Phenotyping of adipose, liver, and skeletal muscle insulin resistance and response to pioglitazone in spontaneously obese rhesus monkeys

Am J Physiol Endocrinol Metab. 2017 Apr 1;312(4):E235-E243. doi: 10.1152/ajpendo.00398.2016. Epub 2017 Jan 31.


Insulin resistance and diabetes can develop spontaneously with obesity and aging in rhesus monkeys, highly similar to the natural history of obesity, insulin resistance, and progression to type 2 diabetes in humans. The current studies in obese rhesus were undertaken to assess hepatic and adipose contributions to systemic insulin resistance-currently, a gap in our knowledge-and to benchmark the responses to pioglitazone (PIO). A two-step hyperinsulinemic-euglycemic clamp, with tracer-based glucose flux estimates, was used to measure insulin resistance, and in an intervention study was repeated following 6 wk of PIO treatment (3 mg/kg). Compared with lean healthy rhesus, obese rhesus has a 60% reduction of glucose utilization during a high insulin infusion and markedly impaired suppression of lipolysis, which was evident at both low and high insulin infusion. However, obese dysmetabolic rhesus manifests only mild hepatic insulin resistance. Six-week PIO treatment significantly improved skeletal muscle and adipose insulin resistance (by ~50%). These studies strengthen the concept that insulin resistance in obese rhesus closely resembles human insulin resistance and indicate the value of obese rhesus for appraising new insulin-sensitizing therapeutics.

Keywords: hyperinsulinemic-euglycemic clamp; insulin resistance; rhesus monkey.

MeSH terms

  • Adipose Tissue / drug effects
  • Adipose Tissue / metabolism*
  • Animals
  • Blood Glucose / metabolism
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / metabolism
  • Glucose Clamp Technique
  • Hypoglycemic Agents / pharmacology*
  • Hypoglycemic Agents / therapeutic use
  • Insulin Resistance / physiology*
  • Lipolysis / physiology
  • Liver / drug effects
  • Liver / metabolism*
  • Macaca mulatta
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism*
  • Obesity / drug therapy
  • Obesity / metabolism*
  • Pioglitazone
  • Thiazolidinediones / pharmacology*
  • Thiazolidinediones / therapeutic use


  • Blood Glucose
  • Hypoglycemic Agents
  • Thiazolidinediones
  • Pioglitazone