GIP and GLP-1 Potentiate Sulfonylurea-Induced Insulin Secretion in Hepatocyte Nuclear Factor 1α Mutation Carriers

Abstract

Sulfonylureas (SUs) provide an efficacious first-line treatment in patients with hepatocyte nuclear factor 1a (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) is 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, 10 HNF1A mutation carriers and 10 control subjects without diabetes were recruited for a double-blinded, placebo-controlled, crossover study including 6 experimental days in a randomized order involving 2-h euglycemic-hyperglycemic clamps with coadministration of: 1) SU (glimepiride 1 mg) or placebo, combined with 2) infusions of 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 SU1GIP and SU1GLP-1, respectively, and 4) increased fasting and arginine-induced glucagon levels compared with control subjects without diabetes. 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.

Maturity Onset Diabetes of the Young—New Approaches for Disease Modelling

“…For example, in patients with GCK-MODY, due to a higher basal glucose level the glucose-lowering therapies are ineffective, therefore the treatment of these patients is not recommended [ 88 ]. On the other hand, patients with HNF1A- or HNF4A-MODY are responsive to low-dose sulfonylureas, due to the increased pancreatic insulin secretion [ 126 , 137 , 138 , 139 ].…”

“…Recently, the usage of incretin hormone glucose-dependent insulinotropic peptide (GIP) and GLP-1 were tested in patients with HNF1A-MODY. These therapeutics were used together with sulfonylurea, and the results suggest that such combinations could be beneficial for HNF1A-MODY patients due to the increase of the glucose-stimulated insulin secretion [ 139 ].…”

Efficacy and Safety of Glimepiride With or Without Linagliptin Treatment in Patients With HNF1A Diabetes (Maturity-Onset Diabetes of the Young Type 3): A Randomized, Double-Blinded, Placebo-Controlled, Crossover Trial (GLIMLINA)

“…The rationale for investigating DPP-4 inhibition in the current study originates from clinical experience with the inhibitors in patients with HNF1A diabetes and their well-known mode of action on the b-cells (32,33). Furthermore, our group has previously shown that patients with HNF1A diabetes have an impaired incretin effect (34) and that sulfonylurea-induced insulin secretion can be potentiated by addition of exogenous GIP and GLP-1 infusions, respectively (24). In line with these observations, we here demonstrate an improved b-cell sensitivity to glucose (as evaluated from the increase in AUC for C-peptide-to-glucose ratio during the combined meal and bicycle test) with glimepiride 1 linagliptin compared with glimepiride 1 placebo.…”

“…However, positive GIP-mediated effects may occur during prolonged DPP-4 inhibitor therapy (23). Recent work from our group has shown additive-to-supraadditive insulinotropic effects of GIP and GLP-1 in patients with HNF1A diabetes treated with sulfonylureas (24). In this study, we evaluated the combination of the sulfonylurea glimepiride and the DPP-4 inhibitor linagliptin versus glimepiride monotherapy with respect to glycemic variability and control (glycated hemoglobin [HbA 1c ]) and risk of hypoglycemia in patients with HNF1A diabetes.…”

HNF1A Mutations and Beta Cell Dysfunction in Diabetes

“…Monotherapy with glucagon-like peptide-1 receptor agonists (GLP-1 RA) [ 153 , 155 ] or dipeptidyl peptidase-4 (DPP4) inhibitors [ 156 , 157 ] may prevent hypoglycemia and achieve good glycemic control in patients with MODY3. Moreover, combination therapy with GLP-1 RA and SU may increase insulin secretion in patients with MODY3 [ 158 ], and combination therapy with DPP4 inhibitors and SU may improve glycemic control without significantly increasing hypoglycemia in patients with MODY3 [ 154 ].…”