During insulin resistance, glucose homeostasis is maintained by increasing plasma insulin via increased secretion and/or decreased first-pass hepatic insulin extraction. However, the relative importance of insulin secretion versus 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 both insulin secretion and first-pass hepatic insulin extraction during development of obesity and insulin resistance. Six dogs were fed an isocaloric diet with ~8% increase in fat calories for 12 weeks and evaluated for changes in: 1) insulin sensitivity (SI) by euglycemic-hyperinsulinemic clamp, 2) first-pass hepatic insulin extraction by direct assessment and 3) glucose-stimulated insulin secretory response by hyperglycemic clamp at weeks 0, 6 and 12 of fat-feeding. We found that 12 weeks of a fat diet increased both subcutaneous and visceral fat as assessed by magnetic resonance imaging. Consistent with increased body fat, the dogs exhibited a ~30% decrease in SI and fasting hyperinsulinemia. Although insulin secretion was substantially increased at week 6, -cell sensitivity returned to pre-diet levels by week 12. However, peripheral hyperinsulinemia was maintained due to 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 is induced by an isocaloric, increased fat diet, an initial increase in insulin secretion by the -cells is followed by a decrease in first-pass hepatic insulin extraction. This may provide a secondary physiological mechanism to preserve pancreatic -cell function during insulin resistance.