An adiponectin-like molecule with antidiabetic properties.
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 microg/kg x 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-3beta, and AMP-activated kinase. Second, HFD mice were chronically treated with sc rgAd110-244 injections (10, 30, and 100 microg/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.
Sulpice
Thierry
T
Physiogenex, Prologue Biotech, 31682 Labège Innopole cedex, France. t.sulpice@physiogenex.com
Prunet-Marcassus
Bénédicte
B
Molveaux
Cécile
C
Cani
Patrice D
PD
Vitte
Pierre-Alain
PA
Graber
Pierre
P
Dreano
Michel
M
Burcelin
Rémy
R
D052242:Adiponectin / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D001835:Body Weight / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000209:etiology; D004041:Dietary Fats / Q000009:adverse effects; D004837:Epinephrine; D005215:Fasting / Q000378:metabolism; D006943:Hyperglycemia / Q000139:chemically induced / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation; D011994:Recombinant Proteins / Q000302:isolation & purification / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction
D052242:Adiponectin; D001786:Blood Glucose; D004041:Dietary Fats; D007004:Hypoglycemic Agents; D007328:Insulin; D010446:Peptide Fragments; D011994:Recombinant Proteins; C544418:adiponectin (110-244), human; D004837:Epinephrine