OBJECTIVE Insulin resistance is a powerful risk factor for Type 2 diabetes and a constellation of chronic diseases, and is most commonly associated with obesity. We examined if factors other than obesity are more substantial predictors of insulin sensitivity under baseline, non-stimulated conditions. DESIGN AND METHODS Metabolic assessment was performed in healthy dogs (n=90). Whole-body sensitivity from euglycemic clamps (SICLAMP) was the primary outcome variable, and was measured independently by IVGTT (n=36). Adiposity was measured by MRI (n=90), and glucose-stimulated insulin response was measured from hyperglycemic clamp or IVGTT (n=86 and 36, respectively). RESULTS SICLAMP was highly variable (5.9 to 75.9 dl/min per kg per μU/ml). Despite narrow range of body weight (mean, 28.7±0.3 kg), adiposity varied ∼8-fold and was inversely correlated with SICLAMP (p<0.025). SICLAMP was negatively associated with fasting insulin, but most strongly associated with insulin clearance. Clearance was the dominant factor associated with sensitivity (r=0.53, p<0.00001), whether calculated from clamp or IVGTT. CONCLUSIONS These data suggest that insulin clearance contributes substantially to insulin sensitivity, and may be pivotal in understanding the pathogenesis of insulin resistance. We propose that hyperinsulinemia due to reduction in insulin clearance is responsible for insulin resistance secondary to changes in body weight.

We investigated whether rimonabant, a type 1 cannabinoid receptor antagonist, reduces visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) in dogs maintained on a hypercaloric high-fat diet (HHFD). To determine whether energy expenditure contributed to body weight changes, we also calculated resting metabolic rate. Twenty male dogs received either rimonabant (1.25 mg.kg(-1).day(-1), orally; n = 11) or placebo (n = 9) for 16 wk, concomitant with a HHFD. VAT, SAT, and nonfat tissue were measured by magnetic resonance imaging. Resting metabolic rate was assessed by indirect calorimetry. By week 16 of treatment, rimonabant dogs lost 2.5% of their body weight (P = 0.029), whereas in placebo dogs body weight increased by 6.2% (P < 0.001). Rimonabant reduced food intake (P = 0.027), concomitant with a reduction of SAT by 19.5% (P < 0.001). In contrast with the VAT increase with placebo (P < 0.01), VAT did not change with rimonabant. Nonfat tissue remained unchanged in both groups. Body weight loss was not associated with either resting metabolic rate (r(2) = 0.24; P = 0.154) or food intake (r(2) = 0.24; P = 0.166). In conclusion, rimonabant reduced body weight together with a reduction in abdominal fat, mainly because of SAT loss. Body weight changes were not associated with either resting metabolic rate or food intake. The findings provide evidence of a peripheral effect of rimonabant to reduce adiposity and body weight, possibly through a direct effect on adipose tissue.

(T2DM) is often characterized by obesity-associated insulin resistance (IR) and ␤-cell function deficiency. Development of relevant large animal models to study T2DM is important and timely, because most existing models have dramatic reductions in pancreatic function and no associated obesity and IR, features that resemble more T1DM than T2DM. Our goal was to create a canine model of T2DM in which obesity-associated IR occurs first, followed by moderate reduction in ␤-cell function, leading to mild diabetes or impaired glucose tolerance. Lean dogs (n ϭ 12) received a high-fat diet that increased visceral (52%, P Ͻ 0.001) and subcutaneous (130%, P Ͻ 0.001) fat and resulted in a 31% reduction in insulin sensitivity (S I) (5.8 Ϯ 0.7 ϫ 10 Ϫ4 to 4.1 Ϯ 0.5 ϫ 10 Ϫ4 U ⅐ ml Ϫ1 ⅐ min Ϫ1 , P Ͻ 0.05). Animals then received a single low dose of streptozotocin (STZ; range 30 -15 mg/kg). The decrease in ␤-cell function was dose dependent and resulted in three diabetes models: 1) frank hyperglycemia (high STZ dose); 2) mild T2DM with normal or impaired fasting glucose (FG), 2-h glucose Ͼ200 mg/dl during OGTT and 77-93% AIR g reduction (intermediate dose); and 3) prediabetes with normal FG, normal 2-h glucose during OGTT and 17-74% AIR g reduction (low dose). Twelve weeks after STZ, animals without frank diabetes had 58% more body fat, decreased ␤-cell function (17-93%), and 40% lower S I. We conclude that high-fat feeding and variable-dose STZ in dog result in stable models of obesity, insulin resistance, and 1) overt diabetes, 2) mild T2DM, or 3) impaired glucose tolerance. These models open new avenues for studying the mechanism of compensatory changes that occur in T2DM and for evaluating new therapeutic strategies to prevent progression or to treat overt diabetes.obesity; animal models; streptozotocin; insulin secretion TYPE 2 DIABETES MELLITUS (T2DM) is a highly prevalent disease with an enormous public and individual health impact. According to the Centers for Disease Control National Diabetes Fact Sheet, in 2007 23.6 million people in the US (7.8% of population) had diabetes, and an estimated 57 million people had prediabetes [impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or both] (10). The disease's increasing prevalence requires adequate and strong intervention for prevention of new cases and new or improved therapeutic tools for the existing cases (11). T2DM is characterized by a combination of resistance to insulin action and an inadequate compensatory insulin secretory response and is usually associated with obesity (15). Increased body fat and especially visceral fat accumulation have been shown to be risk factors for the development of IGT or diabetes (14). The mechanisms of the initial alterations in the development of T2DM, related to fat deposition and the associated changes in liver, muscle, and adipocyte, are not fully elucidated. Studying the relationship between insulin resistance and hyperinsulinemic compensation (or failure thereof) and the change from normal glucose tolerance to IGT ...

OBJECTIVE-Recent progress suggests that exenatide, a mimetic of glucagon-like peptide-1 (GLP-1), might lower glycemia independent of increased ␤-cell response or reduced gastrointestinal motility. We aimed to investigate whether exenatide stimulates glucose turnover directly in insulin-responsive tissues dependent or independent of insulinemia.RESEARCH DESIGN AND METHODS-An intraportal glucose infusion clamp was used in dogs to measure glucose turnover to encompass potent activation of the putative glucose/GLP-1 sensor in the porto-hepatic circulation with exenatide. The modified glucose clamp was performed in the presence of postprandial hyperinsulinemia and hyperglycemia with exenatide (20 g) or saline injected at 0 min. Furthermore, the role of hyperglycemia versus hyperinsulinemia in exenatide-mediated glucose disposal was studied.RESULTS-With hyperinsulinemia and hyperglycemia, exenatide produced a significant increase in total glucose turnover by ϳ30%, as indicated by portal glucose infusion rate (saline 15.9 Ϯ 1.6 vs. exenatide 20.4 Ϯ 2.1 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 , P Ͻ 0.001), resulting from increased whole-body glucose disposal (R d , ϳ20%) and increased net hepatic uptake of exogenous glucose (ϳ80%). Reducing systemic hyperglycemia to euglycemia, exenatide still increased total glucose turnover by ϳ20% (saline 13.2 Ϯ 1.9 vs. exenatide 15.6 Ϯ 2.1 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 , P Ͻ 0.05) in the presence of hyperinsulinemia, accompanied by smaller increments in R d (12%) and net hepatic uptake of exogenous glucose (45%). In contrast, reducing hyperinsulinemia to basal levels, exenatide-increased total glucose turnover was completely abolished despite hyperglycemia (saline 2.9 Ϯ 0.6 vs. exenatide 2.3 Ϯ 0.3 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 , P ϭ 0.29).CONCLUSIONS-Exenatide directly stimulates glucose turnover by enhancing insulin-mediated whole-body glucose disposal and increasing hepatic uptake of exogenous glucose, contributing to its overall action to lower postprandial glucose excursions.

The full impact of the liver, through both glucose production and uptake, on systemic glucose appearance cannot be readily studied in a classical glucose clamp because hepatic glucose metabolism is regulated not only by portal insulin and glucose levels but also portal glucose delivery (the portal signal). In the present study, we modified the classical glucose clamp by giving exogenous glucose through portal vein, the "portal glucose infusion (PoG)-glucose clamp", to determine the net hepatic effect on postprandial systemic glucose supply along with the measurement of whole body glucose disposal. By comparing systemic rate of glucose appearance (Ra) with portal glucose infusion rate (PoGinf), we quantified "net hepatic glucose addition (NHGA)" in the place of endogenous glucose production determined in a regular clamp. When PoG-glucose clamps (n ϭ 6) were performed in dogs at basal insulinemia and hyperglycemia (ϳ150 mg/dl, portal and systemic), we measured consistently higher Ra than PoGinf (4.2 Ϯ 0.6 vs. 2.9 Ϯ 0.6 mg · kg Ϫ1 · min Ϫ1 at steady state, P Ͻ 0.001) and thus positive NHGA at 1.3 Ϯ 0.1 mg · kg Ϫ1 · min Ϫ1 , identifying net hepatic addition of glucose to portal exogenous glucose. In contrast, when PoG-glucose clamps (n ϭ 6) were performed at hyperinsulinemia (ϳ250 pmol/l) and systemic euglycemia (portal hyperglycemia due to portal glucose infusion), we measured consistently lower Ra than PoGinf (13.1 Ϯ 2.4 vs. 14.3 Ϯ 2.4 mg · kg Ϫ1 · min Ϫ1 , P Ͻ 0.001), and therefore negative NHGA at Ϫ1.1 Ϯ 0.1 mg · kg Ϫ1 · min Ϫ1 , identifying a switch of the liver from net production to net uptake of portal exogenous glucose. Steady-state whole body glucose disposal was 4.1 Ϯ 0.5 and 13.0 Ϯ 2.4 mg · kg Ϫ1 · min Ϫ1 , respectively, determined as in a classical glucose clamp. We conclude that the PoG-glucose clamp, simulating postprandial glucose entry and metabolism, enables simultaneous assessment of the net hepatic effect on postprandial systemic glucose supply as well as whole body glucose disposal in various animal models (rodents, dogs, and pigs) with established portal vein catheterization.net hepatic glucose addition FOLLOWING A MEAL, PLASMA GLUCOSE RISES as the gastrointestinal tract digests and absorbs carbohydrates. A dramatic increase in postprandial glycemia is prevented when the systemic supply of the absorbed glucose is matched to the glucose disposal capacity of the body. Various tissues participate in clearing glucose from the bloodstream, including skeletal muscle, adipose tissue, the liver, and non-insulin-dependent tissues (40,41,46). In contrast, the liver, uniquely situated to receive the absorbed glucose through the portal vein, plays a pivotal role in regulating the systemic glucose supply by adjusting the balance between hepatic glucose production and uptake of newly appearing portal glucose (34). It has been challenging to address both the supply and disposal aspects of postprandial glucose metabolism in a single method, especially the full impact of the liver on systemic glucose appearance...