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

Alexander S Christensen, Sofie Hædersdal, Heidi Storgaard, Kathrine Rose, Nina L Hansen, Jens J Holst, Torben Hansen, Filip K Knop, Tina Vilsbøll, Alexander S Christensen, Sofie Hædersdal, Heidi Storgaard, Kathrine Rose, Nina L Hansen, Jens J Holst, Torben Hansen, Filip K Knop, Tina Vilsbøll

Abstract

Sulfonylureas (SUs) provide an efficacious first-line treatment in patients with hepatocyte nuclear factor 1α (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 SU+GIP and SU+GLP-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.

Trial registration: ClinicalTrials.gov NCT03081676.

© 2020 by the American Diabetes Association.

Figures

Figure 1
Figure 1
GIP, GLP-1, plasma glucose, and glucose infused. Plasma GIP (A and B), GLP-1 (C and D), and glucose (E and F) vs. time during the 2-h two-step glucose clamp in 10 HNF1A mutation carriers and 10 control subjects without diabetes. Accumulated glucose infused at time 60 min and 120 min (G and H) (subtracted bolus given at time 60 min) in HNF1A mutation carriers (G) and control subjects without diabetes (H). Data are presented as mean ± SD (A–F) and mean ± SEM (G and H). Continuous infusions of saline (NaCl), GIP, or GLP-1 were started at time 0 min preceded by either single-dose SU 1 mg glimepiride or placebo (PLA) at time −90 min. Symbols show significant differences (P < 0.05) between interventions: *significantly greater than PLA+NaCl; †significantly greater than SU+NaCl; ‡significantly greater than PLA+GIP; §significantly greater than PLA+GLP-1. FPG, fasting plasma glucose.
Figure 2
Figure 2
C-peptide and C-peptide/glucose. Serum C-peptide (A and B) and C-peptide/glucose (E and F) vs. time during the 2-h two-step glucose clamp in 10 HNF1A mutation carriers and 10 control subjects without diabetes. Corresponding bsAUC0–60 min and bsAUC60–120 min are presented in C, D, G, and H. Continuous infusions of saline (NaCl), GIP, or GLP-1 were started at time 0 min preceded by either single-dose SU 1 mg glimepiride or placebo (PLA) at time −90 min. Data from time 120 min to 125 min is magnified in insets in A, B, E, and F. Data are presented as mean ± SEM. Symbols show significant differences (P < 0.05) between interventions: *significantly greater than PLA+NaCl; †significantly greater than SU+NaCl; ‡significantly greater than PLA+GIP; §significantly greater than PLA+GLP-1; ‖significantly greater than SU+GIP.
Figure 3
Figure 3
Insulin and glucagon. Serum insulin (A and B) and plasma glucagon (E and F) vs. time in 10 HNF1A mutation carriers and 10 control subjects without diabetes. Corresponding bsAUC0–60 min and bsAUC60–120 min are presented in C, D, G, and H. Continuous infusions of saline (NaCl), GIP, or GLP-1 were started at time 0 min preceded by either a single-dose SU 1 mg glimepiride or placebo (PLA) at time −90 min. Data from time 120 min to 125 min is magnified in insets in A, B, E, and F. Data are presented as mean ± SEM. Symbols show significant differences (P < 0.05) between interventions: *significantly greater than PLA+NaCl; †significantly greater than SU+NaCl; ‡significantly greater than PLA+GIP; §significantly greater than PLA+GLP-1.
Figure 4
Figure 4
Interaction between SU and the incretin hormones. bsAUC0–120 min for C-peptide and C-peptide/glucose for 10 HNF1A mutation carriers and 10 control subjects without diabetes during the 2-h two-step glucose clamp. Continuous infusions of saline (NaCl), GIP, or GLP-1 were started at time 0 min preceded by either single-dose SU 1 mg glimepiride or placebo (PLA) at time −90 min. Data are shown as mean percentage ± SEM. A: The reference value (100%) is the sum of bsAUC0–120 min, SU+NaCl + bsAUC0–120 min, PLA+GIP, which on the graphs is shown as SU+GIP (additive). SU+GIP (observed) is the observed bsAUC0–120 min, SU+GIP during our study. If SU+GIP (observed) is greater than SU+GIP (additive), this is indicative of an interaction and thus a supra-additive effect. B: The calculations are identical for A, but with GLP-1 instead of GIP.

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