Modulation Of Insulin Release Research Articles

Vitamin B12-Induced Autophagy Alleviates High Glucose-Mediated Apoptosis of Islet β Cells.

High glucose levels can lead to the apoptosis of islet β cells, while autophagy can provide cytoprotection and promote autophagic cell death. Vitamin B12, a water-soluble B vitamin, has been shown to regulate insulin secretion and increase insulin sensitivity. However, the precise mechanism of action remains unclear. In this study, we investigated the influence of vitamin B12 on high glucose-induced apoptosis and autophagy in RIN-m5F cells to elucidate how vitamin B12 modulates insulin release. Our results demonstrate that exposure to 45 mM glucose led to a significant increase in the apoptosis rate of RIN-m5F cells. The treatment with vitamin B12 reduced the apoptosis rate and increased the number of autophagosomes. Moreover, vitamin B12 increased the ratio of microtubule-associated protein 1 light chain 3 beta to microtubule-associated protein 1 light chain 3 alpha (LC3-II/LC3-I), while decreasing the amount of sequestosome 1 (p62) and inhibiting the phosphorylation of p70 ribosomal protein S6 kinase (p70S6K) under both normal- and high-glucose conditions. The additional experiments revealed that vitamin B12 inhibited high glucose-induced apoptosis. Notably, this protective effect was attenuated when the autophagy inhibitor 3-methyladenine was introduced. Our findings suggest that vitamin B12 protects islet β cells against apoptosis induced by high glucose levels, possibly by inducing autophagy.

Identification of a new Kir6 potassium channel and comparison of properties of Kir6 subtypes by structural modelling and molecular dynamics

ATP-sensitive potassium ion channels (KATP) are transmembrane proteins that modulate insulin release and muscle contraction. KATP channels are composed of two types of subunit, Kir6 and SUR, which exist in two and three isoforms respectively with different tissue distribution. In this work, we identify a previously undescribed ancestral vertebrate gene encoding a Kir6-related protein that we have named Kir6.3, which may not have a SUR binding partner, unlike the other two Kir6 proteins. Whereas Kir6.3 was lost in amniotes including mammals, it is still present in several early-diverging vertebrate lineages such as frogs, coelacanth, and rayfinned fishes. Molecular dynamics (MD) simulations using homology models of Kir6.1, Kir6.2, and Kir6.3 from the coelacanth Latimeria chalumnae showed that the three proteins exhibit subtle differences in their dynamics. Steered MD simulations of Kir6-SUR pairs suggest that Kir6.3 has a lower binding affinity for the SUR proteins than either Kir6.1 or Kir6.2. As we found no additional SUR gene in the genomes of the species that have Kir6.3, it most likely forms a lone tetramer. These findings invite studies of the tissue distribution of Kir6.3 in relation to the other Kir6 as well as SUR proteins to determine the functional roles of Kir6.3.

Prospective Nutraceutical Effects of Cinnamon Derivatives Against Insulin Resistance in Type II Diabetes Mellitus-Evidence From the Literature.

Apart from advances in pharmaceutical antidiabetic agents, efforts are being made toward hypoglycemic agents derived from natural sources. Cinnamon has been reported to have significant benefits for human health, particularly as an anti-inflammatory, antidiabetic, and anti-hypertriglyceridemic agent. The phytochemicals in cinnamon can be extracted from different parts of plant by distillation and solvent extraction. These chemicals help in decreasing insulin resistance and can act against hyperglycemia and dyslipidemia, inflammation and oxidative stress, obesity, overweight, and abnormal glycation of proteins. Cinnamon has shown to improve all of these conditions in in vitro, animal, and/or human studies. However, the mechanism of action of active ingredients found in cinnamon remains unclear. The current review presents the outstanding ability of cinnamon derivatives to control diabetes by various pathways modulating insulin release and insulin receptor signaling. It was also found that the type and dosage of cinnamon as well as subject characteristics including drug interactions are likely to affect the response to cinnamon. Future research directions based on this review include the synergistic usage of various cinnamon derivatives in managing and/or preventing diabetes and possible other relevant chronic diseases.

ODP228 Obesity Induced a Down-Regulation of nNOS in Intrapancreatic Nervous System

Abstract Objective Obesity has become a serious global public health problem. Obesity is frequently preceding and the most important risk factor of type 2 diabetes. Pancreas regulates glucose metabolism and glucose homeostasis, and abnormality of pancreas play an important role in insulin resistance and diabetes. Intrapancreatic nerve innervation modulates insulin release and is tightly linked to the onset and development of diabetes. However, it is not known whether the activity of the intrapancreatic nervous system has been altered before the onset of diabetes. In this study, we examined the intrapancreatic nervous system in rats with obesity looking for the changes induced by obesity. Methods Obese Sprague-Dawley rats were developed with feeding high fat diet for 10 weeks. Using Immunofluorescence method, choline acetyl transferase (ChAT) and nNOS positive neurons in intrapancreatic ganglia were counted. ChAT and nNOS expression in pancreas were also measured with western blot method. Results (1) There was no significant difference in fasting blood glucose between obese rats and normal rats, but oral glucose tolerance test showed that the oral glucose tolerance was impaired in obese rats. (2) In rats fed with normal diet, 80.2%±1.5 neurons in intrapancreatic ganglia were ChAT positive, and in the obese rats, 79.3%±1.8 neurons were ChAT positive. There was no significant difference between the two groups (p>0. 05, n=5). In intrapancreatic ganglia of obese rats, 40%±1.4 neurons were nNOS positive, which was significantly lower than that (60.5%±1.2) of rats fed with normal diet (p<0. 01,n=5). (3) In pancreatic tissue, the relative expression level of ChAT protein was 1. 02±0. 03 in rats fed with normal diet and 0.98±0. 05 in obese rats (p>0. 05, n=5). The relative expression level of nNOS protein was 1.70±0. 08 in normal rats and 1.10±0. 05 in obese rats (p>0. 01, n=5). Conclusion The cholinergic nerves in intrapancreatic nervous system was not altered in obese rats, however, nNOS nerves was down-regulated in obese rats. The down-regulation of nNOS would induce a hyperactivity in intrapancreatic nervous system and this would cause an enhancement of insulin release, which has been observed in obese individuals. Presentation: No date and time listed

GPR40 Activation Abolishes Diabetes-Induced Painful Neuropathy by Suppressing VEGF-A Expression.

G-protein-coupled receptor 40 (GPR40) is a promising target to support glucose-induced insulin release in patients with type 2 diabetes. We studied the role of GPR40 in the regulation of blood-nerve barrier integrity and its involvement in diabetes-induced neuropathies. Because GPR40 modulates insulin release, we used the streptozotocin model for type 1 diabetes, in which GPR40 functions can be investigated independently of its effects on insulin release. Diabetic wild-type mice exhibited increased vascular endothelial permeability and showed epineural microlesions in sciatic nerves, which were also observed in naïve GPR40-/- mice. Fittingly, expression of vascular endothelial growth factor-A (VEGF-A), an inducer of vascular permeability, was increased in diabetic wild-type and naïve GPR40-/- mice. GPR40 antagonists increased VEGF-A expression in murine and human endothelial cells as well as permeability of transendothelial barriers. In contrast, GPR40 agonists suppressed VEGF-A release and mRNA expression. The VEGF receptor inhibitor axitinib prevented diabetes-induced hypersensitivities and reduced endothelial and epineural permeability. Importantly, the GPR40 agonist GW9508 reverted established diabetes-induced hypersensitivity, an effect that was blocked by VEGF-A administration. Thus, GPR40 activation suppresses VEGF-A expression, thereby reducing diabetes-induced blood-nerve barrier permeability and reverting diabetes-induced hypersensitivities.

In vivo metabolic effects after acute activation of skeletal muscle Gs signaling

ObjectiveThe goal of this study was to determine the glucometabolic effects of acute activation of Gs signaling in skeletal muscle (SKM) in vivo and its contribution to whole-body glucose homeostasis. MethodsTo address this question, we studied mice that express a Gs-coupled designer G protein-coupled receptor (Gs-DREADD or GsD) selectively in skeletal muscle. We also identified two Gs-coupled GPCRs that are endogenously expressed by SKM at relatively high levels (β2-adrenergic receptor and CRF2 receptor) and studied the acute metabolic effects of activating these receptors in vivo by highly selective agonists (clenbuterol and urocortin 2 (UCN2), respectively). ResultsAcute stimulation of GsD signaling in SKM impaired glucose tolerance in lean and obese mice by decreasing glucose uptake selectively into SKM. The acute metabolic effects following agonist activation of β2-adrenergic and, potentially, CRF2 receptors appear primarily mediated by altered insulin release. Clenbuterol injection improved glucose tolerance by increasing insulin secretion in lean mice. In SKM, clenbuterol stimulated glycogen breakdown. UCN2 injection resulted in decreased glucose tolerance associated with lower plasma insulin levels. The acute metabolic effects of UCN2 were not mediated by SKM Gs signaling. ConclusionsSelective activation of Gs signaling in SKM causes an acute increase in blood glucose levels. However, acute in vivo stimulation of endogenous Gs-coupled receptors enriched in SKM has only a limited impact on whole-body glucose homeostasis, most likely due to the fact that these receptors are also expressed by pancreatic islets where they modulate insulin release.

VMAT2 Safeguards β-Cells Against Dopamine Cytotoxicity Under High-Fat Diet-Induced Stress.

Vesicular monoamine transporter 2 (VMAT2) uptakes cytoplasmic monoamines into vesicles for storage. VMAT2 plays a role in modulating insulin release by regulating dopamine levels in the pancreas, although the exact mechanism remains elusive. We found that VMAT2 expression in β-cells specifically increases under high blood glucose conditions. The islets isolated from β-cell–specific Vmat2 knockout (βVmat2KO) mice show elevated insulin secretion levels in response to glucose stimulation. Under prolonged high-fat diet feedings, the βVmat2KO mice exhibit impaired glucose and insulin tolerance and progressive β-cell dysfunction. Here we demonstrate VMAT2 uptake of dopamine to protect dopamine from degradation by monoamine oxidase, thereby safeguarding β-cells from excess reactive oxygen species (ROS) exposure. In the context of high demand for insulin secretion, the absence of VMAT2 leads to elevated ROS in β-cells, which accelerates β-cell dedifferentiation and β-cell loss. Therefore, VMAT2 controls the amount of dopamine in β-cells, thereby protecting pancreatic β-cells from excessive oxidative stress.

2083-P: Dynamics of D-Amino Acids in Mammalian Pancreatic Islets

Evidence has shown the presence of D-amino acids (D-AAs), unusual cell-to-cell signaling molecules, in the pancreatic islets of rodents and humans. In particular, D-alanine (D-Ala) and serine racemase, the enzyme that converts L- to D-serine (D-Ser), colocalize within insulin-producing beta cells. Both D-Ala and D-Ser function as co-agonists of the N-methyl-D-aspartate (NMDA) receptor, which is also present in islets and modulates insulin release, suggesting potential autocrine or paracrine signaling role of these compounds. Here, we investigated the relationship between the endogenous levels of D-AAs and islet regulation of glucose homeostasis. The glucose-stimulated D-AA profiles in the rat islets revealed that the L-AA forms were released from the pancreatic islets in a dose-dependent manner. Interestingly, we observed between a 20% and 45% reduction of D-Ala and D-Ser levels, respectively, in islets after the stimulation which appears to be independent of the extracellular glucose levels. In addition to islets, significant D-AAs were detected in the surrounding acinar tissue; only D-Ala was abundant at high percentage of 11.6 ± 1.5% to total Ala in the tissue, while other D-AAs were not measured at high levels. As beta cells appear not to be able to synthesize their own D-Ala, this suggests that the D-Ala detected in these cells can be supplied by nearby acinar tissue. We also have measured the D-Ser percentages in healthy and type 2 diabetes (T2D)-affected islets received from the Human Pancreas Analysis Program (UPenn). Preliminary results revealed the lower D-Ser level in the T2D-affected islets compared to healthy islets. We are continuing to accumulate more data to determine the potential correlation of D-AAs, including D-Ala and D-Ser, to diabetes progression. The continued characterization of endogenous D-AAs levels will shed light on their roles in islet normal and pathological functions. Disclosure C.J. Lee: None. A. Patel: None. D. Lee: None. S. Rubakhin: None. J.V. Sweedler: None. Funding American Diabetes Association/Pathway to Stop Diabetes (1-18-VSN-19 to J.V.S.)

Survival in a bad neighborhood: pancreatic islets in cystic fibrosis.

In cystic fibrosis (CF), ductal plugging and acinar loss result in rapid decline of exocrine pancreatic function. This destructive process results in remodeled islets, with only a modest reduction in insulin producing β cells. However, β-cell function is profoundly impaired, with decreased insulin release and abnormal glucose tolerance being present even in infants with CF. Ultimately, roughly half of CF subjects develop diabetes (termed CF-related diabetes, CFRD). Importantly, CFRD increases CF morbidity and mortality via worsening catabolism and pulmonary disease. Current accepted treatment options for CFRD are aimed at insulin replacement, thereby improving glycemia as well as preventing nutritional losses and lung decline. CFRD is a unique form of diabetes with a distinct pathophysiology that is as yet incompletely understood. Recent studies highlight emerging areas of interest. First, islet inflammation and lymphocyte infiltration are common even in young children with CF and may contribute to β-cell failure. Second, controversy exists in the literature regarding the presence/importance of β-cell intrinsic functions of CFTR and its direct role in modulating insulin release. Third, loss of the CF transmembrane conductance regulator (CFTR) from pancreatic ductal epithelium, the predominant site of its synthesis, results in paracrine effects that impair insulin release. Finally, the degree of β-cell loss in CFRD does not appear sufficient to explain the deficit in insulin release. Thus, it may be possible to enhance the function of the remaining β cells using strategies such as targeting islet inflammation or ductal CFTR deficiency to effectively treat or even prevent CFRD.

The association between vitamin D receptor gene polymorphisms (<em>TaqI</em> and <em>FokI</em>), Type 2 diabetes, and micro-/macrovascular complications in postmenopausal women

IntroductionSince there is evidence of the action of vitamin D as a modulator of insulin release and atherosclerosis, it may well be that the vitamin D receptor polymorphisms are associated with diabetes and its chronic complications.AimsTo examine the associations between vitamin D receptor polymorphisms (FokI and TaqI) and Type 2 diabetes (T2DM) and its associated chronic complications in postmenopausal women.MethodsThis cross-sectional study analyzed 100 postmenopausal women with T2DM (mean age 65.7±7.18 years) and 100 postmenopausal women without diabetes in the control group (mean age 65.1±9.18 years; P=0.1608). We evaluated clinical and metabolic parameters and analyzed TaqI and FokI polymorphisms.ResultsThere were no significant differences in genotype and allele frequencies between patients and controls in either of the polymorphisms studied. In the group of patients with diabetes, there were no significant differences in either polymorphism in relation to stroke, retinopathy, nephropathy, or neuropathy. However, in patients with T2DM and coronary artery disease, f genotype (P=0.0361) and the combination of Ff + ff genotypes were observed less frequently (P=0.0462).ConclusionThis study suggests the potential protective factor of FokI polymorphism for coronary artery disease in postmenopausal women with T2DM in the recessive model.

Dopamine modulates insulin release and is involved in the survival of rat pancreatic beta cells.

The local synthesis of dopamine and its effects on insulin release have been described in isolated islets. Thus, it may be accepted that dopamine exerts an auto-paracrine regulation of insulin secretion from pancreatic beta cells. The aim of the present study is to analyze whether dopamine is a regulator of the proliferation and apoptosis of rat pancreatic beta cells after glucose-stimulated insulin secretion. Glucose stimulated pancreatic islets obtained from male Wistar rats were cultured with 1 or 10 μM dopamine from 1 to 12 h. Insulin secretion was analyzed by RIA. The cellular proliferation rate of pancreatic islets and beta cells was studied with immunocytochemical double labelling for both insulin and PCNA (proliferating cell nuclear antigen), and active caspase-3 was detected to evaluate apoptosis. The secretion of insulin from isolated islets was significantly inhibited (p<0.01), by treatment with 1 and 10 μM dopamine, with no differences between either dose as early as 1 h after treatment. The percentage of insulin-positive cells in the islets decreased significantly (p<0.01) after 1 h of treatment up to 12 h. The proliferation rate of insulin-positive cells in the islets decreased significantly (p<0.01) following treatment with dopamine. Apoptosis in pancreatic islets and beta cells was increased by treatment with 1 and 10 μM dopamine along 12 h. In conclusion, these results suggest that dopamine could modulate the proliferation and apoptosis of pancreatic beta cells and that dopamine may be involved in the maintenance of pancreatic islets.

TRPM3.

Like most other members of the TRP family, the Trpm3 gene encodes proteins that form cation-permeable ion channels on the plasma membrane. However, TRPM3 proteins have several unique features that set them apart from the other members of this diverse family. The Trpm3 gene encodes for a surprisingly large number of isoforms generated mainly by alternative splicing. Only for two of the (at least) eight sites at which sequence diversity is generated the functional consequences have been elucidated, one leading to nonfunctional channels, the other one profoundly affecting the ionic selectivity. In the Trpm3 gene an intronic microRNA (miR-204) is co-transcribed with Trpm3. By regulating the expression of a multitude of genes, miR-204 increases the functional complexity of the Trpm3 locus. Over the past years, important progress has been made in discovering pharmacological tools to manipulate TRPM3 channel activity. These substances have facilitated the identification of endogenously expressed functional TRPM3 channels in nociceptive neurons, pancreatic beta cells, and vascular smooth muscle cells, among others. TRPM3 channels, which themselves are temperature sensitive, thus have been implicated in sensing noxious heat, in modulating insulin release, and in secretion of inflammatory cytokines. However, in many tissues where TRPM3 proteins are known to be expressed, no functional role has been identified for these channels so far. Because of the availability of adequate pharmacological and genetic tools, it is expected that future investigations on TRPM3 channels will unravel important new aspects and functions of these channels.

CB1 Cannabinoid Receptors Couple to Focal Adhesion Kinase to Control Insulin Release

Endocannabinoid signaling has been implicated in modulating insulin release from β cells of the endocrine pancreas. β Cells express CB1 cannabinoid receptors (CB1Rs), and the enzymatic machinery regulating anandamide and 2-arachidonoylglycerol bioavailability. However, the molecular cascade coupling agonist-induced cannabinoid receptor activation to insulin release remains unknown. By combining molecular pharmacology and genetic tools in INS-1E cells and in vivo, we show that CB1R activation by endocannabinoids (anandamide and 2-arachidonoylglycerol) or synthetic agonists acutely or after prolonged exposure induces insulin hypersecretion. In doing so, CB1Rs recruit Akt/PKB and extracellular signal-regulated kinases 1/2 to phosphorylate focal adhesion kinase (FAK). FAK activation induces the formation of focal adhesion plaques, multimolecular platforms for second-phase insulin release. Inhibition of endocannabinoid synthesis or FAK activity precluded insulin release. We conclude that FAK downstream from CB1Rs mediates endocannabinoid-induced insulin release by allowing cytoskeletal reorganization that is required for the exocytosis of secretory vesicles. These findings suggest a mechanistic link between increased circulating and tissue endocannabinoid levels and hyperinsulinemia in type 2 diabetes.

“Tasting” fructose with pancreatic beta-cells: modulation of insulin release by sweet taste receptor signaling and its role in metabolic diseases

Background Although glucose is indispensable for the stimulation of insulin release, numerous other insulin secretagogues have been identified. For instance, the dietary monosaccharide fructose potentiates insulin secretion in vitro, but the mechanism and physiological significance remains unclear. The T1R2-T1R3 heterodimer of G protein-coupled receptors mediates sweet sensing in the tongue and ablation of either subunit obliterates sweet taste. We hypothesized that the effects of fructose on insulin release may be mediated by sweet taste receptors (TRs) on beta-cells.

Block of Kv1.7 potassium currents increases glucose‐stimulated insulin secretion

Glucose-stimulated insulin secretion (GSIS) relies on repetitive, electrical spiking activity of the beta cell membrane. Cyclic activation of voltage-gated potassium channels (Kv) generates an outward, ‘delayed rectifier’ potassium current, which drives the repolarizing phase of each spike and modulates insulin release. Although several Kv channels are expressed in pancreatic islets, their individual contributions to GSIS remain incompletely understood. We take advantage of a naturally occurring cone-snail peptide toxin, Conkunitzin-S1 (Conk-S1), which selectively blocks Kv1.7 channels to provide an intrinsically limited, finely graded control of total beta cell delayed rectifier current and hence of GSIS. Conk-S1 increases GSIS in isolated rat islets, likely by reducing Kv1.7-mediated delayed rectifier currents in beta cells, which yields increases in action potential firing and cytoplasmic free calcium. In rats, Conk-S1 increases glucose-dependent insulin secretion without decreasing basal glucose. Thus, we conclude that Kv1.7 contributes to the membrane-repolarizing current of beta cells during GSIS and that block of this specific component of beta cell Kv current offers a potential strategy for enhancing GSIS with minimal risk of hypoglycaemia during metabolic disorders such as Type 2 diabetes.

Modulated insulin release from glucose-sensitive multilayer films

Summary Self-assembled multilayer films were fabricated to modulate insulin release in response to glucose concentration changes. These films showed remarkable glucose-sensitive characteristics and were nontoxic in vitro.

Impact of the 5-HT 3 receptor channel system for insulin secretion and interaction of ginger extracts

The relevance of serotonin and in particular that of 5-HT 3 receptors is unequivocal with respect to emetic/antiemetic effects, but it is controversial with respect to antidiabetic effects. The effects of tropisetron (5-HT 3 receptor antagonist) and various ginger ( Zingiber officinale) extracts (known to interact with the 5-HT 3 receptor channel system) were investigated. Serotonin (32 to 500 µM) inhibits insulin release (RIA) from INS-1 cells which is reversed by tropisetron (10 to 100 µM) and two different ginger extracts (spissum and an oily extract). Their effects are obvious even in the absence of serotonin but are more pronounced in its presence (doubled to tripled). Specific 5-HT 3 binding sites are present in INS-1 cells using 0.4 nM [ 3H] GR65630 in displacement experiments. The in vitro data with respect to ginger are corroborated by in vivo data on glucose-loaded rats showing that blood glucose (Glucoquant ®) is decreased by ~ 35% and plasma insulin (RIA) is increased by ~ 10%. Both the spissum extract and the oily ginger extract are effective in two other models: they inhibit [ 14C] guanidinium uptake into N1E-115 cells (model of 5-HT 3 effects) and relax rat ileum both directly and as a serotonin antagonistic effect. Other receptors addressed by ginger are 5-HT 2 receptors as demonstrated by using methysergide and ketanserin. They weakly antagonize the serotonin effect as well. It may be concluded that serotonin and in particular the 5-HT 3 receptor channel system are involved in modulating insulin release and that tropisetron and various ginger extracts can be used to improve a diabetic situation.

Plasma Membrane Associated ATP as a Regulator of the Secretory Activity of the Pancreatic β-Cell

beta-Cell-rich pancreatic islets from ob/ob-mice were used for evaluating how ATP associated with the plasma membrane participates in the regulation of insulin release. Increase of Ca2+ initiates insulin release from permeabilized beta-cells only in the presence of Mg-ATP. When bound to the inner part of the plasma membrane ATP depolarizes the beta-cells by closing a glucose-regulated K+-channel. It is possible that ATP in a plasma membrane compartment modulates insulin release also by stimulating ion pumps and exchange processes. ATP can regulate the secretory activity by binding also to the exterior of the beta-cells. The addition of ATP resulted in stimulation of insulin release related to polyphosphoinositide breakdown. It is suggested that the granule fusion with the plasma membrane is followed by release of sufficient amounts of ATP and ADP for activating a P2-purinoceptor. This receptor may consequently be part of a system for amplifying the secretory response to glucose and other agents facilitating the entry of Ca2+.

Deletion of the von Hippel-Lindau gene in pancreatic beta cells impairs glucose homeostasis in mice.

Defective insulin secretion in response to glucose is an important component of the beta cell dysfunction seen in type 2 diabetes. As mitochondrial oxidative phosphorylation plays a key role in glucose-stimulated insulin secretion (GSIS), oxygen-sensing pathways may modulate insulin release. The von Hippel-Lindau (VHL) protein controls the degradation of hypoxia-inducible factor (HIF) to coordinate cellular and organismal responses to altered oxygenation. To determine the role of this pathway in controlling glucose-stimulated insulin release from pancreatic beta cells, we generated mice lacking Vhl in pancreatic beta cells (betaVhlKO mice) and mice lacking Vhl in the pancreas (PVhlKO mice). Both mouse strains developed glucose intolerance with impaired insulin secretion. Furthermore, deletion of Vhl in beta cells or the pancreas altered expression of genes involved in beta cell function, including those involved in glucose transport and glycolysis, and isolated betaVhlKO and PVhlKO islets displayed impaired glucose uptake and defective glucose metabolism. The abnormal glucose homeostasis was dependent on upregulation of Hif-1alpha expression, and deletion of Hif1a in Vhl-deficient beta cells restored GSIS. Consistent with this, expression of activated Hif-1alpha in a mouse beta cell line impaired GSIS. These data suggest that VHL/HIF oxygen-sensing mechanisms play a critical role in glucose homeostasis and that activation of this pathway in response to decreased islet oxygenation may contribute to beta cell dysfunction.

GPR119, a novel G protein‐coupled receptor target for the treatment of type 2 diabetes and obesity

GPR119 is a G protein-coupled receptor expressed predominantly in the pancreas (beta-cells) and gastrointestinal tract (enteroendocrine cells) in humans. De-orphanization of GPR119 has revealed two classes of possible endogenous ligands, viz., phospholipids and fatty acid amides. Of these, oleoylethanolamide (OEA) is one of the most active ligands tested so far. This fatty acid ethanolamide is of particular interest because of its known effects of reducing food intake and body weight gain when administered to rodents. Agonists at the GPR119 receptor cause an increase in intracellular cAMP levels via G(alphas) coupling to adenylate cyclase. In vitro studies have indicated a role for GPR119 in the modulation of insulin release by pancreatic beta-cells and of GLP-1 secretion by gut enteroendocrine cells. The effects of GPR119 agonists in animal models of diabetes and obesity are reviewed, and the potential value of such compounds in future therapies for these conditions is discussed.