6-LB: GPR119 Agonist PRM A Increases Glucagon Response to Hypoglycemia in Rats

Abstract

Glucagon (Gcg) is crucial in the counter-regulatory response (CRR) to hypoglycemia yet this is severely impaired in T1D. This pathophysiology was recognized 50 years ago, but only recently have drug targets emerged to amplify Gcg CRR in T1D. One promising target is the receptor GPR119, expressed in gut endocrine cells and pancreatic islets with highest expression on α-cells, 10-fold greater than on β-cells. In the current study, a GPR119 agonist (PRM A) was given by oral gavage at doses of 3, 10 and 30 mg per kg (mpk), to rats (Sprague-Dawley, groups of 8) two hours prior to induction of hypoglycemia by an insulin tolerance test (ITT), using a dose of 1.25 Units per kg, given by intra-peritoneal injection at t=0 min. A vehicle-treated (V) control and a positive comparator group, given the GPR119 agonist MBX-2982 (10 mpk) were also studied. MBX-2982 is currently being used in a clinical trial to assess its effect on Gcg CRR in volunteers with T1D challenged with a hypoglycemic clamp. In rats in the current study, severe hypoglycemia was induced during the ITT; blood glucose nadir was achieved by 60 min in association with peak insulin ≥ 100 µU/ml. Glucose and insulin were similar across groups. The healthy V rats mounted a normal Gcg CRR, with a peak value of 26±10 pM, 5-fold above baseline. Pre-treatment with PRM A significantly amplified Gcg CRR relative to V (to 86±17, 79±18, and 85±12 pM; at 3, 10, and 30 mpk; p<0.0001 vs V). The Gcg AUC during the ITT was nearly 50% greater with all doses of PRM A (p<0.05 vs V) and the peak Gcg CRR was shifted earlier (p<0.01 vs V). MBX-2982 pre-treated rats, relative to V, trended to a higher peak (49±14 vs 26±10 pM) and AUC Gcg (7292±2039 vs 6855±1306 pM*h), but neither difference was significant, whereas the differences for PRM A were strongly significant for time and treatment. In summary, PRM A, a potent GPR119 agonist, tripled peak Gcg CRR during an ITT in healthy rats, affirming that the target of GPR119 holds promise as a novel means to mitigate the dangerous risk of hypoglycemia for individuals with T1D. Disclosure D. W. K. Kwok: None. D. Alexander: None. N. R. A. Beeley: None. D. Kelley: Consultant; Pramana Pharmaceuticals, Inc, Kallyope. Funding Pramana Pharmaceuticals Inc.