A Randomized-Controlled, Double-Masked Cross-Over 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 pre-clinical models. We hypothesized that MBX-2982, a GPR119 agonist, would augment counterregulatory responses to experimental hypoglycemia in participants with type 1 diabetes. To assess this, we designed a phase 2a double-masked, cross-over trial in 18 participants (20–60 years) with type 1 diabetes. Participants were randomized to treatment with 600 mg MBX-2982 or placebo daily for 14 days with a two-week washout between treatments. Counterregulatory responses to hypoglycemia during a hyperinsulinemic-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 vs placebo treatment. MBX-2982 did not alter epinephrine, norepinephrine, pancreatic polypeptide, free fatty acid, or endogenous glucose production responses to hypoglycemia compared to placebo. However, glucagon-like peptide-1 (GLP-1) response during the MMT was 17% higher with MBX-2982 compared to placebo treatment. In conclusion, GPR119 activation with MBX-2982 did not improve counterregulatory responses to hypoglycemia in people with type 1 diabetes. Increases in GLP-1 during the MMT are consistent with GPR119 target engagement and the expected pharmacodynamic response from L-cells.