A Randomized Controlled, Double-Masked, Crossover Study of a GPR119 Agonist on Glucagon Counterregulation During Hypoglycemia in Type 1 Diabetes

Abstract

Activation of GPR119 receptors, expressed on enteroendocrine and pancreatic islet cells, augments glucagon counterregulatory responses to hypoglycemia in preclinical models. We hypothesized that MBX-2982, a GPR119 agonist, would augment counterregulatory responses to experimental hypoglycemia in participants with type 1 diabetes (T1D). To assess this, we designed a phase 2a, double-masked, crossover trial in 18 participants (age 20-60 years) with T1D. Participants were randomized to treatment with 600 mg MBX-2982 or placebo daily for 14 days, with a 2-week washout between treatments. Counterregulatory responses to hypoglycemia during a hyperinsulinemic euglycemic-hypoglycemic clamp and hormonal responses during a mixed-meal test (MMT) were measured. The maximum glucagon response, glucagon area under the curve (AUC), and incremental AUC were not significantly different during MBX-2982 versus placebo treatment. MBX-2982 did not alter epinephrine, norepinephrine, pancreatic polypeptide, free fatty acid, or endogenous glucose production responses to hypoglycemia compared with placebo. However, glucagon-like peptide 1 (GLP-1) response during the MMT was 17% higher with MBX-2982 compared with placebo treatment. In conclusion, GPR119 activation with MBX-2982 did not improve counterregulatory responses to hypoglycemia in people with T1D. Increases in GLP-1 during the MMT are consistent with GPR119 target engagement and the expected pharmacodynamic response from L cells.

Article highlights: Hypoglycemia is the limiting factor for optimal glycemic control in people with type 1 diabetes (T1D). Activation of α-cell GPR119 receptors increases glucagon counterregulatory responses to hypoglycemia in preclinical studies. We assessed the effect of MBX-2982, a GPR119 agonist, on glucagon counterregulatory responses to experimental hypoglycemia in participants with T1D. Activation of GPR119 with MBX-2982 did not improve glucagon counterregulatory responses to hypoglycemia in participants with T1D, though increases in fasting glucagon-like peptide 1 and responses during a mixed-meal test demonstrated appropriate target engagement. GPR119 agonists are unlikely to be effective agents to mitigate hypoglycemia risk in people with T1D.