Maintenance of Glucose Tolerance in Diet‐Induced Insulin Resistant Dogs

Normal glucose tolerance is maintained by a complex interrelationship between insulin secretion (AIRg) and insulin sensitivity (S I ). Previously, we have hypothesized that under normal conditions the product of S I and AIRg (called Disposition Index (DI)) is constant. In this study we examined longitudinally the mechanism by which DI is maintained during the development of obesity induced insulin resistance. Male mongrel dogs (n=9) were fed a hypercaloric high fat diet (~5400kcal/d, 53% kcal from fat) for 6 weeks. The Frequently Sampled Intravenous Glucose Tolerance (FSIGT) test was utilized to assess changes in glucose homeostasis at weeks 0 (pre‐diet), 2, 4 and 6 (W:0; W:2; W:4; W:6, respectively). Body weight was significantly increased by W:2 (+2.5+/−0.33 kg, P<.001) and remained elevated throughout the entire study. There were no changes in the basal glucose, insulin concentration, or glucose tolerance (K G ) over the six week period of fat feeding. Within two weeks of fat feeding, S I dramatically decreased by 45% (5.6+/−0.9 vs. 3.1+/−1.2; W:0 vs. W:2 P=.04). At W:6, S I decreased by 66% (1.9+/−1.3, P=.006). AIRg rose modestly by W:2 (14%, P=NS), increasing by 46% (P<0.02) and 59% (P<0.01) at W:4 and W:6, respectively. Insulin clearance did not change, suggesting that the increase in AIRg was solely due to enhanced ß‐cell function, i.e., insulin secretion and not decreased clearance. Interestingly, even in the face of extreme insulin resistance, DI was unchanged. Thus, 6 weeks of high fat feeding in the canine model exhibits total compensation of the ensuing resistance, thereby maintaining glucose tolerance.