title: Pioglitazone increases whole body insulin sensitivity in obese, insulin-resistant rhesus monkeys.
abstract: Hyperinsulinemic-euglycemic clamps are considered the "gold standard" for assessing whole body insulin sensitivity. When used in combination with tracer dilution techniques and physiological insulin concentrations, insulin sensitization can be dissected and attributed to hepatic and peripheral (primarily muscle) effects. Non-human primates (NHPs), such as rhesus monkeys, are the closest pre-clinical species to humans, and thus serve as an ideal model for testing of compound efficacy to support translation to human efficacy. We determined insulin infusion rates that resulted in high physiological insulin concentrations that elicited maximal pharmacodynamic responses during hyperinsulinemic-euglycemic clamps. These rates were then used with [U-13C]-D-glucose, to assess and document the degrees of hepatic and peripheral insulin resistance between healthy and insulin-resistant, dysmetabolic NHPs. Next, dysmetabolic NHPs were treated for 28 days with pioglitazone (3 mg/kg) and again had their insulin sensitivity assessed, illustrating a significant improvement in hepatic and peripheral insulin sensitivity. This coincided with a significant increase in insulin clearance, and normalization of circulating adiponectin. In conclusion, we have determined a physiological clamp paradigm (similar to humans) for assessing glucose turnover in NHPs. We have also demonstrated that insulin-resistant, dysmetabolic NHPs respond to the established insulin sensitizer, pioglitazone, thus confirming their use as an ideal pre-clinical translational model to assess insulin sensitizing compounds.
authors.affiliation: Department of Diabetes, Merck Research Laboratories, Kenilworth, New Jersey, United States of America.
authors.forename: Effie
authors.initials: E
authors.lastname: Tozzo
authors.affiliation: Department of Molecular Biomarkers, Merck Research Laboratories, Kenilworth, New Jersey, United States of America.
authors.forename: Gowri
authors.initials: G
authors.lastname: Bhat
authors.affiliation: Department of Biometrics Research, Merck Research Laboratories, West Point, Pennsylvania, United States of America.
authors.forename: Kyeongmi
authors.initials: K
authors.lastname: Cheon
authors.affiliation: Department of Diabetes, Merck Research Laboratories, Kenilworth, New Jersey, United States of America.
authors.forename: Raul C
authors.initials: RC
authors.lastname: Camacho
mesh_terms: D000818:Animals; D005260:Female; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000494:pharmacology / Q000627:therapeutic use*; D007333:Insulin Resistance; D008253:Macaca mulatta; D008297:Male; D009765:Obesity / Q000188:drug therapy*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D045162:Thiazolidinediones; D000077205:Pioglitazone