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.
Highlights
The hyperinsulinemic-euglycemic clamp paradigm [1] is the gold standard for assessing insulin sensitivity
We have determined an insulin infusion rate that results in high physiological insulin concentrations (~120 μU/mL) in dysmetabolic monkeys
A pharmacodynamics response (GIR) was observed, which is ~50% less than that of healthy monkeys, providing a substantial window for improvement with a pharmaceutical intervention. This 50% decrement in the pharmacodynamic response to insulin in dysmetabolic versus healthy monkeys was further dissected into quantitative differences in hepatic (EGP) and peripheral (Rd) insulin sensitivity using stable isotopes
Summary
The hyperinsulinemic-euglycemic clamp paradigm [1] is the gold standard for assessing insulin sensitivity. The clamp paradigm (once using isotopes [3]) has been employed in rhesus macaques, insulin infusion rates and concentrations (400 mU/m2 min, ~5000 μU/mL) to assure maximal insulin-stimulated Rd and complete suppression of EGP are routinely used [4,5,6,7,8,9] Using such pharmacological doses of insulin may mask any differentiation of hepatic, and/or perhaps, peripheral insulin sensitivity as well as considerably reduce the therapeutic improvement window for an insulin sensitizing compound. An appropriate high physiological insulin infusion rate and concentration (similar to those used in human studies) that would elicit appropriate corresponding pharmacodynamic (i.e. glucose infusion rates, GIR) responses was determined With this insulin infusion rate, the differences in hepatic and peripheral insulin sensitivity between healthy and dysmetabolic (obese and insulin resistant) rhesus monkeys, were documented using stable isotopes, for the first time to our knowledge. The hypothesis that a short duration of treatment (28 days) of dysmetabolic monkeys with pioglitazone would increase insulin sensitivity and glucose metabolism (and to what extent) was tested
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call