IMG-1 Lowers Insulin Resistance by Decreasing Hepatic Glucose Production in a DIO Mouse Clamp Test

IMG-1 is a novel therapeutic compound for the treatment of diabetes. IMG-1 has been shown to successfully treat both type 1 mice and rats (STZ models) and type 2 ZDF rats. To test how IMG-1 is able to treat type II diabetes, diet-Induced Obese (DIO) C57BL/6J mice were used in a hyperinsulinemic-euglycemic clamp assay. The hyperinsulinemic-euglycemic clamp is the gold-standard method to assess insulin sensitivity. The euglycemic clamp is widely used in clinics and laboratories to measure insulin action on glucose utilization in humans and animals for clinical and basic science research. Sixteen DIO C57BL/6J mice underwent a 2-hour hyperinsulinemic-euglycemic clamping to assess insulin action and glucose metabolism in IMG-1 treated (2µg IMG-1 administered IV via tail vein 48 and 24hours prior to the clamp test, n=8) or PBS treated animals (n=8). IMG-1 treated animals had significantly higher steady-state glucose infusion rates during clamping than PBS treated animals, indicating that IMG-1 is able to decrease insulin resistance in DIO mice. IMG-1 did not affect whole-body glucose turnover, glycolysis or glycogen synthesis in any of the treated animals. Glucose metabolism in skeletal muscle and adipose tissue was not significantly different in either IMG-1 or PBS treated animals during the clamp assay. However, Hepatic Glucose Production (HGP) was dramatically suppressed in all animals treated with IMG-1 (a decrease from 3.mg/kg/m to -6.16 mg/kg/m). Furthermore, hepatic insulin action (the percent suppression of HGP) was increased in all IMG-1 treated animals
during the hyperinsulinemic-euglycemic clamp (from 70.9 control to 99.7 IMG-1). IMG-1 is a novel compound for the treatment of diabetes. These results show that IMG-1 decreases insulin resistance in a type 2 diabetic mouse model by suppressing HGP and increasing hepatic insulin action. Disclosure J.B. Pollett: Employee; Self; Imagine Pharma. H. Noh: None. J.K. Kim: None. N. Thai: Board Member; Self; Imagine Pharma.