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Open access

Esben Thyssen Vestergaard, Morten B Krag, Morten M Poulsen, Steen B Pedersen, Niels Moller, Jens Otto Lunde Jorgensen, and Niels Jessen

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.

Open access

Peter L Kristensen, Ulrik Pedersen-Bjergaard, Rikke Due-Andersen, Thomas Høi-Hansen, Lise Grimmeshave, Valeriya Lyssenko, Leif Groop, Jens J Holst, Allan A Vaag, and Birger Thorsteinsson

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.

Open access

Marie Reeberg Sass, Nicolai Jacob Wewer Albrechtsen, Jens Pedersen, Kristine Juul Hare, Nis Borbye-Lorenzen, Katalin Kiss, Tina Vilsbøll, Filip Krag Knop, Steen Seier Poulsen, Niklas Rye Jørgensen, Jens Juul Holst, Cathrine Ørskov, and Bolette Hartmann

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.

Open access

Jes Sloth Mathiesen, Jens Peter Kroustrup, Peter Vestergaard, Per Løgstrup Poulsen, Åse Krogh Rasmussen, Ulla Feldt-Rasmussen, Sten Schytte, Stefano Christian Londero, Henrik Baymler Pedersen, Christoffer Holst Hahn, Jens Bentzen, Sören Möller, Mette Gaustadnes, Maria Rossing, Finn Cilius Nielsen, Kim Brixen, Christian Godballe, and Danish Thyroid Cancer Group (DATHYRCA)

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.

Open access

Jes Sloth Mathiesen, Jens Peter Kroustrup, Peter Vestergaard, Kirstine Stochholm, Per Løgstrup Poulsen, Åse Krogh Rasmussen, Ulla Feldt-Rasmussen, Sten Schytte, Stefano Christian Londero, Henrik Baymler Pedersen, Christoffer Holst Hahn, Bjarki Ditlev Djurhuus, Jens Bentzen, Sören Möller, Mette Gaustadnes, Maria Rossing, Finn Cilius Nielsen, Kim Brixen, Anja Lisbeth Frederiksen, Christian Godballe, and the Danish Thyroid Cancer Group (DATHYRCA)

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.

Open access

Charlotte Janus, Dorte Vistisen, Hanan Amadid, Daniel R Witte, Torsten Lauritzen, Søren Brage, Anne-Louise Bjerregaard, Torben Hansen, Jens J Holst, Marit E Jørgensen, Oluf Pedersen, Kristine Færch, and Signe S Torekov

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.

Open access

Kim K B Clemmensen, Jonas S Quist, Dorte Vistisen, Daniel R Witte, Anna Jonsson, Oluf Pedersen, Torben Hansen, Jens J Holst, Torsten Lauritzen, Marit E Jørgensen, Signe Torekov, and Kristine Færch

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.