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Download fileGIP and GLP-1 Potentiate Sulfonylurea-Induced Insulin Secretion in Hepatocyte Nuclear Factor 1-Alpha Mutation Carriers
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posted on 09.06.2020, 19:42 by Ada AdminAda Admin, Alexander S. Christensen, Sofie Hædersdal, Heidi Storgaard, Kathrine Rose, Nina L. Hansen, Jens J. Holst, Torben Hansen, Filip K. Knop, Tina VilsbøllSulfonylureas
(SUs) provide an efficacious first-line treatment in patients with hepatocyte
nuclear factor 1-alpha (HNF1A)-diabetes, but SUs have limitations due to risk
of hypoglycemia. Treatment based on the incretin hormones, glucose-dependent
insulinotropic peptide (GIP) and glucagon-like-peptide 1 (GLP-1), are characterized
by their glucose-dependent insulinotropic actions without risk of hypoglycemia.
The effect of SUs together with GIP or
GLP-1, respectively, on insulin and glucagon secretion in patients with
HNF1A-diabetes is currently unknown. To investigate this, ten HNF1A mutation carriers and ten
non-diabetic controls were recruited for a double-blinded, placebo-controlled,
crossover study including six experimental days in a randomized order involving
2h euglycemic-hyperglycemic clamps with co-administration of 1) SU (glimepiride
1 mg) or placebo, combined with 2) infusions of either GIP (1.5 pmol/kg/min),
GLP-1 (0.5 pmol/kg/min) or saline (NaCl). In HNF1A mutation carriers we observed: 1)
hypoinsulinemia, 2) insulinotropic effects of both GIP and GLP-1, 3) additive to supra-additive effects on insulin secretion
when combining SU+GIP and SU+GLP1, respectively, and 4) increased fasting and
arginine-induced glucagon levels compared to non-diabetic controls. Our study suggests
that a combination of SU and incretin-based treatment may be efficacious in patients
with HNF1A-diabetes via potentiation of glucose-stimulated insulin secretion.