Obesity is a major health problem in cats and a risk factor for diabetes. It has been postulated that cats are always gluconeogenic and that the rise in obesity might be related to high dietary carbohydrates. We examined the effect of a high-carbohydrate/low-protein (HC) and a high-protein/low-carbohydrate (HP) diet on glucose and fat metabolism during euglycemic hyperinsulinemic clamp, adipocytokines, and fat distribution in 12 lean and 16 obese cats before and after weight loss. Feeding diet HP led to greater heat production in lean but not in obese cats. Regardless of diet, obese cats had markedly decreased glucose effectiveness and insulin resistance, but greater suppression of nonesterified fatty acids during the euglycemic hyperinsulinemic clamp was seen in obese cats on diet HC compared with lean cats on either diet or obese cats on diet HP. In contrast to humans, obese cats had abdominal fat equally distributed subcutaneously and intra-abdominally. Weight loss normalized insulin sensitivity; however, increased nonesterified fatty acid suppression was maintained and fat loss was less in cats on diet HC. Adiponectin was negatively and leptin positively correlated with fat mass. Lean cats and cats during weight loss, but not obese cats, adapted to the varying dietary carbohydrate/protein content with changes in substrate oxidation. We conclude that diet HP is beneficial through maintenance of normal insulin sensitivity of fat metabolism in obese cats, facilitating the loss of fat during weight loss, and increasing heat production in lean cats. These data also show that insulin sensitivity of glucose and fat metabolism can be differentially regulated in cats.

Abstract-This study assessed the effect of metformin treatment on insulin, mean arterial pressure (MAP), and endothelial function in insulin-resistant (IR) rats. In addition, we assessed the direct effect of metformin in vitro. Sprague-Dawley rats were randomized to control (nϭ28) or IR (nϭ28) groups. Rats were further randomized to receive metformin (300 mg/kg) or placebo for 2 weeks. MAP and insulin were measured. Subsequently, a third-order branch of the superior mesenteric artery was isolated, and endothelial function was assessed. Specifically, dose-response experiments of acetylcholine (ACh) with or without N-nitro-L-arginine (LNNA) were performed. For in vitro experiments, mesenteric arteries were removed from untreated control and IR rats and treated with metformin (100 mol/L) before AChϮLNNA. MAP and insulin levels were improved in IR-metformin compared with IR-placebo rats. Maximal relaxation (E max ) to ACh was enhanced in IR-metformin (92Ϯ2%) compared with IR-placebo rats (44Ϯ4%) (PϽ0.05). Relaxation in response to AChϩLNNA was greater in IR-metformin (33Ϯ4%) than in IR-placebo rats (12Ϯ4%) but remained depressed compared with control rats (E max ϭ68Ϯ5%). The control group was not affected by metformin. In vitro treatment of arteries with metformin in response to ACh produced results similar to those in the experiments with metformin-treated rats. Although metformin improves metabolic abnormality in IR rats, this action does not appear to mediate its effect on vascular function. Both in vivo and in vitro metformin improved ACh-induced relaxation in IR rats to control levels, apparently through nitric oxide-dependent relaxation. These data suggest that metformin improves vascular function through a direct mechanism rather than by improving metabolic abnormalities. Key Words: insulin resistance Ⅲ relaxation Ⅲ metformin Ⅲ nitric oxide Ⅲ blood pressure E xcess cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus) is not explained by the presence of traditional cardiovascular risk factors. 1,2 In addition, glucose control with traditional agents, such as sulfonylureas or insulin, does not alter the risk of macrovascular complications. 3 Epidemiological and observational studies suggest that insulin resistance (IR) may play a role in the development of vascular disease in type 2 diabetes mellitus. 4 -6 Moreover, a recent study has shown that treatment of obese type 2 diabetes mellitus patients with metformin, an insulinsensitizing agent, improves cardiovascular sequelae. 7 Taken together, these data suggest that IR is an important risk factor for the development of cardiovascular disease. Unfortunately, the underlying mechanism(s) by which IR promotes vascular disease remains unknown. Previous data from our laboratory and others suggest endothelial dysfunction as a possible mechanism linking IR to vascular disease. 8,9 Specifically, we have shown that endothelium-dependent relaxation is impaired in IR rats because of a defect in nitric o...