TAS1R- and TAS2R-type taste receptors are expressed in the gustatory system, where they detect sweet- and bitter-tasting stimuli, respectively. These receptors are also expressed in subsets of cells within the mammalian gastrointestinal tract, where they mediate nutrient assimilation and endocrine responses. For example, sweeteners stimulate taste receptors on the surface of gut enteroendocrine L cells to elicit an increase in intracellular Ca2+ and secretion of the incretin hormone glucagon-like peptide-1 (GLP-1), an important modulator of insulin biosynthesis and secretion. Because of the importance of taste receptors in the regulation of food intake and the alimentary responses to chemostimuli, we hypothesized that differences in taste receptor efficacy may impact glucose homeostasis. To address this issue, we initiated a candidate gene study within the Amish Family Diabetes Study and assessed the association of taste receptor variants with indicators of glucose dysregulation, including a diagnosis of type 2 diabetes mellitus and high levels of blood glucose and insulin during an oral glucose tolerance test. We report that a TAS2R haplotype is associated with altered glucose and insulin homeostasis. We also found that one SNP within this haplotype disrupts normal responses of a single receptor, TAS2R9, to its cognate ligands ofloxacin, procainamide and pirenzapine. Together, these findings suggest that a functionally compromised TAS2R receptor negatively impacts glucose homeostasis, providing an important link between alimentary chemosensation and metabolic disease.

OBJECTIVEOptimal glucose homeostasis requires exquisitely precise adaptation of the number of insulin-secreting β-cells in the islets of Langerhans. Insulin itself positively regulates β-cell proliferation in an autocrine manner through the insulin receptor (IR) signaling pathway. It is now coming to light that cannabinoid 1 receptor (CB1R) agonism/antagonism influences insulin action in insulin-sensitive tissues. However, the cells on which the CB1Rs are expressed and their function in islets have not been firmly established. We undertook the current study to investigate if intraislet endogenous cannabinoids (ECs) regulate β-cell proliferation and if they influence insulin action.RESEARCH DESIGN AND METHODSWe measured EC production in isolated human and mouse islets and β-cell line in response to glucose and KCl. We evaluated human and mouse islets, several β-cell lines, and CB1R-null (CB1R−/−) mice for the presence of a fully functioning EC system. We investigated if ECs influence β-cell physiology through regulating insulin action and demonstrated the therapeutic potential of manipulation of the EC system in diabetic (db/db) mice.RESULTSECs are generated within β-cells, which also express CB1Rs that are fully functioning when activated by ligands. Genetic and pharmacologic blockade of CB1R results in enhanced IR signaling through the insulin receptor substrate 2-AKT pathway in β-cells and leads to increased β-cell proliferation and mass. CB1R antagonism in db/db mice results in reduced blood glucose and increased β-cell proliferation and mass, coupled with enhanced IR signaling in β-cells. Furthermore, CB1R activation impedes insulin-stimulated IR autophosphorylation on β-cells in a Gαi-dependent manner.CONCLUSIONSThese findings provide direct evidence for a functional interaction between CB1R and IR signaling involved in the regulation of β-cell proliferation and will serve as a basis for developing new therapeutic interventions to enhance β-cell function and proliferation in diabetes.

One of the basic functions of insulin in the body is to inhibit lipolysis in adipocytes. Recently, we have found that insulin inhibits lipolysis and promotes triglyceride storage by decreasing transcription of adipose triglyceride lipase via the mTORC1-mediated pathway (P. Chakrabarti et al., Diabetes 59:775-781, 2010), although the mechanism of this effect remained unknown. Here, we used a genetic screen in Saccharomyces cerevisiae in order to identify a transcription factor that mediates the effect of Tor1 on the expression of the ATGL ortholog in yeast. This factor, Msn4p, has homologues in mammalian cells that form a family of early growth response transcription factors. One member of the family, Egr1, is induced by insulin and nutrients and directly inhibits activity of the ATGL promoter in vitro and expression of ATGL in cultured adipocytes. Feeding animals a high-fat diet increases the activity of mTORC1 and the expression of Egr1 while decreasing ATGL levels in epididymal fat. We suggest that the evolutionarily conserved mTORC1-Egr1-ATGL regulatory pathway represents an important component of the antilipolytic effect of insulin in the mammalian organism. C urrent epidemics of metabolic diseases, such as type 2 diabetes, cardiac dysfunction, hypertension, hepatic steatosis, etc., are largely caused by widespread obesity. Although obesity can affect human health via several different mechanisms, the bestestablished connection between obesity and metabolic disease is elevated and/or dysregulated levels of circulating free fatty acids (FFA). In addition to their direct pathological effects, superfluous FFA accumulate in the form of lipids, and their metabolic products in nonadipose peripheral tissues, such as liver, skeletal muscle, heart, and pancreas and cause detrimental effects on human health via mechanisms that are currently under intense investigation (1-5).The levels of circulating FFA depend primarily on the rates of lipolysis in the adipose tissue. One of the key physiological functions of insulin as the major anabolic hormone in the body is to restrain lipolysis and to promote fat storage in adipose tissue in the postprandial state. The failure of insulin to suppress lipolysis in adipocytes has been long considered as a very serious metabolic defect and one of the most important if not the most important causative factor of insulin resistance and diabetes mellitus (6, 7).Complete hydrolysis of triglycerides to glycerol and fatty acids is performed jointly by tri-, di-, and monoacylglyceride lipases (8-11). The recently discovered enzyme, adipose triglyceride lipase (ATGL; also known as desnutrin, PNPLA2, TTS2.2, and iPLA 2 ) (12-14), is responsible for the bulk of triacylglycerol hydrolase activity in various cells and represents the rate-limiting lipolytic enzyme. In every experimental model tested thus far, elevated ATGL expression increases, while attenuated ATGL expression decreases, both basal and cAMP-stimulated lipolysis (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). At the same time, ATGL h...

OBJECTIVE-Glucose-dependent insulinotropic polypeptide (GIP), unlike glucagon-like peptide (GLP)-1, lacks glucose-lowering properties in patients with type 2 diabetes. We designed this study to elucidate the underlying pathophysiology.RESEARCH DESIGN AND METHODS-Twenty-two insulinnaïve subjects with type 2 diabetes were given either synthetic human GIP (20 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 ) or placebo (normal saline) over 180 min, starting with the first bite of a mixed meal (plus 1 g of acetaminophen) on two separate occasions. Frequent blood samples were obtained over 6 h to determine plasma GIP, GLP-1, glucose, insulin, glucagon, resistin, and acetaminophen levels.RESULTS-Compared with placebo, GIP induced an early postprandial increase in insulin levels. Intriguingly, GIP also induced an early postprandial augmentation in glucagon, a significant elevation in late postprandial glucose, and a decrease in late postprandial GLP-1 levels. Resistin and acetaminophen levels were comparable in both interventions. By immunocytochemistry, GIP receptors were present on human and mouse ␣-cells. In ␣TC1 cell line, GIP induced an increase in intracellular cAMP and glucagon secretion.CONCLUSIONS-GIP, given to achieve supraphysiological plasma levels, still had an early, short-lived insulinotropic effect in type 2 diabetes. However, with a concomitant increase in glucagon, the glucose-lowering effect was lost. GIP infusion further worsened hyperglycemia postprandially, most likely through its suppressive effect on GLP-1. These findings make it unlikely that GIP or GIP receptor agonists will be useful in treating the hyperglycemia of patients with type 2 diabetes. Diabetes 58: [1342][1343][1344][1345][1346][1347][1348][1349] 2009 I n response to glucose and fat in digested food, two enteroendocrine hormones, glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP), are secreted from L-and K-cells, respectively, in the gut. GLP-1 and GIP play important roles in postprandial glucose homeostasis. In healthy individuals, the potent insulinotropic effects of GLP-1 and GIP account for up to 60% of the insulin secreted postprandially (1). Exogenous GLP-1 acts to improve glycemic control in patients with type 2 diabetes by 1) stimulating insulin secretion in a glucose concentration-dependent manner during the fasted state, 2) suppressing glucagon secretion in the presence of hyperglycemia and euglycemia but not hypoglycemia, and 3) decelerating gastric emptying, leading to a delay in the absorption of ingested nutrients and a dampening of postprandial glucose excursion (2-4). However, it is still unclear which of these properties of exogenous GLP-1 plays a more prominent role in lowering postprandial glucose (5). GIP has not been studied as extensively as GLP-1. Similar to GLP-1, the insulinotropic effect of GIP in healthy humans is glucose concentration dependent under glucose clamp conditions (6). Unlike GLP-1, the administration of GIP in healthy humans was reported to have a dose-dependent glucagonotropic effec...

BackgroundThe gustatory system plays a critical role in determining food preferences, food intake and energy balance. The exact mechanisms that fine tune taste sensitivity are currently poorly defined, but it is clear that numerous factors such as efferent input and specific signal transduction cascades are involved.Methodology/Principal FindingsUsing immunohistochemical analyses, we show that ghrelin, a hormone classically considered to be an appetite-regulating hormone, is present within the taste buds of the tongue. Prepro-ghrelin, prohormone convertase 1/3 (PC 1/3), ghrelin, its cognate receptor (GHSR), and ghrelin-O-acyltransferase (GOAT , the enzyme that activates ghrelin) are expressed in Type I, II, III and IV taste cells of mouse taste buds. In addition, ghrelin and GHSR co-localize in the same taste cells, suggesting that ghrelin works in an autocrine manner in taste cells. To determine a role for ghrelin in modifying taste perception, we performed taste behavioral tests using GHSR null mice. GHSR null mice exhibited significantly reduced taste responsivity to sour (citric acid) and salty (sodium chloride) tastants.Conclusions/SignificanceThese findings suggest that ghrelin plays a local modulatory role in determining taste bud signaling and function and could be a novel mechanism for the modulation of salty and sour taste responsivity.