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Small-Molecule Insulin Mimetic Reduces Hyperglycemia and Obesity in a Nongenetic Mouse Model of Type 2 Diabetes

Medizinische Klinik mit Schwerpunkt Hepatologie, Gastroenterologie, Endokrinologie, und Stoffwechsel (M.Z.S., S.J.), Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Departments of Metabolic Disorders-Diabetes (M.Z.S., Z.L., D.S., D.E.M., B.B.Z.), Comparative Medicine (X.S.), and Obesity Research (X.-M.G.), Merck Research Laboratories, Rahway, New Jersey 07065

Address all correspondence and requests for reprints to: Mathias Z. Strowski, M.D., Medizinische Klinik mit Schwerpunkt Hepatologie, Gastroenterologie, Endokrinologie, und Stoffwechsel Charité-Universitätsmedizin Berlin, Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany. E-mail: mathias.strowski{at}charite.de.

Adiposity positively correlates with insulin resistance and is a major risk factor of type 2 diabetes. Administration of exogenous insulin, which acts as an anabolic factor, facilitates adipogenesis. Recently nonpeptidal insulin receptor (IR) activators have been discovered. Here we evaluate the effects of the orally bioavailable small-molecule IR activator (Compound-2) on metabolic abnormalities associated with type 2 diabetes using a nongenetic mouse model in comparison with the effects of a novel non-thiazolidinedione (nTZD) peroxisome proliferator-activated receptor- agonist. Both Compound-2 and nTZD alleviated fasting and postprandial hyperglycemia; accelerated glucose clearance rate; and normalized plasma levels of nonesterified fatty acids, triglycerides, and leptin. Unlike nTZD, which increased body weight gain, and total fat mass, which is a common feature for PPAR agonists, Compound-2 prevented body weight gain and hypertrophy of brown, and white adipose tissue depots and the development of hepatic steatosis in the mouse model of type 2 diabetes. The effect of the two compounds on proximal steps in insulin signal transduction pathway was analyzed in tissues. Compound-2 enhanced insulin-stimulated phosphorylation of IR tyrosine and/or Akt in the liver, skeletal muscle, and white adipose tissue, whereas nTZD potentiated the phosphorylation of IR and Akt in the adipose tissue only. In conclusion, small-molecule IR activators have unique features as insulin sensitizers and hold potential utility in the treatment of type 2 diabetes and obesity.

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