Circulating Concentrations of the Adipocyte Protein Adiponectin Are Decreased in Parallel With Reduced Insulin Sensitivity During the Progression to Type 2 Diabetes in Rhesus Monkeys
- Kikuko Hotta1,
- Tohru Funahashi1,
- Noni L. Bodkin2,
- Heidi K. Ortmeyer2,
- Yukio Arita1,
- Barbara C. Hansen2 and
- Yuji Matsuzawa1
- 1Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
- 2Obesity and Diabetes Research Center, Department of Physiology, University of Maryland, Baltimore, Maryland
Adiponectin is an adipose-specific plasma protein whose plasma concentrations are decreased in obese subjects and type 2 diabetic patients. This protein possesses putative antiatherogenic and anti-inflammatory properties. In the current study, we have analyzed the relationship between adiponectin and insulin resistance in rhesus monkeys (Macaca mulatta), which spontaneously develop obesity and which subsequently frequently progress to overt type 2 diabetes. The plasma levels of adiponectin were decreased in obese and diabetic monkeys as in humans. Prospective longitudinal studies revealed that the plasma levels of adiponectin declined at an early phase of obesity and remained decreased after the development of type 2 diabetes. Hyperinsulinemic-euglycemic clamp studies revealed that the obese monkeys with lower plasma adiponectin showed significantly lower insulin-stimulated peripheral glucose uptake (M rate). The plasma levels of adiponectin were significantly correlated to M rate (r = 0.66, P < 0.001). Longitudinally, the plasma adiponectin decreased in parallel to the progression of insulin resistance. No clear association was found between the plasma levels of adiponectin and its mRNA levels in adipose tissue. These results suggest that reduction in circulating adiponectin may be related to the development of insulin resistance.
Address correspondence and reprint requests to Kikuko Hotta, MD, Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871 Japan. E-mail:.
Received for publication 28 September 2000 and accepted in revised form 5 February 2001.
AIR, acute insulin response; ELISA, enzyme-linked immunosorbent assay; FFM, fat-free mass; HSP83, heat shock protein 83; KG, glucose disappearance rate; M rate, insulin-stimulated glucose uptake rate; PAI-1, plasminogen activator inhibitor-1; PCR, polymerase chain reaction; RT, reverse transcriptase; TNF-α, tumor necrosis factor-α.