severe GHD is confirmed, recommence GH replacement.

  • 34. Jakob, F.
    et al.
    Oertel, H.
    Langdahl, B.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Barrett, A.
    Karras, D.
    Walsh, J. B.
    Fahrleitner-Pammer, A.
    Rajzbaum, G.
    Barker, C.
    Lems, W. F.
    Marin, F.
    Effects of teriparatide in postmenopausal women with osteoporosis pre-treated with bisphosphonates: 36-month results from the European Forsteo Observational Study2012In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 166, no 1, p. 87-97Article in journal (Refereed)
    Abstract [en]

    Objectives: To describe fracture rates, back pain, and health-related quality of life (HRQoL) in postmenopausal women with osteoporosis and prior bisphosphonate therapy, treated with teriparatide for up to 18 months and followed up for a further 18 months.

    Design: Prospective, multinational, and observational study.

    Methods: Data on prior bisphosphonate use, clinical fractures, back pain visual analog scale (VAS), and HRQoL (EQ-5D) were collected over 36 months. Fracture data were summarized in 6-month intervals and analyzed using logistic regression with repeated measures. Changes from baseline in back pain VAS and EQ-VAS were analyzed using a repeated measures model.

    Results: Of the 1581 enrolled patients with follow-up data, 1161 (73.4%) had a history of prior bisphosphonate use (median duration: 36 months). Of them, 169 (14.6%) sustained >= 1 fracture during 36-month follow-up. Adjusted odds of fracture were significantly decreased at each 6-month interval compared with the first 6 months of teriparatide treatment: 37% decrease in the 12 to ! 18 months period during teriparatide treatment (P=0.03) and a 76% decrease in the 12- to 18-month period after teriparatide was discontinued (P<0.001). Significant reductions in back pain and improvement in HRQoL were observed.

    Conclusions: Postmenopausal women with severe osteoporosis previously treated with bisphosphonates had a significant reduction in the incidence of fractures compared with the first 6 months of therapy, a reduction in back pain and an improvement in HRQoL during up to 18 months of teriparatide treatment. These outcomes were still evident for at least 18 months after teriparatide was discontinued. The results should be interpreted in the context of an uncontrolled, observational study in a routine clinical setting.

  • 35. Johannsson, Gudmundur
    et al.
    Bergthorsdottir, Ragnhildur
    Nilsson, Anna G
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Hedner, Thomas
    Skrtic, Stanko
    Improving glucocorticoid replacement therapy using a novel modified-release hydrocortisone tablet: a pharmacokinetic study2009In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 161, no 1, p. 119-130Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Endogenous plasma cortisol levels have a well-defined circadian rhythm. The aim of this project is to develop a once daily oral dual-release formulation for cortisol replacement therapy that mimics the diurnal variation in the plasma cortisol profile. OBJECTIVE: To determine single-dose plasma pharmacokinetics and dose-proportionality of oral 5 and 20 mg dual-release hydrocortisone tablets in healthy volunteers. In addition, the effect of food intake was investigated for the 20 mg dose. DESIGN: A randomised, controlled, two-way cross-over, double-blind, phase I study of oral hydrocortisone (modified (dual) release; 5 and 20 mg) with an open food-interaction arm. METHODS: The single dose pharmacokinetic studies were performed with betamethasone suppression. The two first study days were blinded and randomised between morning administration of 5 and 20 mg tablet in a fasting state. The third day was open with a 20 mg tablet taken 30 min after a high-calorie, high-fat meal. The plasma samples were assayed using both a validated LC-MS/MS and an immunoassay. The plasma pharmacokinetic variables were calculated using non-compartmental data analysis. RESULTS: The time to reach a clinically significant plasma concentration of cortisol (>200 nmol/l) was within 20 min and a mean peak of 431 (s.d. 126) nmol/l was obtained within 50 min after administration of the 20 mg tablet. Plasma cortisol levels remained above 200 nmol/l for around 6 h thereafter and all plasma concentrations 18-24 h after intake were below 50 nmol/l. In the fed state the time to reach 200 nmol/l was delayed by 28 and 9 min based on LC-MS/MS and immunoassay, respectively. The 5 and 20 mg tablets produced an increase in plasma exposure of cortisol that was not fully dose proportional. CONCLUSION: The dual release hydrocortisone tablet with once-daily administration produced a diurnal plasma cortisol profile mimicking the physiological serum cortisol profile.

  • 36.
    Johannsson, Gudmundur
    et al.
    Univ Gothenburg, Dept Endocrinol, Sahlgrenska Acad, Inst Med, Gothenburg, Sweden..
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Marelli, Claudio
    Shire Int GmbH, Zug, Switzerland..
    Rockich, Kevin
    Shire PLC, Wayne, PA USA..
    Skrtic, Stanko
    Univ Gothenburg, Dept Endocrinol, Sahlgrenska Acad, Inst Med, Gothenburg, Sweden.;AstraZeneca R&D, Molndal, Sweden..
    Achieving a physiological cortisol profile with once-daily dual-release hydrocortisone: a pharmacokinetic study2016In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 175, no 1, p. 85-93Article in journal (Refereed)
    Abstract [en]

    Objective: Oral once-daily dual-release hydrocortisone (DR-HC) replacement therapy was developed to provide a cortisol exposure-time profile that closely resembles the physiological cortisol profile. This study aimed to characterize single-dose pharmacokinetics (PK) of DR-HC 5-20 mg and assess intrasubject variability. Methods: Thirty-one healthy Japanese or non-Hispanic Caucasian volunteers aged 20-55 years participated in this randomized, open-label, PK study. Single doses of DR-HC 5, 15 (3 x 5), and 20 mg were administered orally after an overnight fast and suppression of endogenous cortisol secretion. After estimating the endogenous cortisol profile, PK of DR-HC over 24 h were evaluated to assess dose proportionality and impact of ethnicity. Plasma cortisol concentrations were analyzed using liquid chromatography-tandem mass spectrometry. PK parameters were calculated from individual cortisol concentration-time profiles. Results: DR-HC 20 mg provided higher than endogenous cortisol plasma concentrations 0-4 h post-dose but similar concentrations later in the profile. Cortisol concentrations and PK exposure parameters increased with increasing doses. Mean maximal serum concentration (C-max) was 82.0 and 178.1 ng/mL, while mean area under the concentration-time curve (AUC)(0-infinity) was 562.8 and 1180.8 h x ng/mL with DR-HC 5 and 20 mg respectively. Within-subject PK variability was low (<15%) for DR-HC 20 mg. All exposure PK parameters were less than dose proportional (slope < 1). PK differences between ethnicities were explained by body weight differences. Conclusions: DR-HC replacement resembles the daily normal cortisol profile. Within-subject day-to-day PK variability was low, underpinning the safety of DR-HC for replacement therapy. DR-HC PK were less than dose proportional - an important consideration when managing intercurrent illness in patients with adrenal insufficiency.

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  • 37.
    Kallak, Theodora Kunovac
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health.
    Hellgren, Charlotte
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health.
    Skalkidou, Alkistis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research.
    Sandelin-Francke, Lotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health.
    Ubhayasekera, Kumari
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Axelsson, Ove
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Centrum för klinisk forskning i Sörmland (CKFD). Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Obstetrics and Reproductive Health Research.
    Comasco, Erika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neuro-psycho-pharmacology.
    Campbell, Rebecca E
    Centre for Neuroendocrinology, Department of Physiology, University of Otago School of Medical Sciences, Dunedin, New Zealand.
    Sundström Poromaa, Inger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Research group (Dept. of women´s and children´s health), Reproductive Health.
    Maternal and female fetal testosterone levels are associated with maternal age and gestational weight gain2017In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 177, no 4, p. 379-388Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Prenatal androgen exposure has been suggested to play a role in polycystic ovary syndrome. Given the limited information on what maternal characteristics influence maternal testosterone levels, and the even less explored routes by which female fetus androgen exposure would occur, the aim of this study was to investigate the impact of maternal age, BMI, weight gain, depressed mood and aromatase SNPs on testosterone levels in maternal serum and amniotic fluid of female fetuses.

    METHODS: Blood samples from pregnant women (n = 216) obtained in gestational weeks 35-39, and pre-labor amniotic fluid samples from female fetuses (n = 56), taken at planned Caesarean section or in conjunction with amniotomy for induction of labor, were analyzed. Maternal serum testosterone and amniotic fluid testosterone and cortisol were measured by tandem mass spectrometry.

    RESULTS: Multiparity (β = -0.28, P < 0.001), self-rated depression (β = 0.26, P < 0.001) and weight gain (β = 0.18, P < 0.05) were independent explanatory factors for the maternal total testosterone levels. Maternal age (β = -0.34, P < 0.001), weight gain (β = 0.19, P < 0.05) and amniotic fluid cortisol levels (β = 0.44, P < 0.001) were independent explanatory factors of amniotic fluid testosterone in female fetuses, explaining 64.3% of the variability in amniotic fluid testosterone.

    WIDER IMPLICATIONS OF THE FINDINGS: Young maternal age and excessive maternal weight gain may increase the prenatal androgen exposure of female fetuses. Further studies are needed to explore this finding.

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  • 38. Klose, M.
    et al.
    Jonsson, B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Abs, R.
    Popovic, V.
    Koltowska-Häggström, M.
    Saller, B.
    Feldt-Rasmussen, U.
    Kourides, I.
    From isolated GH deficiency to multiple pituitary hormone deficiency: an evolving continuum - a KIMS analysis2009In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 161, p. S75-S83Article in journal (Refereed)
    Abstract [en]

    Objective: To describe baseline clinical presentation, treatment effects and evolution of isolated GH deficiency (IGHD) to multiple pituitary hormone deficiency (MPHD) in adult-onset (AO) GHD. Design: Observational prospective study. Methods: Baseline characteristics were recorded in 4110 patients with organic AO-GHD, who were GH naive prior to entry into the Pfizer International Metabolic Database (KIMS: 283 (7%) IGHD, 3827 MPHD). The effect of GH replacement after 2 years was assessed in those with available follow-up data (1.33 IGHD, 2207 MPHD), and development of new deficiencies in those with available data on concomitant medication (165 IGHD, 3006 MPHD). Results: IGHD and MPHD patients had similar baseline clinical presentation, and both groups responded similarly to 2 years of GH therapy, with favourable changes in lipid profile and improved quality of life. New deficiencies were observed in 35%, of IGHD patients, which was similar to MPHD patients with one additional deficit other than GH. New deficiencies most often presented within the first year but were observed up to 6 years after GH commencement. Conversion of IGHD into MPHD was not predicted by aetiology, baseline characteristics, surgery or radiotherapy, whereas in MPHD additional deficits were predicted by age (P<0.001) and pituitary disease duration (P<0.01). Conclusion: Both AO-IGHD and -MPHD patients have similar baseline clinical presentation and respond equally well to 2 years of GH replacement. Hypopituitarism in adults seems to be a dynamic condition where new deficiencies can appear years after the initial diagnosis, and careful endocrine follow-up of all hypopituitary patients, including those with IGHD, is warranted.

  • 39.
    Koltowska-Häggström, Maria
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Mattsson, Anders F.
    Monson, John P.
    Kind, Paul
    Badia, Xavier
    Casanueva, Felipe F.
    Busschbach, Jan
    Koppeschaar, Hans P. F.
    Johannsson, Gudmundur
    Does long-term GH replacement therapy in hypopituitary adults with GH deficiency normalise quality of life?2006In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 155, no 1, p. 109-119Article in journal (Refereed)
    Abstract [en]

    Objective: To determine whether impaired quality of life (QoL) in adults with GH deficiency (GHD) is reversible with long-term GH therapy and whether the responses in QoL dimensions differ from each other. Methods: QoL was measured by the Quality of Life-Assessment for Growth Hormone Deficiency in Adults (QoL-AGHDA) in general population samples in England & Wales, The Netherlands, Spain and Sweden (n = 892, 1038, 868 and 1682 respectively) and compared with corresponding patients' data from KIMS (Pfizer International Metabolic Database) (n = 758, 247, 197 and 484 respectively) for 4-6 years a follow-up. The subsets of patients from England and Wales, and Sweden with longitudinal data for 5 years' follow-up were also analysed. The change of the total OoL-AGHDA scores and responses within dimensions were evaluated. Subanalyses were performed to identify any specificity in response pattern for gender, age, disease-onset and aetiology. Results: Irrespective of the degree of impairment, overall OoL improved dramatically in the first 12 months, with steady progress thereafter towards the country-specific population mean. Problems with memory and tiredness were the most serious burden for untreated patients, followed by tenseness, self-confidence and problems with socialising. With treatment, these improved in the reverse order, normalising for the latter three. Conclusions: Long-term GH replacement results in sustained improvements towards the normative country-specific values in overall QoL and in most impaired dimensions. The lasting improvement and almost identical pattern of response in each patient subgroup and independent of the level of QoL impairment support the hypothesis that GHD may cause these patients' psychological problems.

  • 40. Lima, Kari
    et al.
    Abrahamsen, Tore G.
    Wolff, Anette Boe
    Husebye, Eystein
    Alimohammadi, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kämpe, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Folling, Ivar
    Hypoparathyroidism and autoimmunity in the 22q11.2 deletion syndrome2011In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 165, no 2, p. 345-352Article in journal (Refereed)
    Abstract [en]

    Objective: To characterize the endocrine and autoimmune disturbances with emphasis on parathyroid dysfunction in patients with 22q11.2 deletion syndrome (22q11.2 DS). Design: In this nationwide survey; 59 patients (age 1-54 years) out of 86 invited with a 22q11.2 DS were recruited through all the genetic institutes in Norway. Methods: Data was collected from blood tests, medical records, a physical examination and a semi-structured interview. We registered autoimmune diseases and measured autoantibodies, hormone levels and HLA types. Results: Twenty-eight (47%) patients had hypoparathyroidism or a history of neonatal or transient hypocalcemia. Fifteen patients had neonatal hypocalcemia. Fourteen patients had permanent hypoparathyroidism including seven (54%) of those above age 15 years. A history of neonatal hypocalcemia did not predict later occurring hypoparathyroidism. Parathyroid hormone levels were generally low indicating a low reserve capacity. Twenty-eight patients were positive for autoantibodies. Six (10%) persons had developed an autoimmune disease, and all were females (P<0.02). Hypoparathyroidism correlated with autoimmune diseases (P<0.05), however, no antibodies were detected against the parathyroid glands. Conclusions: Hypoparathyroidism and autoimmunity occur frequently in the 22q11.2 DS. Neonatal hypocalcemia is not associated with later development of permanent hypoparathyroidism. Hypoparathyroidism may present at any age, also in adults, and warrants regular measurement of calcium levels. Hypoparathyroidism and autoimmunity occur frequently together. Our findings of autoimmune diseases in 10% of the patients highlight the importance of stringent screening and follow-up routines.

  • 41.
    Lindahl, Katarina
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Langdahl, Bente
    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. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Therapy of Endocrine Disease: Treatment of osteogenesis imperfecta in adults2014In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 171, no 2, p. R79-R90Article, review/survey (Refereed)
    Abstract [en]

    Background: Osteogenesis imperfecta (OI) is a heterogeneous rare connective tissue disorder commonly caused by mutations in the collagen type I genes. Pharmacological treatment has been most extensively studied in children, and there are only few studies comprising adult OI patients. Objectives: i) To review the literature on the current medical management of OI in children and adults, and thereby identify unmet medical needs and ii) to present an overview of possible future treatment options. Results: Individualization and optimization of OI treatment in adults remain a challenge, because available treatments do not target the underlying collagen defect, and available literature gives weak support for treatment decisions for adult patients. Conclusions: Bisphosphonates are still the most widely used pharmacological treatment for adult OI, but the current evidence supporting this is sparse and investigations on indications for choice and duration of treatment are needed.

  • 42.
    Lundtoft, Christian
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Eriksson, Daniel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Karolinska Inst, Ctr Mol Med, Dept Med Solna, Stockholm, Sweden.;Uppsala Univ Hosp, Dept Clin Genet, Uppsala, Sweden.
    Bianchi, Matteo
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.
    Aranda-Guillen, Maribel
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, Stockholm, Sweden.
    Landegren, Nils
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Karolinska Inst, Ctr Mol Med, Dept Med Solna, Stockholm, Sweden.
    Rantapää-Dahlqvist, Solbritt
    Umeå Univ, Dept Publ Hlth & Clin Med Rheumatol, Umeå, Sweden.
    Söderkvist, Peter
    Linköping Univ, Dept Biomed & Clin Sci, Linköping, Sweden.
    Meadows, Jennifer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Consortium, D I S S E C T
    Consortium, Immunoarray
    Grp, Swedish Addison Registry Study
    Bensing, Sophie
    Karolinska Univ Hosp, Dept Endocrinol, Stockholm, Sweden.;Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
    Pielberg, Gerli Rosengren
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Lindblad-Toh, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Broad Inst & Harvard, Cambridge, MA USA.
    Rönnblom, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kämpe, Olle
    Karolinska Inst, Ctr Mol Med, Dept Med Solna, Stockholm, Sweden.;Karolinska Univ Hosp, Dept Endocrinol, Stockholm, Sweden.;Univ Bergen, Dept Clin Sci, Bergen, Norway.;Univ Bergen, KG Jebsen Ctr Autoimmune Dis, Bergen, Norway.
    Relation between HLA and copy number variation of steroid 21-hydroxylase in a Swedish cohort of patients with autoimmune Addison's disease2023In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 189, no 2, p. 235-241Article in journal (Refereed)
    Abstract [en]

    Objective Autoantibodies against the adrenal enzyme 21-hydroxylase is a hallmark manifestation in autoimmune Addison's disease (AAD). Steroid 21-hydroxylase is encoded by CYP21A2, which is located in the human leucocyte antigen (HLA) region together with the highly similar pseudogene CYP21A1P. A high level of copy number variation is seen for the 2 genes, and therefore, we asked whether genetic variation of the CYP21 genes is associated with AAD.

    Design Case-control study on patients with AAD and healthy controls.

    Methods Using next-generation DNA sequencing, we estimated the copy number of CYP21A2 and CYP21A1P, together with HLA alleles, in 479 Swedish patients with AAD and autoantibodies against 21-hydroxylase and in 1393 healthy controls.

    Results With 95% of individuals carrying 2 functional 21-hydroxylase genes, no difference in CYP21A2 copy number was found when comparing patients and controls. In contrast, we discovered a lower copy number of the pseudogene CYP21A1P among AAD patients (P = 5 x 10(-44)), together with associations of additional nucleotide variants, in the CYP21 region. However, the strongest association was found for HLA-DQB1*02:01 (P = 9 x 10(-63)), which, in combination with the DRB1*04:04-DQB1*03:02 haplotype, imposed the greatest risk of AAD.

    Conclusions We identified strong associations between copy number variants in the CYP21 region and risk of AAD, although these associations most likely are due to linkage disequilibrium with disease-associated HLA class II alleles.

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  • 43.
    Löfvenborg, Josefin E.
    et al.
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden..
    Andersson, Tomas
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden.;Stockholm Cty Council, Ctr Occupat & Environm Med, Stockholm, Sweden..
    Carlsson, Per-Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Transplantation and regenerative medicine.
    Dorkhan, Mozhgan
    Lund Univ, Dept Clin Sci, Malmo, Sweden..
    Groop, Leif
    Lund Univ, Dept Clin Sci, Malmo, Sweden..
    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.
    Tuomi, Tiinamaija
    Univ Helsinki, Res Program Diabet & Obes, Helsinki Univ Hosp, Abdominal Ctr,Endocrinol, Helsinki, Finland.;Univ Helsinki, Finnish Inst Mol Med, Helsinki, Finland..
    Wolk, Alicja
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden..
    Carlsson, Sofia
    Karolinska Inst, Inst Environm Med, Stockholm, Sweden..
    Sweetened beverage intake and risk of latent autoimmune diabetes in adults (LADA) and type 2 diabetes2016In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 175, no 6, p. 605-614Article in journal (Refereed)
    Abstract [en]

    Objective: Sweetened beverage intake is associated with increased risk of type 2 diabetes, but its association with autoimmune diabetes is unclear. We aimed to investigate sweetened beverage intake and risk of latent autoimmune diabetes in adults (LADA); autoimmune diabetes with features of type 2 diabetes. Design/methods: Data from a Swedish population-based study was used, including incident cases of LADA (n = 357) and type 2 diabetes (n = 1136) and randomly selected controls (n = 1371). Diabetes classification was based on onset age (= 35), glutamic acid decarboxylase autoantibodies (GADA) and C-peptide. Sweetened beverage intake information was derived from a validated food frequency questionnaire. ORs adjusted for age, sex, family history of diabetes, education, lifestyle, diet, energy intake and BMI were estimated using logistic regression. Results: Daily intake of >2 servings of sweetened beverages (consumed by 6% of participants) was associated with increased risk of LADA (OR: 1.99, 95% CI: 1.11-3.56), and for each 200 mL daily serving, OR was 1.15 (95% CI: 1.02-1.29). Findings were similar for sugar-sweetened (OR: 1.18, 95% CI: 1.00-1.39) and artificially sweetened beverages (OR: 1.12, 95% CI: 0.95-1.32). Similarly, each daily serving increment in total sweetened beverage conferred 20% higher type 2 diabetes risk (95% CI: 1.07-1.34). In type 2 diabetes patients, high consumers displayed higher HOMA-IR levels (4.5 vs 3.5, P = 0.0002), but lower HOMA-B levels (55 vs 70, P = 0.0378) than non-consumers. Similar tendencies were seen in LADA. Conclusions: High intake of sweetened beverages was associated with increased risk of LADA. The observed relationship resembled that with type 2 diabetes, suggesting common pathways possibly involving insulin resistance.

  • 44. Maiter, D.
    et al.
    Abs, R.
    Johannsson, G.
    Scanlon, M.
    Jonsson, P. J.
    Wilton, P..
    Koltowska-Häggström, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Baseline characteristics and response to GH replacement of hypopituitary patients previously irradiated for pituitary adenoma or craniopharyngioma: data from the Pfizer International Metabolic Database2006In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 155, no 2, p. 253-260Article in journal (Refereed)
    Abstract [en]

    Objective: To test the hypothesis whether the effects of GH replacement therapy in adults could be affected by prior pituitary irradiation, the baseline characteristics and response to GH were evaluated in adults with severe GH deficiency (GHD), who had received or not irradiation for the treatment of pituitary adenoma or craniopharyngioma.

    Design: Data from 44 7 patients, who had received radiotherapy (42 7 in addition to surgery), and 6 3 0 patients, who were operated on but not irradiated for their tumour, were retrieved from Pfizer International Metabolic Database (KIMS) and compared at baseline and 1 and 2 years following the onset of GH replacement.

    Results: Irradiated and non-irradiated patients exhibited the expected phenotype of GHD at baseline. However, irradiated patients had a greater impairment in the quality of life (QoL), a higher fat mass, lower high-density lipoprotein cholesterol levels and a lower bone mineral content (BMC) than non-irradiated patients. Treatment with GH induced similar changes in both groups. After 1 year of GH replacement, there was an increase in serum IGF-1 and fat-free mass, a reduction in fat mass and an improvement in QoL, all changes being equivalent in irradiated and non-irradiated patients. The lipid profile also improved with the irradiated patients showing a better response. These beneficial effects were maintained and the BMC also increased in both groups by the second year of treatment.

    Conclusions: This analysis shows that prior irradiation for pituitary adenoma or craniopharyngioma does not compromise the beneficial effects of GH replacement therapy.

  • 45. Mantzoros, Christos
    et al.
    Petridou, Eleni
    Alexe, Delia-Marina
    Skalkidou, Alkistis
    Dessypris, Nick
    Papathoma, Eugenia
    Salvanos, Heraklis
    Shetty, Greeshma
    Gavrila, Alina
    Kedikoglou, Simos
    Chrousos, George
    Trichopoulos, Dimitrios
    Serum adiponectin concentrations in relation to maternal and perinatal characteristics in newborns.2004In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 151, no 6Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To assess serum adiponectin levels of neonates in relation to ponderal index and birth length with and without adjustment for potential confounding factors including maternal factors and perinatal characteristics.

    DESIGN: A cross-sectional study.

    METHODS: Three hundred and three newborns (Caucasian, singleton, full term, with a birth weight of > or =2500 g, and apparently healthy) were included in the study. Blood samples were collected from the newborns no later than the fifth day of life for measurements of adiponectin and major IGF system components (IGF-I, IGF-II, IGF binding protein-3 (IGFBP-3)). The data were analyzed using simple and multiple regression analyses.

    RESULTS: Adiponectin is substantially higher in neonates than in adults, with no evidence of the gender dimorphism observed among adults. We found an inverse association between neonatal adiponectin levels and newborn ponderal index and a positive association with newborn length by univariate analysis. We also found a statistically significant inverse association of adiponectin with jaundice/bilirubin, and a marginally significant positive association of this hormone with IGFBP-3 but no significant association with any maternal factors. In multivariate analysis, the inverse association between serum adiponectin and ponderal index does not remain significant after adjustment for potential confounding factors. In contrast, neonatal adiponectin levels correlate inversely significantly and independently with liver maturity and IGF-II and tend to remain positively associated with IGFBP-3 and increased birth length.

    CONCLUSIONS: An inverse association of adiponectin with ponderal index by univariate analysis is not independent from confounding factors. In contrast, the positive association between serum adiponectin and birth length may reflect either a direct effect of adiponectin or an adiponectin-mediated increase in the sensitivity of tissues to insulin and components of the IGF system, and needs to be explored further.

  • 46.
    Marsell, Richard
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Grundberg, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Krajisnik, Tijana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Karlsson, Magnus
    Clinical and Molecular Osteoporosis Research Unit, Departments of Clinical Sciences and Orthopaedics, Malmö University Hospital, Lund University, 20502, Malmö, Sweden.
    Mellström, Dan
    Orwoll, Eric
    Ohlsson, Claes
    Jonsson, Kenneth B.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Larsson, Tobias E.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Fibroblast growth factor-23 is associated with parathyroid hormone and renal function in a population-based cohort of elderly men2008In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 158, no 1, p. 125-129Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Fibroblast growth factor-23 (FGF23) is a circulating factor involved in phosphate (Pi) and vitamin D metabolism. Serum FGF23 is increased at later stages of chronic kidney disease due to chronic hyperphosphatemia and decreased renal clearance. Recent studies also indicate that FGF23 may directly regulate the expression of parathyroid hormone (PTH) in vitro. Therefore, the objective of the current study was to determine the relationship between FGF23, PTH, and other biochemistries in vivo in subjects with no history of renal disease.

    DESIGN: Serum biochemistries were measured in a subsample of the population-based Swedish part of the MrOS study. In total, 1000 Caucasian men aged 70-80 years were randomly selected from the population.

    METHODS: Intact FGF23, Pi, calcium, albumin, estimated glomerular filtration rate (eGFR, calculated from cystatin C), PTH, and 25(OH)D3 were measured. Association studies were performed using linear univariate and multivariate regression analyses.

    RESULTS: The median FGF23 level was 36.6 pg/ml, ranging from 0.63 to 957 pg/ml. There was a significant correlation between log FGF23 and eGFR (r=-0.21; P<0.00001) and log PTH (r=0.13; P<0.001). These variables remained as independent predictors of FGF23 in multivariate analysis. In addition, log PTH (beta=0.082; P<0.05) and eGFR (beta=-0.090; P<0.05) were associated with log FGF23 in subjects with eGFR>60 ml/min. Only eGFR (beta=-0.35; P<0.0001) remained as a predictor of log FGF23 in subjects with eGFR<60 ml/min.

    CONCLUSIONS: Serum FGF23 and PTH are associated in vivo, supporting recent findings that FGF23 directly regulates PTH expression in vitro. Additionally, eGFR is associated with FGF23 in subjects with normal or mildly impaired renal function, indicating that GFR may modulate FGF23 levels independent of serum Pi.

  • 47. Moock, Joern
    et al.
    Albrecht, Christin
    Friedrich, Nele
    Volzke, Henry
    Nauck, Matthias
    Koltowska-Häggström, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Kohlmann, Thomas
    Wallaschofski, Henri
    Health-related quality of life and IGF-1 in GH-deficient adult patients on GH replacement therapy: analysis of the German KIMS data and the Study of Health in Pomerania2009In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 160, no 1, p. 17-24Article in journal (Refereed)
    Abstract [en]

    Objective: To analyse 12-month response to GH treatment in a single-country cohort of hypopituitary adult patients with GH deficiency (GHD) in regards to health-related quality of life (HRQoL) and insulin-like growth factor-1 (IGF-1) compared with values from general population sample. Moreover, association between the response in HRQoL and the IGF-1 values in patients and in the background population was investigated. Design: HRQoL was assessed by quality of life assessment of GH deficiency in adults (QoL-AGHDA) in 651 patients retrieved from the German KIMS (Pfizer International Metabolic Database) before and after 12 months of GH replacement and in a sample drawn from a cross-sectional study in Germany (n=2734). IGF-1 was measured in KIMS patients and in the population-based study with the same assay technique. Results: in KIMS patients, mean QoL-AGHDA scores before GH replacement were 9.2 +/- 6.8 (8.7 +/- 6.8) in women (men) and in the general population sample 4.5 +/- 5.3 (4.3 +/- 5.0) in women (men). Mean differences in QoL-AGHDA scores were statistically significant for all age categories (P<0.05). The mean IGF-1 SDS of KIMS patients before GH replacement was -1.1 +/- 1.4 (-0.8 +/- 1.4) in women (men). After GH replacement, a significant increase of IGF-1 concentration and a significant decrease of QoL-AGHDA scores near to age- and gender-specific population-based values were observed. Conclusions: This Study confirms an improvement in HRQoL and an increase of IGF-1 SDS in GH-replaced adults, which approximated the values of general population. However, there was no association between IGF-1 values and HRQoL assessment as one of the important treatment outcomes.

  • 48. Nelson, A E
    et al.
    Mason, R S
    Robinson, B G
    Hogan, J J
    Martin, E A
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Åström, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Radiology, Oncology and Radiation Science, Radiology.
    Larsson, T
    Jonsson, K
    Wibell, L
    Ljunggren, O
    Diagnosis of a patient with oncogenic osteomalacia using a phosphate uptake bioassay of serum and magnetic resonance imaging2001In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 145, no 4, p. 469-476Article in journal (Refereed)
    Abstract [en]

    A previously healthy man with no family history of fractures presented with muscle pain, back pain and height loss. Investigations revealed hypophosphataemia, phosphaturia, undetectable serum 1,25-dihydroxyvitamin D and severe osteomalacia on bone biopsy, suggestive of a diagnosis of oncogenic osteomalacia. Thorough physical examination did not locate a tumour. Support for the diagnosis was obtained by detection of phosphate uptake inhibitory activity in a blinded sample of the patient's serum using a renal cell bioassay. On the basis of detection of this bioactivity, a total body magnetic resonance (MR) examination was performed. A small tumour was located in the right leg. Removal of the tumour resulted in the rapid reversal of symptoms and the abnormal biochemistry typical of oncogenic osteomalacia. Inhibitory activity was also demonstrated using the bioassay in serum from two other patients with confirmed or presumptive oncogenic osteomalacia, but not in serum from two patients with hypophosphataemia of other origin. This is the first case to be reported in which the diagnosis of oncogenic osteomalacia was assisted by demonstration of inhibitory activity of the patient's serum in a renal cell phosphate bioassay that provided an impetus for total body MR imaging.

  • 49. Nilsson, A. G.
    et al.
    Marelli, C.
    Fitts, D.
    Bergthorsdottir, R.
    Burman, P.
    Dahlqvist, P.
    Ekman, B.
    Engstrom, B. Eden
    Olsson, T.
    Ragnarsson, O.
    Ryberg, M.
    Wahlberg, J.
    Lennernäs, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Skrtic, S.
    Johannsson, G.
    Prospective evaluation of long-term safety of dual-release hydrocortisone replacement administered once daily in patients with adrenal insufficiency2014In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 171, no 3, p. 369-377Article in journal (Refereed)
    Abstract [en]

    Objective: The objective was to assess the long-term safety profile of dual-release hydrocortisone (DR-HC) in patients with adrenal insufficiency (AI). Design: Randomised, open-label, crossover trial of DR-HC or thrice-daily hydrocortisone for 3 months each (stage 1) followed by two consecutive, prospective, open-label studies of DR-HC for 6 months (stage 2) and 18 months (stage 3) at five university clinics in Sweden. Methods: Sixty-four adults with primary AI started stage 1, and an additional 16 entered stage 3. Patients received DR-HC 20-40 mg once daily and hydrocortisone 20-40 mg divided into three daily doses (stage 1 only). Main outcome measures were adverse events (AEs) and intercurrent illness (self-reported hydrocortisone use during illness). Results: In stage 1, patients had a median 1.5 (range, 1-9) intercurrent illness events with DR-HC and 1.0 (1-8) with thrice-daily hydrocortisone. AEs during stage 1 were not related to the cortisol exposure-time profile. The percentage of patients with one or more AEs during stage 1 (73.4% with DR-HC; 65.6% with thrice-daily hydrocortisone) decreased during stage 2, when all patients received DR-HC (51% in the first 3 months; 54% in the second 3 months). In stages 1-3 combined, 19 patients experienced 27 serious AEs, equating to 18.6 serious AEs/100 patient-years of DR-HC exposure. Conclusions: This long-term prospective trial is the first to document the safety of DR-HC in patients with primary AI and demonstrates that such treatment is well tolerated during 24 consecutive months of therapy. European Journal of Endocrinology

  • 50.
    Nilsson, Anna G.
    et al.
    Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Endocrinol, Gothenburg, Sweden;Univ Gothenburg, Inst Med, Sahlgrenska Acad, Gothenburg, Sweden.
    Bergthorsdottir, Ragnhildur
    Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Endocrinol, Gothenburg, Sweden;Univ Gothenburg, Inst Med, Sahlgrenska Acad, Gothenburg, Sweden.
    Burman, Pia
    Lund Univ, Skane Univ Hosp Malmo, Dept Endocrinol, Lund, Sweden.
    Dahlqvist, Per
    Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden.
    Ekman, Bertil
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden;Linkoping Univ, Dept Endocrinol, Linkoping, Sweden.
    Engström, Britt E
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrinology and mineral metabolism.
    Ragnarsson, Oskar
    Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Endocrinol, Gothenburg, Sweden;Univ Gothenburg, Inst Med, Sahlgrenska Acad, Gothenburg, Sweden.
    Skrtic, Stanko
    Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Endocrinol, Gothenburg, Sweden;AstraZeneca R&D, Molndal, Sweden;Univ Gothenburg, Inst Med, Sahlgrenska Acad, Gothenburg, Sweden.
    Wahlberg, Jeanette
    Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden;Linkoping Univ, Dept Endocrinol, Linkoping, Sweden.
    Achenbach, Heinrich
    Shire Int GmbH, Zug, Switzerland.
    Uddin, Sharif
    Shire, Lexington, MA USA.
    Marelli, Claudio
    Shire Int GmbH, Zug, Switzerland.
    Johannsson, Gudmundur
    Univ Gothenburg, Sahlgrenska Univ Hosp, Dept Endocrinol, Gothenburg, Sweden;Univ Gothenburg, Inst Med, Sahlgrenska Acad, Gothenburg, Sweden.
    Long-term safety of once-daily, dual-release hydrocortisone in patients with adrenal insufficiency: a phase 3b, open-label, extension study2017In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 176, no 6, p. 715-725Article in journal (Refereed)
    Abstract [en]

    Objective: To investigate the long-term safety and tolerability of a once-daily, dual-release hydrocortisone (DR-HC) tablet as oral glucocorticoid replacement therapy in patients with primary adrenal insufficiency (AI). Design: Prospective, open-label, multicenter, 5-year extension study of DR-HC conducted at five university clinics in Sweden. Methods: Seventy-one adult patients diagnosed with primary AI who were receiving stable glucocorticoid replacement therapy were recruited. Safety and tolerability outcomes included adverse events (AEs), intercurrent illness episodes, laboratory parameters and vital signs. Quality of life (QoL) was evaluated using generic questionnaires. Results: Total DR-HC exposure was 328 patient-treatment years. Seventy patients reported 1060 AEs (323 per 100 patient-years); 85% were considered unrelated to DR-HC by the investigator. The most common AEs were nasopharyngitis (70%), fatigue (52%) and gastroenteritis (48%). Of 65 serious AEs reported by 32 patients (20 per 100 patient-years), four were considered to be possibly related to DR-HC: acute AI (n = 2), gastritis (n = 1) and syncope (n = 1). Two deaths were reported (fall from height and subarachnoid hemorrhage), both considered to be unrelated to DR-HC. From baseline to 5 years, intercurrent illness episodes remained relatively stable (mean 2.6-5.4 episodes per patient per year), fasting plasma glucose (0.7 mmol/L; P < 0.0001) and HDL cholesterol (0.2 mmol/L; P < 0.0001) increased and patient-/investigator-assessed tolerability improved. QoL total scores were unchanged but worsening physical functioning was recorded (P = 0.008). Conclusions: In the first prospective study evaluating the long-term safety of glucocorticoid replacement therapy in patients with primary AI, DR-HC was well tolerated with no safety concerns observed during 5-year treatment.

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