Beta-cell "rest" accompanies reduced first-pass hepatic insulin extraction in the insulin-resistant, fat-fed canine model.
During insulin resistance, glucose homeostasis is maintained by an increase in plasma insulin via increased secretion and/or decreased first-pass hepatic insulin extraction. However, the relative importance of insulin secretion vs. clearance to compensate for insulin resistance in obesity has yet to be determined. This study utilizes the fat-fed dog model to examine longitudinal changes in insulin secretion and first-pass hepatic insulin extraction during development of obesity and insulin resistance. Six dogs were fed an isocaloric diet with an approximately 8% increase in fat calories for 12 wk and evaluated at weeks 0, 6, and 12 for changes in 1) insulin sensitivity by euglycemic-hyperinsulinemic clamp, 2) first-pass hepatic insulin extraction by direct assessment, and 3) glucose-stimulated insulin secretory response by hyperglycemic clamp. We found that 12 wk of a fat diet increased subcutaneous and visceral fat as assessed by MR imaging. Consistent with increased body fat, the dogs exhibited a approximately 30% decrease in insulin sensitivity and fasting hyperinsulinemia. Although insulin secretion was substantially increased at week 6, beta-cell sensitivity returned to prediet levels by week 12. However, peripheral hyperinsulinemia was maintained because of a significant decrease in first-pass hepatic insulin extraction, thus maintaining hyperinsulinemia, despite changes in insulin release. Our results indicate that when obesity and insulin resistance are induced by an isocaloric, increased-fat diet, an initial increase in insulin secretion by the beta-cells is followed by a decrease in first-pass hepatic insulin extraction. This may provide a secondary physiological mechanism to preserve pancreatic beta-cell function during insulin resistance.
Kim
Stella P
SP
Department of Physiology and Biophysics, Keck School of Medicine of USC, 1333 San Pablo St. MMR 626, Los Angeles, CA 90033, USA.
Ellmerer
Martin
M
Kirkman
Erlinda L
EL
Bergman
Richard N
RN
D000273:Adipose Tissue / Q000473:pathology; D000818:Animals; D001823:Body Composition; D004041:Dietary Fats / Q000008:administration & dosage*; D004285:Dogs; D005215:Fasting / Q000097:blood; D015309:Glucose Clamp Technique; D006946:Hyperinsulinism / Q000209:etiology; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D009765:Obesity / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology*
D004041:Dietary Fats; D007328:Insulin