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1 Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA
2 Diabetes Research & Training Center, Vanderbilt University School of Medicine, Nashville, TN, USA
3 Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA; Diabetes Research & Training Center, Vanderbilt University School of Medicine, Nashville, TN, USA
* To whom correspondence should be addressed. E-mail: genie.moore{at}vanderbilt.edu.
We evaluated the effect of chronic (3 wk) subcutaneous treatment with progesterone and estradiol (PE; producing serum levels observed in the 3rd trimester of pregnancy) or placebo (C) on hepatic and whole body insulin sensitivity and response to hypoglycemia in conscious, overnight-fasted nonpregnant female dogs, using tracer and arteriovenous difference techniques. Insulin was infused peripherally for 3h at 1.8 mU.kg-1.min-1. Glucose was allowed to fall to 3 mM (Hypo) or maintained at 6 mM (Eugly) by peripheral glucose infusion. Insulin concentrations were significantly higher in Eugly-PE (n=7) and Hypo-PE (n=7) than in Eugly-C (n=6) and Hypo-C (n=7) (432±21, 384±19, 332±22, and 344±34 pmol/l, respectively), but there were no significant differences in hepatic insulin extraction. The concentrations of glucagon, cortisol, epinephrine, and norepinephrine did not differ significantly between the Eugly groups or between the Hypo groups. Whole body glucose disposal, adjusted for the differences in insulin between groups, was 35% higher in Eugly-C vs Eugly-PE (P<0.05). Eugly-C and Eugly-PE exhibited similar rates of net hepatic glucose uptake, but glucose Ra was greater in Eugly-PE in the last h (P<0.05). Net hepatic glucose output was greater (P<0.05) in Hypo-PE than in Hypo-C (14.5±1.1 vs 6.3±1.6 µmol.kg-1.min-1), and the glucose infusion rate required to maintain equivalent hypoglycemia was less (3.6±1.4 vs 7.1±1.6 µmol.kg-1.min-1, P<0.05). The rate of gluconeogenic flux did not differ between Hypo groups. Chronic progesterone and estradiol exposure caused whole body (primarily skeletal muscle) insulin resistance and enhanced the liver's response to hypoglycemia without altering counterregulatory hormone concentrations.
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