Effects of obesity and ovarian steroids on insulin secretion and removal in sheep

The interactive effects of sex steroids and obesity on glucose metabolism and pancreatic secretion and organ removal of insulin were determined in multicatheterized lean and obese sheep by multiplying venoarterial concentration differences by plasma flows. Ovariectomized lean and dietary obese ewes received implants of progesterone and estradiol-17 beta that produced plasma concentrations of each equivalent to those during either anestrus (low progesterone), diestrus or pregnancy (high progesterone), or estrus (high estradiol). Sheep were exposed to each of the three steroid treatments for 2 days and fasted overnight before blood samples were collected for 5 h before (basal) and 90 min after injecting glucose (200 mg/kg) to simulate an intravenous glucose tolerance test (IVGTT). Regardless of steroid treatment, pancreatic secretory (18 vs. 5 mU/min) and hepatic (10 vs. 2 mU/min) and hindquarters (1.8 vs. 0.5 mU/min) removal rates of insulin in the basal state were greater (P less than 0.005) in obese than lean sheep. Obese sheep had greater (P less than 0.025) basal hepatic glucose output (66 vs. 47 mg/min) and similar hindquarters glucose removal (37 vs. 32 mg/min) as lean sheep even though arterial concentrations of insulin were fourfold higher (25 vs. 6 microU/ml; P less than 0.01) in the obese sheep. High progesterone increased (P less than 0.05) basal hepatic insulin removal in obese sheep. High progesterone and high estradiol increased insulin but decreased (P less than 0.05) glucose removal in hindquarters of obese sheep in the basal state. High progesterone potentiated significantly glucose-induced hyperinsulinemia in obese sheep, whereas high estradiol suppressed hepatic insulin removal but increased the removal of insulin by hindquarters during glucose stimulation in the obese sheep. We concluded that excessive insulin secretion, not decreased insulin removal, maintains the basal hyperinsulinemia in moderately obese sheep and that the progesterone-to-estradiol ratio has marked and divergent effects on insulin and glucose metabolism in individual tissues of sheep both in the basal state and during an IVGTT.