Effects of obesity on insulin sensitivity and responsiveness in sheep

To assess the mechanisms of insulin resistance in the ruminant, severe and adult-onset obesity was produced in Dorset ewes by overfeeding a high-energy ration over a 1- to 2-yr period. Body weights increased to 100 kg compared with 50 kg in lean control sheep; significant hyperinsulinemia (40 +/- 4 vs 10 +/- 1 microU/ml) also developed as did a moderate hyperglycemia (62 +/- 2 vs. 52 +/- 1 mg/100 ml). Tissue sensitivity and responsiveness to insulin were then determined in both obese and lean sheep by the euglycemic glucose-clamp technique. Insulin was infused at eight different rates from 0.2 to 50 mU.kg-1.min-1 and [6-3H]-glucose was infused for measurement of glucose kinetics. The mean dose-response curves for glucose utilization and clearance rates were displaced to the right in obese compared with lean sheep. As a result, the half-maximally effective insulin concentrations usually were elevated two- to fourfold, indicating decreased insulin sensitivity in obese sheep, and this is consistent with decr...