Beta-cell dysfunction induced by non-cytotoxic concentrations of Interleukin-1β is associated with changes in expression of beta-cell maturity genes and associated histone modifications.

Decreased insulin secretory capacity in Type 2 diabetes mellitus is associated with beta-cell dedifferentiation and inflammation. We hypothesize that prolonged exposure of beta-cells to low concentrations of IL-1β induce beta-cell dedifferentiation characterized by impaired glucose-stimulated insulin secretion, reduced expression of key beta-cell genes and changes in histone modifications at gene loci known to affect beta-cell function. Ten days exposure to IL-1β at non-cytotoxic concentrations reduced insulin secretion and beta-cell proliferation and decreased expression of key beta-cell identity genes, including MafA and Ucn3 and decreased H3K27ac at the gene loci, suggesting that inflammatory cytokines directly affects the epigenome.

The aromatic amino acid sensor GPR142 controls metabolism through balanced regulation of pancreatic and gut hormones.

Objectives: GPR142, which is highly expressed in pancreatic islets, has recently been deorphanized as a receptor for aromatic amino acids; however, its physiological role and pharmacological potential is unclear.

Methods And Results: We find that GPR142 is expressed not only in β- but also in α-cells of the islets as well as in enteroendocrine cells, and we confirm that GPR142 is a highly selective sensor of essential aromatic amino acids, in particular Trp and oligopeptides with N-terminal Trp. GPR142 knock-out mice displayed a very limited metabolic phenotype but demonstrated that L-Trp induced secretion of pancreatic and gut hormones is mediated through GPR142 but that the receptor is not required for protein-induced hormone secretion.

Impact of fetal and neonatal environment on beta cell function and development of diabetes.

The global epidemic of diabetes is a serious threat against health and healthcare expenses. Although genetics is important it does not explain the dramatic increase in incidence, which must involve environmental factors. Two decades ago the concept of the thrifty phenotype was introduced, stating that the intrauterine environment during pregnancy has an impact on the gene expression that may persist until adulthood and cause metabolic diseases like obesity and type 2 diabetes.

A critical role for CK2 in cytokine-induced activation of NFκB in pancreatic β cell death.

This study aimed to assess the role of constitutive protein kinase CK2 in cytokine-induced activation of NFκB in pancreatic β cell death. The CK2 inhibitors DRB (5,6-dichloro-1-β-D-ribofuranosylbenzimidazole) (50 μM) and DMAT (2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole) (5 μM), which decreased CK2 activity by approx. 65 %, rescued INS-1E β cells and mouse islets from cytokine (IL-1β, TNF-α plus IFN-γ)-induced β cell death without affecting H2O2- or palmitate-induced β cell death.

The L-α-amino acid receptor GPRC6A is expressed in the islets of Langerhans but is not involved in L-arginine-induced insulin release.

GPRC6A is a seven-transmembrane receptor activated by a wide range of L-α-amino acids, most potently by L-arginine and other basic amino acids. The receptor is broadly expressed, but its exact physiological role remains to be elucidated. It is well established that L-arginine stimulates insulin secretion; therefore, the receptor has been hypothesized to have a role in regulating glucose metabolism.

Transgenic rescue of adipocyte glucose-dependent insulinotropic polypeptide receptor expression restores high fat diet-induced body weight gain.

The glucose-dependent insulinotropic polypeptide receptor (GIPr) has been implicated in high fat diet-induced obesity and is proposed as an anti-obesity target despite an uncertainty regarding the mechanism of action. To independently investigate the contribution of the insulinotropic effects and the direct effects on adipose tissue, we generated transgenic mice with targeted expression of the human GIPr to white adipose tissue or beta-cells, respectively. These mice were then cross-bred with the GIPr knock-out strain.

Suppression of FAT/CD36 mRNA by human growth hormone in pancreatic β-cells.

Fatty acid-induced damage in pancreatic β-cells is assumed to play an important role in the development of type 2 diabetes. Lactogens (prolactin, placental lactogen and growth hormone) improve β-cell survival via STAT5 activation but the molecular targets are incompletely characterized. The aim of this study was to examine the effect of human growth hormone (hGH) on mRNAs of fatty acid transport and binding proteins expressed in pancreatic β-cells, and to examine this in relation to β-cell survival after exposure to fatty acids.

AKAP 18 alpha and gamma have opposing effects on insulin release in INS-1E cells.

A-kinase anchoring proteins (AKAPs) are known to compartmentalise protein kinase(s) to discrete cellular locations. Here we show that silencing of AKAP 18 alpha or gamma expression results in decreased or increased glucose-stimulated insulin secretion in INS-1E cells. Glucose stimulates AKAP 18 alpha and inhibits AKAP 18 gamma mRNA expressions while palmitate markedly reduces AKAP 18 alpha expression.

Serum albumin protects from cytokine-induced pancreatic beta cell death by a phosphoinositide 3-kinase-dependent mechanism.

The present study was undertaken to investigate the biological activity of serum albumin when pancreatic beta cells were challenged by cytokines and pro-apoptotic reactive oxygen species like H(2)O(2). Culture of mouse islets or INS-1E beta cells for 24 h in the presence of H(2)O(2) (25 micromol/l) increased cell death. This demise was prevented by serum albumin, dependent on its free sulfhydryl group, emphasizing that albumin may scavenge H(2)O(2) due to its antioxidant properties.

G protein-coupled receptor 39 deficiency is associated with pancreatic islet dysfunction.

G protein-coupled receptor (GPR)-39 is a seven-transmembrane receptor expressed mainly in endocrine and metabolic tissues that acts as a Zn(++) sensor signaling mainly through the G(q) and G(12/13) pathways. The expression of GPR39 is regulated by hepatocyte nuclear factor (HNF)-1alpha and HNF-4alpha, and in the present study, we addressed the importance of GPR39 for glucose homeostasis and pancreatic islets function. The expression and localization of GPR39 were characterized in the endocrine pancreas and pancreatic cell lines.

STAT5 activity in pancreatic beta-cells influences the severity of diabetes in animal models of type 1 and 2 diabetes.

Pancreatic beta-cell growth and survival and insulin production are stimulated by growth hormone and prolactin through activation of the transcription factor signal transducer and activator of transcription (STAT)5. To assess the role of STAT5 activity in beta-cells in vivo, we generated transgenic mice that expressed a dominant-negative mutant of STAT5a (DNSTAT5) or constitutive active mutant of STAT5b (CASTAT5) under control of the rat insulin 1 promoter (RIP). When subjected to a high-fat diet, RIP-DNSTAT5 mice showed higher body weight, increased plasma glucose levels, and impairment of glucose tolerance, whereas RIP-CASTAT5 mice were more glucose tolerant and less hyperleptinemic than wild-type mice.

Trefoil factors are expressed in human and rat endocrine pancreas: differential regulation by growth hormone.

Trefoil factors (TFFs) 1, 2, and 3 are expressed in mucosal epithelia. TFFs are particular abundant in the intestine in which they play a crucial role in maintenance and restitution of the epithelium. Because pancreas developmentally arises from the primitive foregut, we explored the expression of TFFs in the pancreas in man and rat.

Glucose triggers protein kinase A-dependent insulin secretion in mouse pancreatic islets through activation of the K+ATP channel-dependent pathway.

Objective: To assess the significance of protein kinase A (PKA) in glucose triggering of ATP-sensitive K(+) (K(+)(ATP)) channel-dependent insulin secretion and in glucose amplification of K(+)(ATP) channel-independent insulin secretion.

Methods: Insulin release from cultured perifused mouse pancreatic islets was determined by radioimmunoassay.

Results: In islets cultured at 5.

Phosphatidylinositol 4-kinase serves as a metabolic sensor and regulates priming of secretory granules in pancreatic beta cells.

Insulin secretion is controlled by the beta cell's metabolic state, and the ability of the secretory granules to undergo exocytosis increases during glucose stimulation in a membrane potential-independent fashion. Here, we demonstrate that exocytosis of insulin-containing secretory granules depends on phosphatidylinositol 4-kinase (PI 4-kinase) activity and that inhibition of this enzyme suppresses glucose-stimulated insulin secretion. Intracellular application of phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate [PI(4,5)P(2)] stimulated exocytosis by promoting the priming of secretory granules for release and increasing the number of granules residing in a readily releasable pool.

Imidazoline NNC77-0074 stimulates Ca2+-evoked exocytosis in INS-1E cells by a phospholipase A2-dependent mechanism.

We have previously demonstrated that the novel imidazoline compound (+)-2-(2-(4,5-dihydro-1H-imidazol-2-yl)-thiopene-2-yl-ethyl)-pyridine (NNC77-0074) increases insulin secretion from pancreatic beta-cells by stimulation of Ca(2+)-dependent exocytosis. Using capacitance measurements, we now show that NNC77-0074 stimulates exocytosis in clonal INS-1E cells. NNC77-0074-stimulated exocytosis was antagonised by the cytoplasmic phospholipase A(2) (cPLA(2)) inhibitors ACA and AACOCF(3) and in cells treated with antisense oligonucleotide against cPLA(2)alpha.

Pancreatic islet insulin secretion and metabolism in adult rats malnourished during neonatal life.

Pancreatic islets were isolated from rats that had been nursed by dams fed with a control or an 8.7% protein diet during the first 12 d of the lactation period. Glucose-induced insulin secretion from islets in the 8.