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Normal glucose tolerance is maintained by a complex interrelationship between insulin secretion (AIRg) and insulin sensitivity (SI). Previously, we have hypothesized that under normal conditions the product of SI 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 (KG) over the six week period of fat feeding. Within two weeks of fat feeding, SI dramatically decreased by 45% (5.6+/-0.9 vs. 3.1+/-1.2; W:0 vs. W:2 P=.04). At W:6, SI 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 β-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. [ABSTRACT FROM AUTHOR]

Recent studies have implicated the endocannabinoid system in the central regulation of energy homeostasis. Selective antagonism of the cannabinoid (CBI) receptor with rimonabant (RIM) has been shown to suppress appetite and reduce body weight (BW). We sought to examine the effects of RIM on longitudinal changes of food intake (FI) and BW during induction of obesity with a hypercaloric high fat diet (HHFD). Male dogs (n=9) were offered a HHFD (∼5400 kcal/d, 53% kcal fat) for l0 wks and BW and FI measured. Average FI over 10wks HHFD was 81 kcal/kg/d, resulting in an increase in BW from 27.9±1.5 to 29.9±1.7 kg (p<.001). After 10 wks, animals remained on the HHFD and were randomly divided into two groups, placebo (PB, n=4) and RIM (n=5; 1.25 mg/kg/d). Over 16wks of drug treatment, PB group increased BW by 6% (30.8±2.8 vs 32.8±3.5 kg, p=.07); RIM group increased BW by 0.8% (29.1±2.4 vs 29.3±2.2 kg, p=.45). Rate of weight gain was 90% less with RIM despite continuing HHFD (125 vs 12.5 g/wk, p=.03). Average daily FI within each group did not change between 10wks HHFD and 16wks drug treatment (PB: 89 vs 86 kcal/kg/d, p=.32; RIM: 74 vs 77 kcal/kg/d, p=.31) and was not different between groups (p=.22). Maintenance of BW on a HHFD in apparent absence of changes in FI as seen in dogs receiving RIM suggests an important role for modification of metabolism (ie: energy expenditure) in the effects of RIM on BW in addition to possible changes in appetite and FI. [ABSTRACT FROM AUTHOR]