MA-[D-Leu-4)-OB3, a Small Molecule Synthetic Peptide Leptin Mimetic, Improves Serum Lipid Profiles in Mouse Models of Type 1 and Type 2 Diabetes Mellitus

Diabetic dyslipidemia, a common pattern of lipid abnormalities associated with diabetes, is characterized by hyperglycemia, elevated serum levels of triglycerides and low-density lipoprotein (LDL)-cholesterol, and reduced serum levels of high-density lipoprotein (HDL)-cholesterol. These lipid abnormalities make diabetes an independent risk-factor for the development of cardiovascular disease. Two mouse models of diabetes were used in the present study: 1) streptozotocin (STZ)-induced insulin-deficient male Swiss Webster mice (a model of T1DM), and 2) male diet-induced obese (DIO) mice rendered insulin-resistant by maintenance on a high-fat diet for 30 weeks (a model of T2DM). Both models were then treated with MA-[D-Leu-4]-OB3 by oral gavage for 14 or 17 days. At the end of the test period, the mice were exsanguinated by cardiac puncture; serum was prepared from the whole blood and analyzed by ELISA for total-, HDL-, LDL/VLDL-cholesterol, and triglyceride content. In mouse models of both T1DM and T2DM, MA-[D-Leu-4]-OB3 significantly (P < 0.05) reduced serum levels of triglycerides and LDL/VLDL-cholesterol, and elevated serum HDL-cholesterol to levels approaching or equivalent to those seen in normal non-diabetic mice of the same age and sex. Our results suggest that in addition to its effects on energy balance, glycemic control, and cognitive function, MA-[D-Leu-4]-OB3, by modulating serum lipid levels, may also be beneficial in reducing the risk of adverse cardiovascular events associated with both T1DM and T2DM.