Glucagon, the counter-regulatory hormone to insulin, is secreted from pancreatic ␣ cells in response to low blood glucose. To examine the role of glucagon in glucose homeostasis, mice were generated with a null mutation of the glucagon receptor (Gcgr ؊/؊ ). These mice display lower blood glucose levels throughout the day and improved glucose tolerance but similar insulin levels compared with control animals. Gcgr ؊/؊ mice displayed supraphysiological glucagon levels associated with postnatal enlargement of the pancreas and hyperplasia of islets due predominantly to ␣ cell, and to a lesser extent, ␦ cell proliferation. In addition, increased proglucagon expression and processing resulted in increased pancreatic glucogen-like peptide 1 (GLP-1) (1-37) and GLP-1 amide (1-36 amide) content and a 3-to 10-fold increase in circulating GLP-1 amide. Gcgr ؊/؊ mice also displayed reduced adiposity and leptin levels but normal body weight, food intake, and energy expenditure. These data indicate that glucagon is essential for maintenance of normal glycemia and postnatal regulation of islet and ␣ and ␦ cell numbers. Furthermore, the lean phenotype of Gcgr ؊/؊ mice suggests glucagon action may be involved in the regulation of whole body composition.

Obesity is the driving force behind the worldwide increase in the prevalence of type 2 diabetes mellitus. Hyperglycaemia is a hallmark of diabetes and is largely due to increased hepatic gluconeogenesis. The medial hypothalamus is a major integrator of nutritional and hormonal signals, which play pivotal roles not only in the regulation of energy balance but also in the modulation of liver glucose output. Bidirectional changes in hypothalamic insulin signalling therefore result in parallel changes in both energy balance and glucose metabolism. Here we show that activation of ATP-sensitive potassium (K(ATP)) channels in the mediobasal hypothalamus is sufficient to lower blood glucose levels through inhibition of hepatic gluconeogenesis. Finally, the infusion of a K(ATP) blocker within the mediobasal hypothalamus, or the surgical resection of the hepatic branch of the vagus nerve, negates the effects of central insulin and halves the effects of systemic insulin on hepatic glucose production. Consistent with these results, mice lacking the SUR1 subunit of the K(ATP) channel are resistant to the inhibitory action of insulin on gluconeogenesis. These findings suggest that activation of hypothalamic K(ATP) channels normally restrains hepatic gluconeogenesis, and that any alteration within this central nervous system/liver circuit can contribute to diabetic hyperglycaemia.

The Mouse Metabolic Phenotyping Center (MMPC) Consortium was established to address the need to characterize the growing number of mouse models of metabolic diseases, particularly diabetes and obesity. A goal of the MMPC Consortium is to propose standard methods for assessing metabolic phenotypes in mice. In this article, we discuss issues pertaining to the design and performance of various tests of glucose metabolism. We also propose guidelines for the description of methods, presentation of data and interpretation of results. The recommendations presented in this article are based on the experience of the MMPC Consortium and other investigators.

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The hypothalamus and other regions within the central nervous system (CNS) link the sensing of nutrients to the control of metabolism and feeding behavior. Here, we report that intracerebroventricular (ICV) administration of the long-chain fatty acid oleic acid markedly inhibits glucose production and food intake. The anorectic effect of oleic acid was independent of leptin and was accompanied by a decrease in the hypothalamic expression of neuropeptide Y. The short-chain fatty acid octanoic acid failed to reproduce the metabolic effects of oleic acid, and ICV coadministration of inhibitors of ATP-sensitive K ؉ channels blunted the effect of oleic acid on glucose production. This is the first demonstration that fatty acids can signal nutrient availability to the CNS, which in turn limits further delivery of nutrients to the circulation. Diabetes 51:271-275, 2002 E xcessive consumption of nutrients with high caloric density is largely responsible for the epidemic of obesity and type 2 diabetes in the western hemisphere and in developing nations (1,2). The association of nutrient excess and obesity with type 2 diabetes is largely mediated via their negative impact on intermediary metabolism and insulin action (1-3). Control of metabolism and food intake in response to nutrients occurs partly at the level of hypothalamic nuclei (3-5). In this regard, macronutrients, such as carbohydrates and lipids, regulate the circulating levels of leptin and insulin (3,6,7), which in turn modulate appetite, energy expenditure, and intermediary metabolism mainly via their hypothalamic receptors (Fig. 1A) (3-5). However, central nervous system (CNS) neurons may also sense nutrients directly via metabolic signaling (8). In this regard, the potential role of CNS lipid metabolism in the control of appetite is supported by the potent anorectic property of fatty acid synthase inhibitors (9,10). Further- FIG. 1. Rapid effects of ICV oleic acid on plasma insulin and glucose levels.A: Hypothesis on the negative feedback mechanisms regulating circulating nutrients. There are two main sources of circulating nutrients: intake and absorption of food (Food) and hepatic production of glucose and lipids (Liver). Increased levels of plasma glucose and lipids regulate hypothalamic efferent pathways via their stimulatory effects on insulin and leptin biosynthesis and secretion. The activation of these central responses leads to decreases in food intake and in hepatic output of glucose and lipids. It is proposed herein that circulating nutrients may also directly signal the nutritional status to the hypothalamus and may therefore play a role in this feedback system. B: Schematic representation of the experimental procedures. Surgical implantation of ICV cannulae was performed on day 1 (ϳ3 weeks before the in vivo study). Full recovery of body weight and food intake was achieved by day 7. Surgical implantation of IV catheters was performed on day 14. Finally, on day 21, ICV infusions were started and blood chemistries, food intake, and/or insulin ac...

The association between obesity and diabetes supports an endocrine role for the adipocyte in maintaining glucose homeostasis. Here we report that mice lacking the adipocyte hormone resistin exhibit low blood glucose levels after fasting, due to reduced hepatic glucose production. This is partly mediated by activation of adenosine monophosphate-activated protein kinase and decreased expression of gluconeogenic enzymes in the liver. The data thus support a physiological function for resistin in the maintenance of blood glucose during fasting. Remarkably, lack of resistin diminishes the increase in post-fast blood glucose normally associated with increased weight, suggesting a role for resistin in mediating hyperglycemia associated with obesity.

Circulating insulin inhibits endogenous glucose production. Here we report that bidirectional changes in hypothalamic insulin signaling affect glucose production. The infusion of either insulin or a small-molecule insulin mimetic in the third cerebral ventricle suppressed glucose production independent of circulating levels of insulin and of other glucoregulatory hormones. Conversely, central antagonism of insulin signaling impaired the ability of circulating insulin to inhibit glucose production. Finally, third-cerebral-ventricle administration of inhibitors of ATP-sensitive potassium channels, but not of antagonists of the central melanocortin receptors, also blunted the effect of hyperinsulinemia on glucose production. These results reveal a new site of action of insulin on glucose production and suggest that hypothalamic insulin resistance can contribute to hyperglycemia in type 2 diabetes mellitus.

The enzyme carnitine palmitoyltransferase-1 (CPT1) regulates long-chain fatty acid (LCFA) entry into mitochondria, where the LCFAs undergo beta-oxidation. To investigate the mechanism(s) by which central metabolism of lipids can modulate energy balance, we selectively reduced lipid oxidation in the hypothalamus. We decreased the activity of CPT1 by administering to rats a ribozyme-containing plasmid designed specifically to decrease the expression of this enzyme or by infusing pharmacological inhibitors of its activity into the third cerebral ventricle. Either genetic or biochemical inhibition of hypothalamic CPT1 activity was sufficient to substantially diminish food intake and endogenous glucose production. These results indicated that changes in the rate of lipid oxidation in selective hypothalamic neurons signaled nutrient availability to the hypothalamus, which in turn modulated the exogenous and endogenous inputs of nutrients into the circulation.