KBP-042

Sprague Dawley (male, 6 weeks old at study start, fed 60% fat kcal high-fat diet for 10 weeks to induce obesity and prediabetic status)^[1]

0.625-10 μg/kg (8-week treatment); 5 μg/kg (hyperinsulinemic-euglycemic clamp)

s.c.; daily; 56 days (8-week treatment); 21 days (hyperinsulinemic-euglycemic clamp)

Induced a dose-dependent, sustained weight loss up to 20% compared to high-fat diet vehicle; caused significant weight reduction at 2.5, 5, and 10 μg/kg vs. vehicle. Reduced epididymal and perirenal adipose tissue weights significantly at 10 μg/kg; reduced perirenal adipose tissue also at 2.5 and 5 μg/kg. Reduced hepatic triacylglycerol accumulation significantly at 2.5 μg/kg and 10 μg/kg. Increased plasma adiponectin significantly at 1.25, 2.5, 5, and 10 μg/kg; reduced plasma leptin significantly at 10 μg/kg. Showed impaired glucose tolerance (increased total area under the curve) at 10 μg/kg in acute OGTT, but reduced glucose total area under the curve at 2.5, 5, and 10 μg/kg vs. vehicle after 3 weeks of chronic treatment; improved glucose tolerance at 5 and 10 μg/kg after 7 weeks. Reduced insulin total area under the curve at 1.25-10 μg/kg after 3 weeks of IVGTT and at 2.5 and 5 μg/kg after 7 weeks while maintaining glucose tolerance. Increased glucose infusion rate by 82% vs. high-fat diet vehicle (and 27% vs. normal diet controls) during hyperinsulinemic-euglycemic clamp at 5 μg/kg.