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Signe Harring Østoft, Jonatan Ising Bagger, Torben Hansen, Bolette Hartmann, Oluf Pedersen, Jens Juul Holst, Filip Krag Knop, and Tina Vilsbøll

Objective

The role of the incretin hormones in the pathophysiology of maturity onset diabetes of the young (MODY) is unclear.

Design

We studied the postprandial plasma responses of glucagon, incretin hormones (glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP)) and dipeptidyl-peptidase 4 (DPP4) enzymatic activity in patients with glucokinase (GCK) diabetes (MODY2) and hepatocyte nuclear factor 1α (HNF1A) diabetes (MODY3) as well as in matched healthy individuals (CTRLs).

Subjects and methods

Ten patients with MODY2 (mean age±s.e.m. 43±5 years; BMI 24±2 kg/m2; fasting plasma glucose (FPG) 7.1±0.3 mmol/l: HbA1c 6.6±0.2%), ten patients with MODY3 (age 31±3 years; BMI 24±1 kg/m2; FPG 8.9±0.8 mmol/l; HbA1c 7.0±0.3%) and ten CTRLs (age 40±5 years; BMI 24±1 kg/m2; FPG 5.1±0.1 mmol/l; HbA1c 5.3±0.1%) were examined with a liquid test meal.

Results

All of the groups exhibited similar baseline values of glucagon (MODY2: 7±1 pmol/l; MODY3: 6±1 pmol/l; CTRLs: 8±2 pmol/l, P=0.787), but patients with MODY3 exhibited postprandial hyperglucagonaemia (area under the curve (AUC) 838±108 min×pmol/l) as compared to CTRLs (182±176 min×pmol/l, P=0.005) and tended to have a greater response than did patients with MODY2 (410±154 min×pmol/l, P=0.063). Similar peak concentrations and AUCs for plasma GIP and plasma GLP1 were observed across the groups. Increased fasting DPP4 activity was seen in patients with MODY3 (17.7±1.2 mU/ml) vs CTRLs (13.6±0.8 mU/ml, P=0.011), but the amount of activity was similar to that in patients with MODY2 (15.0±0.7 mU/ml, P=0.133).

Conclusion

The pathophysiology of MODY3 includes exaggerated postprandial glucagon responses and increased fasting DPP4 enzymatic activity but normal postprandial incretin responses both in patients with MODY2 and in patients with MODY3.

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Mia Demant, Malte Palm Suppli, Signe Foghsgaard, Lise Gether, Magnus Frederik Gluud Grøndahl, Niels Bjørn Dalsgaard, Sigrid S Bergmann, Amalie Rasmussen Lanng, Lærke S Gasbjerg, Martin Thomasen, Jonatan Ising Bagger, Charlotte Strandberg, Merete Juhl Kønig, Henning Grønbæk, Ulrik Becker, Jens J Holst, Joachim Knop, Matthew Paul Gillum, Tina Vilsbøll, and Filip K. Knop

Aims/hypothesis. Metabolic effects of intermittent unhealthy lifestyle in young adults are poorly studied. We investigated the gluco-metabolic and hepatic effects of participation in Roskilde Festival (one week of binge drinking and junk food consumption) in young, healthy males.

Methods. Fourteen festival participants (FP) were studied before, during and after one week’s participation in Roskilde Festival. Fourteen matched controls (CTRL) who did not participate in Roskilde Festival or change their lifestyle in other ways were investigated along a similar timeline.

Results. The FP group consumed more alcohol compared to their standard living conditions (2.0±3.9 vs 16.3±8.3 units/day, p<0.001). CTRLs did not change their alcohol consumption. AUC for glucose during OGTT did not change in either group. C-peptide responses increased in the FP group (320±31 vs 376±25 nmol/l×min, p=0.055) and the Matsuda index of insulin sensitivity decreased (6.2±2.4 vs 4.7±1.4, p = 0.054). AUC for glucagon during OGTT increased in the FP group (1,115±114 vs 1,599±183 pmol/l×min, p=0.003) together with fasting fibroblast growth factor 21 (FGF21) (62±30 vs 132±72 pmol/L, p<0.001), growth differentiation factor 15 (GDF5) (276±78 vs 330±83 pg/mL, p=0.009) and aspartate aminotransferase (AST) levels (37.6±6.8 vs 42.4±11 U/l, p=0.043). Four participants (29%) developed ultrasound-detectable steatosis and mean strain elastography-assessed liver stiffness increased (p=0.026) in the FP group.

Conclusions/interpretation. Participation in Roskilde Festival did not affect oral glucose tolerance, but was associated with a reduction in insulin sensitivity, increases in glucagon, FGF21, GDF15 and AST and lead to increased liver stiffness and, in 29% of the participants, ultrasound-detectable hepatic steatosis.