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Esben Thyssen Vestergaard Medical Research Laboratories, Department of Endocrinology and Diabetes, Department of Pediatrics, Department of Endocrinology and Diabetes, Institute of Clinical Medicine, Aarhus University, Norrebrogade 44, DK-8000 Aarhus C, Denmark
Medical Research Laboratories, Department of Endocrinology and Diabetes, Department of Pediatrics, Department of Endocrinology and Diabetes, Institute of Clinical Medicine, Aarhus University, Norrebrogade 44, DK-8000 Aarhus C, Denmark
Medical Research Laboratories, Department of Endocrinology and Diabetes, Department of Pediatrics, Department of Endocrinology and Diabetes, Institute of Clinical Medicine, Aarhus University, Norrebrogade 44, DK-8000 Aarhus C, Denmark

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Morten B Krag Medical Research Laboratories, Department of Endocrinology and Diabetes, Department of Pediatrics, Department of Endocrinology and Diabetes, Institute of Clinical Medicine, Aarhus University, Norrebrogade 44, DK-8000 Aarhus C, Denmark

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Morten M Poulsen Medical Research Laboratories, Department of Endocrinology and Diabetes, Department of Pediatrics, Department of Endocrinology and Diabetes, Institute of Clinical Medicine, Aarhus University, Norrebrogade 44, DK-8000 Aarhus C, Denmark

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Steen B Pedersen Medical Research Laboratories, Department of Endocrinology and Diabetes, Department of Pediatrics, Department of Endocrinology and Diabetes, Institute of Clinical Medicine, Aarhus University, Norrebrogade 44, DK-8000 Aarhus C, Denmark

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Niels Moller Medical Research Laboratories, Department of Endocrinology and Diabetes, Department of Pediatrics, Department of Endocrinology and Diabetes, Institute of Clinical Medicine, Aarhus University, Norrebrogade 44, DK-8000 Aarhus C, Denmark
Medical Research Laboratories, Department of Endocrinology and Diabetes, Department of Pediatrics, Department of Endocrinology and Diabetes, Institute of Clinical Medicine, Aarhus University, Norrebrogade 44, DK-8000 Aarhus C, Denmark

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Jens Otto Lunde Jorgensen Medical Research Laboratories, Department of Endocrinology and Diabetes, Department of Pediatrics, Department of Endocrinology and Diabetes, Institute of Clinical Medicine, Aarhus University, Norrebrogade 44, DK-8000 Aarhus C, Denmark
Medical Research Laboratories, Department of Endocrinology and Diabetes, Department of Pediatrics, Department of Endocrinology and Diabetes, Institute of Clinical Medicine, Aarhus University, Norrebrogade 44, DK-8000 Aarhus C, Denmark

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Niels Jessen Medical Research Laboratories, Department of Endocrinology and Diabetes, Department of Pediatrics, Department of Endocrinology and Diabetes, Institute of Clinical Medicine, Aarhus University, Norrebrogade 44, DK-8000 Aarhus C, Denmark
Medical Research Laboratories, Department of Endocrinology and Diabetes, Department of Pediatrics, Department of Endocrinology and Diabetes, Institute of Clinical Medicine, Aarhus University, Norrebrogade 44, DK-8000 Aarhus C, Denmark

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Objective

Supraphysiological levels of ghrelin and GH induce insulin resistance. Serum levels of retinol-binding protein-4 (RBP4) correlate inversely with insulin sensitivity in patients with type 2 diabetes. We aimed to determine whether ghrelin and GH affect RBP4 levels in human subjects.

Materials and methods

To study GH-independent effects of ghrelin, seven hypopituitary men undergoing replacement therapy with GH and hydrocortisone were given ghrelin (5 pmol/kg per min) and saline infusions for 300 min in a randomized, double-blind, placebo-controlled, crossover design. Circulating RBP4 levels were measured at baseline and during a hyperinsulinemic–euglycemic clamp on both study days. To study the direct effects of GH, nine healthy men were treated with GH (2 mg at 2200 h) and placebo for 8 days in a randomized, double-blind, placebo-controlled, crossover study. Serum RBP4 levels were measured before and after treatment, and insulin sensitivity was measured by the hyperinsulinemic–euglycemic clamp technique.

Results

Ghrelin acutely decreased peripheral insulin sensitivity. Serum RBP4 concentrations decreased in response to insulin infusion during the saline experiment (mg/l): 43.2±4.3 (baseline) vs 40.4±4.2 (clamp), P<0.001, but this effect was abrogated during ghrelin infusion (mg/l): 42.4±4.5 (baseline) vs 42.9±4.7 (clamp), P=0.73. In healthy subjects, serum RBP4 levels were not affected by GH administration (mg/l): 41.7±4.1 (GH) vs 43.8±4.6 (saline), P=0.09, although GH induced insulin resistance.

Conclusions

i) Serum RBP4 concentrations decrease in response to hyperinsulinemia, ii) ghrelin abrogates the inhibitory effect of insulin on circulating RBP4 concentrations, and iii) ghrelin as well as GH acutely induces insulin resistance in skeletal muscle without significant changes in circulating RBP4 levels.

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Peter L Kristensen Department of Cardiology, Nephrology and Endocrinology, Nordsjællands Hospital, Hillerød, Denmark

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Ulrik Pedersen-Bjergaard Department of Cardiology, Nephrology and Endocrinology, Nordsjællands Hospital, Hillerød, Denmark
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Rikke Due-Andersen Department of Cardiology, Nephrology and Endocrinology, Nordsjællands Hospital, Hillerød, Denmark
Lægerne på Ellemarksvej, Køge, Denmark

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Thomas Høi-Hansen Department of Cardiology, Nephrology and Endocrinology, Nordsjællands Hospital, Hillerød, Denmark
Department of Cardiology, Herlev-Gentofte University Hospital, Herlev, Denmark

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Lise Grimmeshave Department of Cardiology, Nephrology and Endocrinology, Nordsjællands Hospital, Hillerød, Denmark
Novo Nordisk A/S, Søborg, Denmark

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Valeriya Lyssenko Steno Diabetes Center, Gentofte, Denmark
Lund University Diabetes Centre, Skåne University Hospital, Malmø, Sweden

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Leif Groop Lund University Diabetes Centre, Skåne University Hospital, Malmø, Sweden
Finnish Institute for Molecular Medicine (FIMM), Helsinki University, Helsinki, Finland

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Jens J Holst Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Department of Biomedical Sciences, NNF Center for Basic Metabolic Research, The Panum Institute, Copenhagen, Denmark

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Allan A Vaag Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Department of Endocrinology, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark

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Birger Thorsteinsson Department of Cardiology, Nephrology and Endocrinology, Nordsjællands Hospital, Hillerød, Denmark
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Introduction

In healthy carriers of the T allele of the transcription factor 7-like 2 (TCF7L2), fasting plasma glucagon concentrations are lower compared with those with the C allele. We hypothesised that presence of the T allele is associated with a diminished glucagon response during hypoglycaemia and a higher frequency of severe hypoglycaemia (SH) in type 1 diabetes (T1DM).

Material and methods

This is a post hoc study of an earlier prospective observational study of SH and four mechanistic studies of physiological responses to hypoglycaemia. 269 patients with T1DM were followed in a one-year observational study. A log-linear negative binomial model was applied with events of SH as dependent variable and TCF7L2 alleles as explanatory variable. In four experimental studies including 65 people, TCF7L2 genotyping was done and plasma glucagon concentration during experimental hypoglycaemia was determined.

Results

Incidences of SH were TT 0.54, TC 0.98 and CC 1.01 episodes per patient-year with no significant difference between groups. During experimental hypoglycaemia, the TCF7L2 polymorphism did not influence glucagon secretion.

Discussion

Patients with T1DM carrying the T allele of the TCF7L2 polymorphism do not exhibit diminished glucagon response during hypoglycaemia and are not at increased risk of severe hypoglycaemia compared with carriers of the C allele.

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Katrine M Lauritsen Steno Diabetes Center Aarhus, Aarhus, Denmark
Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
Danish Diabetes Academy, Odense University Hospital, Odense, Denmark

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Jens Hohwü Voigt Steno Diabetes Center Aarhus, Aarhus, Denmark

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Steen Bønløkke Pedersen Steno Diabetes Center Aarhus, Aarhus, Denmark
Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark

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Troels K Hansen Steno Diabetes Center Aarhus, Aarhus, Denmark

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Niels Møller Steno Diabetes Center Aarhus, Aarhus, Denmark
Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark

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Niels Jessen Steno Diabetes Center Aarhus, Aarhus, Denmark
Department of Biomedicine, Aarhus University, Aarhus, Denmark

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Lars C Gormsen Department of Nuclear Medicine and PET Centre, Aarhus University Hospital, Aarhus, Denmark

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Esben Søndergaard Steno Diabetes Center Aarhus, Aarhus, Denmark
Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark
Danish Diabetes Academy, Odense University Hospital, Odense, Denmark

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SGLT2 inhibition induces an insulin-independent reduction in plasma glucose causing increased lipolysis and subsequent lipid oxidation by energy-consuming tissues. However, it is unknown whether SGLT2 inhibition also affects lipid storage in adipose tissue. Therefore, we aimed to determine the effects of SGLT2 inhibition on lipid storage and lipolysis in adipose tissue. We performed a randomized, double-blinded, placebo-controlled crossover design of 4 weeks of empagliflozin 25 mg and placebo once-daily in 13 individuals with type 2 diabetes treated with metformin. Adipose tissue fatty acid uptake, lipolysis rate and clearance were measured by 11C-palmitate PET/CT. Adipose tissue glucose uptake was measured by 18F-FDG PET/CT. Protein and gene expression of pathways involved in lipid storage and lipolysis were measured in biopsies of abdominal s.c. adipose tissue. Subjects were weight stable, which allowed us to quantify the weight loss-independent effects of SGLT2 inhibition. We found that SGLT2 inhibition did not affect free fatty acids (FFA) uptake in abdominal s.c. adipose tissue but increased FFA uptake in visceral adipose tissue by 27% (P  < 0.05). In addition, SGLT2 inhibition reduced GLUT4 protein (P  = 0.03) and mRNA content (P  = 0.01) in abdominal s.c. adipose tissue but without affecting glucose uptake. In addition, SGLT2 inhibition decreased the expression of genes involved in insulin signaling in adipose tissue. We conclude that SGLT2 inhibition reduces GLUT4 gene and protein expression in abdominal s.c. adipose tissue, which could indicate a rebalancing of substrate utilization away from glucose oxidation and lipid storage capacity through reduced glycerol formation.

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Jes Sloth Mathiesen Department of ORL Head & Neck Surgery and Audiology, Odense University Hospital, Odense, Denmark
Department of Clinical Research, University of Southern Denmark, Odense, Denmark

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Jens Peter Kroustrup Department of Clinical Medicine and Endocrinology, Aalborg University Hospital, Aalborg, Denmark

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Peter Vestergaard Department of Clinical Medicine and Endocrinology, Aalborg University Hospital, Aalborg, Denmark
Steno Diabetes Center North Jutland, Aalborg, Denmark

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Per Løgstrup Poulsen Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark

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Åse Krogh Rasmussen Department of Medical Endocrinology, Copenhagen University Hospital, Copenhagen, Denmark

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Ulla Feldt-Rasmussen Department of Medical Endocrinology, Copenhagen University Hospital, Copenhagen, Denmark

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Sten Schytte Department of ORL Head & Neck Surgery, Aarhus University Hospital, Aarhus, Denmark

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Stefano Christian Londero Department of ORL Head & Neck Surgery, Aarhus University Hospital, Aarhus, Denmark

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Henrik Baymler Pedersen Department of ORL Head & Neck Surgery, Aalborg University Hospital, Aalborg, Denmark

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Christoffer Holst Hahn Department of ORL Head & Neck Surgery, Copenhagen University Hospital, Copenhagen, Denmark

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Jens Bentzen Department of Oncology, Herlev Hospital, Herlev, Denmark

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Sören Möller Department of Clinical Research, University of Southern Denmark, Odense, Denmark
Odense Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark

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Mette Gaustadnes Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark

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Maria Rossing Center for Genomic Medicine, Copenhagen University Hospital, Copenhagen, Denmark

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Finn Cilius Nielsen Center for Genomic Medicine, Copenhagen University Hospital, Copenhagen, Denmark

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Kim Brixen Department of Clinical Research, University of Southern Denmark, Odense, Denmark

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Christian Godballe Department of ORL Head & Neck Surgery and Audiology, Odense University Hospital, Odense, Denmark

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Danish Thyroid Cancer Group (DATHYRCA)
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A recent study proposed new TNM groupings for better survival discrimination among stage groups for medullary thyroid carcinoma (MTC) and validated these groupings in a population-based cohort in the United States. However, it is unknown how well the groupings perform in populations outside the United States. Consequently, we conducted the first population-based study aiming to evaluate if the recently proposed TNM groupings provide better survival discrimination than the current American Joint Committee on Cancer (AJCC) TNM staging system (seventh and eighth edition) in a nationwide MTC cohort outside the United States. This retrospective cohort study included 191 patients identified from the nationwide Danish MTC cohort between 1997 and 2014. In multivariate analysis, hazard ratios for overall survival under the current AJCC TNM staging system vs the proposed TNM groupings with stage I as reference were 1.32 (95% CI: 0.38–4.57) vs 3.04 (95% CI: 1.38–6.67) for stage II, 2.06 (95% CI: 0.45–9.39) vs 3.59 (95% CI: 1.61–8.03) for stage III and 5.87 (95% CI: 2.02–17.01) vs 59.26 (20.53–171.02) for stage IV. The newly proposed TNM groupings appear to provide better survival discrimination in the nationwide Danish MTC cohort than the current AJCC TNM staging. Adaption of the proposed TNM groupings by the current AJCC TNM staging system may potentially improve accurateness in survival discrimination. However, before such an adaption further population-based studies securing external validity are needed.

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Marie Reeberg Sass Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Nicolai Jacob Wewer Albrechtsen Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark

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Jens Pedersen Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Department of Endocrinology and Nephrology, Nordsjællands University Hospital, Hillerød, Denmark

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Kristine Juul Hare Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Nis Borbye-Lorenzen Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Center for Neonatal Screening, Department of Congenital Disorders, Statens Serum Institute, Copenhagen, Denmark

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Katalin Kiss Department of Pathology, Rigshospitalet, Copenhagen, Denmark

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Tina Vilsbøll Steno Diabetes Center Copenhagen, Gentofte, Denmark
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark

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Filip Krag Knop Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Steno Diabetes Center Copenhagen, Gentofte, Denmark
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, Hellerup, Denmark

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Steen Seier Poulsen Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Niklas Rye Jørgensen Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Jens Juul Holst Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Cathrine Ørskov Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Bolette Hartmann Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Objective:

Parathyroid hormone (PTH) is a key hormone in regulation of calcium homeostasis and its secretion is regulated by calcium. Secretion of PTH is attenuated during intake of nutrients, but the underlying mechanism(s) are unknown. We hypothesized that insulin acts as an acute regulator of PTH secretion.

Methods:

Intact PTH was measured in plasma from patients with T1D and matched healthy individuals during 4-h oral glucose tolerance tests (OGTT) and isoglycemic i.v. glucose infusions on 2 separate days. In addition, expression of insulin receptors on surgical specimens of parathyroid glands was assessed by immunochemistry (IHC) and quantitative PCR (qPCR).

Results:

The inhibition of PTH secretion was more pronounced in healthy individuals compared to patients with T1D during an OGTT (decrementalAUC0–240min: −5256 ± 3954 min × ng/L and −2408 ± 1435 min × ng/L, P = 0.030). Insulin levels correlated significantly and inversely with PTH levels, also after adjusting for levels of several gut hormones and BMI (P = 0.002). Expression of insulin receptors in human parathyroid glands was detected by both IHC and qPCR.

Conclusion:

Our study suggests that insulin may act as an acute regulator of PTH secretion in humans.

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Jes Sloth Mathiesen Department of ORL Head & Neck Surgery, Odense University Hospital, Odense, Denmark
Department of Clinical Research, University of Southern Denmark, Odense, Denmark

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Jens Peter Kroustrup Department of Clinical Medicine and Endocrinology, Aalborg University Hospital, Aalborg, Denmark

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Peter Vestergaard Department of Clinical Medicine and Endocrinology, Aalborg University Hospital, Aalborg, Denmark

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Kirstine Stochholm Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark
Center for Rare Diseases, Aarhus University Hospital, Aarhus N, Denmark

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Per Løgstrup Poulsen Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmark

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Åse Krogh Rasmussen Department of Medical Endocrinology, Copenhagen University Hospital, Copenhagen, Denmark

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Ulla Feldt-Rasmussen Department of Medical Endocrinology, Copenhagen University Hospital, Copenhagen, Denmark

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Sten Schytte Department of ORL Head & Neck Surgery, Aarhus University Hospital, Aarhus, Denmark

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Stefano Christian Londero Department of ORL Head & Neck Surgery, Aarhus University Hospital, Aarhus, Denmark

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Henrik Baymler Pedersen Department of ORL Head & Neck Surgery, Aalborg University Hospital, Aalborg, Denmark

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Christoffer Holst Hahn Department of ORL Head & Neck Surgery, Copenhagen University Hospital, Copenhagen, Denmark

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Bjarki Ditlev Djurhuus Department of ORL Head & Neck Surgery, Zealand University Hospital, Køge, Denmark

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Jens Bentzen Department of Oncology, Herlev Hospital, Herlev, Denmark

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Sören Möller Department of Clinical Research, University of Southern Denmark, Odense, Denmark
Odense Patient data Explorative Network (OPEN), Odense University Hospital, Odense, Denmark

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Mette Gaustadnes Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark

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Maria Rossing Center for Genomic Medicine, Copenhagen University Hospital, Copenhagen, Denmark

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Finn Cilius Nielsen Center for Genomic Medicine, Copenhagen University Hospital, Copenhagen, Denmark

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Kim Brixen Department of Clinical Research, University of Southern Denmark, Odense, Denmark

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Anja Lisbeth Frederiksen Department of Clinical Research, University of Southern Denmark, Odense, Denmark
Department of Clinical Genetics, Odense University Hospital, Odense, Denmark

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Christian Godballe Department of ORL Head & Neck Surgery, Odense University Hospital, Odense, Denmark

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the Danish Thyroid Cancer Group (DATHYRCA)
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Recent studies have shown a significant increase in the temporal trend of medullary thyroid carcinoma (MTC) incidence. However, it remains unknown to which extent sporadic medullary thyroid carcinoma (SMTC) and hereditary MTC (HMTC) affect the MTC incidence over time. We conducted a nationwide retrospective study using previously described RET and MTC cohorts combined with review of medical records, pedigree comparison and relevant nationwide registries. The study included 474 MTC patients diagnosed in Denmark between 1960 and 2014. In the nationwide period from 1997 to 2014, we recorded a mean age-standardized incidence of all MTC, SMTC and HMTC of 0.19, 0.13 and 0.06 per 100,000 per year, respectively. The average annual percentage change in incidence for all MTC, SMTC and HMTC were 1.0 (P = 0.542), 2.8 (P = 0.125) and −3.1 (P = 0.324), respectively. The corresponding figures for point prevalence at January 1, 2015 were 3.8, 2.5 and 1.3 per 100,000, respectively. The average annual percentage change in prevalence from 1998 to 2015 for all MTC, SMTC and HMTC was 2.8 (P < 0.001), 3.8 (P < 0.001) and 1.5 (P = 0.010), respectively. We found no significant change in the incidence of all MTC, SMTC and HMTC possibly due to our small sample size. However, due to an increasing trend in the incidence of all MTC and opposing trends of SMTC (increasing) and HMTC (decreasing) incidence, it seems plausible that an increase for all MTC seen by others may be driven by the SMTC group rather than the HMTC group.

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Charlotte Janus Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Danish Diabetes Academy, Odense University Hospital, Odense, Denmark

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Dorte Vistisen Steno Diabetes Center Copenhagen, Gentofte, Denmark

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Hanan Amadid Steno Diabetes Center Copenhagen, Gentofte, Denmark
Department of Public Health, Research Unit of Epidemiology, Aarhus University, Aarhus, Denmark

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Daniel R Witte Danish Diabetes Academy, Odense University Hospital, Odense, Denmark
Department of Public Health, Research Unit of Epidemiology, Aarhus University, Aarhus, Denmark
Steno Diabetes Center Aarhus, Aarhus, Denmark

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Torsten Lauritzen Department of Public Health, Research Unit of Epidemiology, Aarhus University, Aarhus, Denmark

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Søren Brage MRC Epidemiology Unit, University of Cambridge, Cambridge, UK

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Anne-Louise Bjerregaard Department of Public Health, Research Unit of Epidemiology, Aarhus University, Aarhus, Denmark

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Torben Hansen Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

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Jens J Holst Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

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Marit E Jørgensen Steno Diabetes Center Copenhagen, Gentofte, Denmark
National Institute of Public Health, University of Southern Denmark, Odense, Denmark

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Oluf Pedersen Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

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Kristine Færch Steno Diabetes Center Copenhagen, Gentofte, Denmark

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Signe S Torekov Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

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Rationale

The hormone glucagon-like peptide-1 (GLP-1) decreases blood glucose and appetite. Greater physical activity (PA) is associated with lower incidence of type 2 diabetes. While acute exercise may increase glucose-induced response of GLP-1, it is unknown how habitual PA affects GLP-1 secretion. We hypothesised that habitual PA associates with greater glucose-induced GLP-1 responses in overweight individuals.

Methods

Cross-sectional analysis of habitual PA levels and GLP-1 concentrations in 1326 individuals (mean (s.d.) age 66 (7) years, BMI 27.1 (4.5) kg/m2) from the ADDITION-PRO cohort. Fasting and oral glucose-stimulated GLP-1 responses were measured using validated radioimmunoassay. PA was measured using 7-day combined accelerometry and heart rate monitoring. From this, energy expenditure (PAEE; kJ/kg/day) and fractions of time spent in activity intensities (h/day) were calculated. Cardiorespiratory fitness (CRF; mL O2/kg/min) was calculated using step tests. Age-, BMI- and insulin sensitivity-adjusted associations between PA and GLP-1, stratified by sex, were evaluated by linear regression analysis.

Results

In 703 men, fasting GLP-1 concentrations were 20% lower (95% CI: −33; −3%, P = 0.02) for every hour of moderate-intensity PA performed. Higher CRF and PAEE were associated with 1–2% lower fasting GLP-1 (P = 0.01). For every hour of moderate-intensity PA, the glucose-stimulated GLP-1 response was 16% greater at peak 30 min (1; 33%, P rAUC0-30 = 0.04) and 20% greater at full response (3; 40%, P rAUC0-120 = 0.02). No associations were found in women who performed PA 22 min/day vs 32 min/day for men.

Conclusion

Moderate-intensity PA is associated with lower fasting and greater glucose-induced GLP-1 responses in overweight men, possibly contributing to improved glucose and appetite regulation with increased habitual PA.

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Kim K B Clemmensen Department of Clinical Epidemiology, Steno Diabetes Center Copenhagen, Gentofte, Denmark

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Jonas S Quist Department of Clinical Epidemiology, Steno Diabetes Center Copenhagen, Gentofte, Denmark

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Dorte Vistisen Department of Clinical Epidemiology, Steno Diabetes Center Copenhagen, Gentofte, Denmark

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Daniel R Witte Department of Public Health, Aarhus University, Aarhus, Denmark
Danish Diabetes Academy, Odense, Denmark

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Anna Jonsson NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

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Oluf Pedersen NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

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Torben Hansen NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

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Jens J Holst NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

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Torsten Lauritzen Section for General Practice, Department of Public Health, Aarhus University, Aarhus, Denmark

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Marit E Jørgensen Department of Clinical Epidemiology, Steno Diabetes Center Copenhagen, Gentofte, Denmark
National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark

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Signe Torekov NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

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Kristine Færch Department of Clinical Epidemiology, Steno Diabetes Center Copenhagen, Gentofte, Denmark

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Kim K B Clemmensen Department of Clinical Epidemiology, Steno Diabetes Center Copenhagen, Gentofte, Denmark

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Jonas S Quist Department of Clinical Epidemiology, Steno Diabetes Center Copenhagen, Gentofte, Denmark

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Dorte Vistisen Department of Clinical Epidemiology, Steno Diabetes Center Copenhagen, Gentofte, Denmark

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Daniel R Witte Department of Public Health, Aarhus University, Aarhus, Denmark
Danish Diabetes Academy, Odense, Denmark

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Anna Jonsson NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

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Oluf Pedersen NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

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Torben Hansen NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

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Jens J Holst NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

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Torsten Lauritzen Section for General Practice, Department of Public Health, Aarhus University, Aarhus, Denmark

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Marit E Jørgensen Department of Clinical Epidemiology, Steno Diabetes Center Copenhagen, Gentofte, Denmark
National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark

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Signe Torekov NNF Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

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Kristine Færch Department of Clinical Epidemiology, Steno Diabetes Center Copenhagen, Gentofte, Denmark

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Fasting duration has been associated with lower fasting blood glucose levels, but higher 2-h post-load levels, and research has indicated an adverse effect of ‘weekend behavior’ on human metabolism. We investigated associations of fasting duration and weekday of examination with glucose, insulin, glucagon and incretin responses to an oral glucose tolerance test (OGTT). This cross-sectional study is based on data from the ADDITION-PRO study, where 2082 individuals attended a health examination including an OGTT. Linear regression analysis was applied to study the associations of overnight fasting duration and day of the week with glucose, insulin, glucagon, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) responses to an OGTT. We found that a 1 h longer fasting duration was associated with 1.7% (95% CI: 0.8,2.5) higher 2-h glucose levels, as well as a 3.0% (95% CI: 1.3,4.7) higher GIP and 2.3% (95% CI: 0.3,4.4) higher GLP-1 response. Fasting insulin levels were 20.6% (95% CI: 11.2,30.7) higher on Mondays compared to the other weekdays, with similar fasting glucose levels (1.7%, 95% CI: 0.0,3.4). In this study, longer overnight fasting duration was associated with a worsening of glucose tolerance and increased incretin response to oral glucose. We found higher fasting insulin levels on Mondays compared to the other days of the week, potentially indicating a worsened glucose regulation after the weekend.

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