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.

Fig 1. Insulin infusion rate dose-finding and reproducibility studies.

Time courses of (A) plasma glucose, (B) glucose infusion rate, and (C) plasma insulin concentrations during two hour (one hour per insulin infusion rate) hyperinsulinemic-euglycemic clamps. (D) Reproducibility of glucose infusion rate requirements during two separate hyperinsulinemic-euglycemic clamps (both at 20 mU/m² min) separated by two weeks. Values are means ± SEM.

Fig 2. Insulin sensitivity measures of healthy, dysmetabolic, and dysmetabolic monkeys treated with pioglitazone for 28 days.

(A) Basal plasma C-peptide/insulin ratio. (B) Time course of insulin, (C) period insulin, and time courses of (D) plasma glucose and (E) glucose infusion rates during hyperinsulinemic-euglycemic clamps. Values are means ± SEM. *p<0.05 versus healthy; #p<0.05 versus dysmetabolic-baseline

Fig 3. Glucose turnover data in healthy, dysmetabolic, and dysmetabolic monkeys treated with pioglitazone for 28 days.

(A) Steady-state glucose fluxes normalized for steady-state insulin concentrations, (B) percent suppression of EGP, and (C) insulin clearance during hyperinsulinemic-euglycemic clamps. (D) Fasting adiponectin concentrations. Values are means ± SEM. *p<0.05 versus healthy; #p<0.05 versus dysmetabolic-baseline