Physiological and Molecular Determinants of Insulin Action in the Baboon
- Alberto O. Chavez1,
- Juan C. Lopez-Alvarenga2,3,
- M. Elizabeth Tejero2,
- Curtis Triplitt1,
- Raul A. Bastarrachea2,3,
- Apiradee Sriwijitkamol1,
- Puntip Tantiwong1,
- V. Saroja Voruganti2,
- Nicolas Musi1,
- Anthony G. Comuzzie2,3,
- Ralph A. DeFronzo1 and
- Franco Folli1,2
- 1Diabetes Division, University of Texas Health Science Center at San Antonio, San Antonio, Texas
- 2Genetics Department, Southwest Foundation for Biomedical Research, San Antonio, Texas
- 3Southwest National Primate Research Center, San Antonio, Texas
- Address correspondence and reprint requests to Franco Folli, MD, PhD, Diabetes Division, Department of Medicine, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229. E-mail:
OBJECTIVE—To quantitate insulin sensitivity in lean and obese nondiabetic baboons and examine the underlying cellular/molecular mechanisms responsible for impaired insulin action to characterize a baboon model of insulin resistance.
RESEARCH DESIGN AND METHODS—Twenty baboons received a hyperinsulinemic-euglycemic clamp with skeletal muscle and visceral adipose tissue biopsies at baseline and at 30 and 120 min after insulin. Genes and protein expression of key molecules involved in the insulin signaling cascade (insulin receptor, insulin receptor substrate-1, p85, phosphatidylinositol 3-kinase, Akt, and AS160) were sequenced, and insulin-mediated changes were analyzed.
RESULTS—Overall, baboons show a wide range of insulin sensitivity (6.2 ± 4.8 mg · kg−1 · min−1), and there is a strong inverse correlation between indexes of adiposity and insulin sensitivity (r = −0.946, P < 0.001 for % body fat; r = −0.72, P < 0.001 for waist circumference). The genes and protein sequences analyzed were found to have ∼98% identity to those of man. Insulin-mediated changes in key signaling molecules were impaired both in muscle and adipose tissue in obese insulin-resistant compared with lean insulin-sensitive baboons.
CONCLUSIONS—The obese baboon is a pertinent nonhuman primate model to examine the underlying cellular/molecular mechanisms responsible for insulin resistance and eventual development of type 2 diabetes.
- FFA, free fatty acid
- FFM, fat-free mass
- FPG, fasting plasma glucose
- FPI, fasting plasma insulin
- HOMA-β, homeostasis model assessment of β-cell function
- HOMA-IR, homeostasis model assessment of insulin resistance
- IRS, insulin receptor substrate
- PI 3-kinase, phosphatidylinositol 3-kinase
- Rd, glucose disposal rate
- Received June 8, 2007.
- Accepted December 23, 2007.