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An Adiponectin-Like Molecule with Antidiabetic Properties

Physiogenex S.A.S. (T.S., B.P.-M., C.M.), 31682 Labège Innopole, France; Institut National de la Santé et de la Recherche Médicale (P.D.C., R.B.), Unité 858, Institute of Molecular Medicine Rangueil, 31432 Toulouse, France; and Merck Serono S.A.-Genève (P.-A.V., P.G., M.D.), 1202 Geneva, Switzerland

Address all correspondence and requests for reprints to: Dr. Thierry Sulpice, Physiogenex, Prologue Biotech, Rue Pierre et Marie Curie-BP 28 262, 31682 Labège Innopole cedex, France. E-mail: t.sulpice{at}physiogenex.com.

Adiponectin increases glucose transport, reduces inflammation, and controls vascular functions. Hence, we propose that treatment with a recombinant globular domain of adiponectin (rgAd110-244) has significant therapeutic potential to treat insulin resistance. Mice were fed for 3 months on a high-fat diet (HFD) to induce insulin resistance, diabetes, and moderate weight gain. The mice were first infused iv with different doses of rgAd110-244 (0.12, 0.4, and 1.2 µg/kg · min) for 5 h. Basal and insulin-sensitive glucose use rates were assessed by the use of a submaximal rate of insulin in the awake free-moving mouse. rgAd110-244 reduced, with dose dependence, epinephrine-induced hyperglycemia and HFD-induced insulin resistance by increasing whole-body glucose use (35% at the highest dose) and glycolysis rates. Similarly, the reduction of plasma free fatty acid concentrations by insulin was dramatically improved. Basal hepatic glucose production was unchanged by rgAd110-244 infusion. This acute rgAd110-244 treatment improved glucose homeostasis and was associated with an increased content of muscle phospho-Akt, glycogen synthase kinase-3β, and AMP-activated kinase. Second, HFD mice were chronically treated with sc rgAd110-244 injections (10, 30, and 100 µg/kg). Fasting glycemia and insulin-sensitive glucose use were improved by rgAd110-244 at the highest dose at completion of the treatment, with concomitant reduction in body weight gain. We here show for the first time that a recombinant adiponectin fragment (110-244 amino acids called rgAd110-244) is able to treat insulin-resistant diabetes. Our results strongly suggest further pharmacological investigation of rgAd110-244 with the objective of developing a new treatment of insulin-resistant diabetes.