Stimulatory effect of imeglimin on incretin secretion.

Aims/introduction: Imeglimin is a new antidiabetic drug structurally related to metformin. Despite this structural similarity, only imeglimin augments glucose-stimulated insulin secretion (GSIS), with the mechanism underlying this effect remaining unclear. Given that glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) also enhance GSIS, we examined whether these incretin hormones might contribute to the pharmacological actions of imeglimin.

Dopamine Negatively Regulates Insulin Secretion Through Activation of D1-D2 Receptor Heteromer.

There is increasing evidence that dopamine (DA) functions as a negative regulator of glucose-stimulated insulin secretion; however, the underlying molecular mechanism remains unknown. Using total internal reflection fluorescence microscopy, we monitored insulin granule exocytosis in primary islet cells to dissect the effect of DA. We found that D1 receptor antagonists rescued the DA-mediated inhibition of glucose-stimulated calcium (Ca2+) flux, thereby suggesting a role of D1 in the DA-mediated inhibition of insulin secretion.

O-GlcNAcylation of myocyte-specific enhancer factor 2D negatively regulates insulin secretion from pancreatic β-cells.

Patients with type 2 diabetes often exhibit impairments in both glucose-induced insulin secretion (GIIS) and incretin-induced insulin secretion (IIIS). These phenotypes are associated with altered glucose metabolism in pancreatic β-cells, although the molecular mechanisms remain unclear. Here, we used MIN6-K8 pancreatic β-cell lines as a model to examine the effect of O-linked N-acetylglucosamine glycosylation (O-GlcNAcylation), a glucose-induced protein posttranslational modification, on insulin secretion.

-deficient mice develop somatosensory dysfunction and axonal loss in the peripheral nerves.

Glucose-responsive ATP-sensitive potassium channels (K) are expressed in a variety of tissues including nervous systems. The depolarization of the membrane potential induced by glucose may lead to hyperexcitability of neurons and induce excitotoxicity. However, the roles of K in the peripheral nervous system (PNS) are poorly understood.

Increased glycolysis affects β-cell function and identity in aging and diabetes.

Objective: Age is a risk factor for type 2 diabetes (T2D). We aimed to elucidate whether β-cell glucose metabolism is altered with aging and contributes to T2D.

Methods: We used senescence-accelerated mice (SAM), C57BL/6J (B6) mice, and ob/ob mice as aging models.

Lactate is an energy substrate for rodent cortical neurons and enhances their firing activity.

Glucose is the mandatory fuel for the brain, yet the relative contribution of glucose and lactate for neuronal energy metabolism is unclear. We found that increased lactate, but not glucose concentration, enhances the spiking activity of neurons of the cerebral cortex. Enhanced spiking was dependent on ATP-sensitive potassium (K) channels formed with KCNJ11 and ABCC8 subunits, which we show are functionally expressed in most neocortical neuronal types.

Glutamate is an essential mediator in glutamine-amplified insulin secretion.

Aims/introduction: Glutamine is the most abundant amino acid in the circulation. In this study, we investigated cell signaling in the amplification of insulin secretion by glutamine.

Materials And Methods: Clonal pancreatic β-cells MIN6-K8, wild-type B6 mouse islets, glutamate dehydrogenase (GDH) knockout clonal β-cells (Glud1KOβCL), and glutamate-oxaloacetate transaminase 1 (GOT1) knockout clonal β-cells (Got1KOβCL) were studied.

Gs/Gq signaling switch in β cells defines incretin effectiveness in diabetes.

By restoring glucose-regulated insulin secretion, glucagon-like peptide-1-based (GLP-1-based) therapies are becoming increasingly important in diabetes care. Normally, the incretins GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) jointly maintain normal blood glucose levels by stimulation of insulin secretion in pancreatic β cells. However, the reason why only GLP-1-based drugs are effective in improving insulin secretion after presentation of diabetes has not been resolved.

The PDK1-FoxO1 signaling in adipocytes controls systemic insulin sensitivity through the 5-lipoxygenase-leukotriene B axis.

Although adipocytes are major targets of insulin, the influence of impaired insulin action in adipocytes on metabolic homeostasis remains unclear. We here show that adipocyte-specific PDK1 (3'-phosphoinositide-dependent kinase 1)-deficient (A-PDK1KO) mice manifest impaired metabolic actions of insulin in adipose tissue and reduction of adipose tissue mass. A-PDK1KO mice developed insulin resistance, glucose intolerance, and hepatic steatosis, and this phenotype was suppressed by additional ablation of FoxO1 specifically in adipocytes (A-PDK1/FoxO1KO mice) without an effect on adipose tissue mass.

GCN2 regulates pancreatic β cell mass by sensing intracellular amino acid levels.

EIF2AK4, which encodes the amino acid deficiency-sensing protein GCN2, has been implicated as a susceptibility gene for type 2 diabetes in the Japanese population. However, the mechanism by which GCN2 affects glucose homeostasis is unclear. Here, we show that insulin secretion is reduced in individuals harboring the risk allele of EIF2AK4 and that maintenance of GCN2-deficient mice on a high-fat diet results in a loss of pancreatic β cell mass.

Tumor-like features of gene expression and metabolic profiles in enlarged pancreatic islets are associated with impaired incretin-induced insulin secretion in obese diabetes: A study of Zucker fatty diabetes mellitus rat.

Aims/introduction: Pancreatic islets are heterogenous. To clarify the relationship between islet heterogeneity and incretin action in the islets, we studied gene expression and metabolic profiles of non-large and enlarged islets of the Zucker fatty diabetes mellitus rat, an obese diabetes model, as well as incretin-induced insulin secretion (IIIS) in these islets.

Materials And Methods: Pancreatic islets of control (fa/+) and fatty (fa/fa) rats at 8 and 12 weeks-of-age were isolated.

Braving the Element: Pancreatic β-Cell Dysfunction and Adaptation in Response to Arsenic Exposure.

Type 2 diabetes mellitus (T2DM) is a serious global health problem, currently affecting an estimated 451 million people worldwide. T2DM is characterized by hyperglycemia and low insulin relative to the metabolic demand. The precise contributing factors for a given individual vary, but generally include a combination of insulin resistance and insufficient insulin secretion.

Glutamate as intracellular and extracellular signals in pancreatic islet functions.

l-Glutamate is one of the most abundant amino acids in the body and is a constituent of proteins and a substrate in metabolism. It is well known that glutamate serves as a primary excitatory neurotransmitter and a critical neuromodulator in the brain. Recent studies have shown that in addition to its pivotal role in neural functions, glutamate plays many important roles in a variety of cellular functions, including those as intracellular and extracellular signals.

Arsenic modifies serotonin metabolism through glucuronidation in pancreatic β-cells.

In arsenic-endemic regions of the world, arsenic exposure correlates with diabetes mellitus. Multiple animal models of inorganic arsenic (iAs, as As) exposure have revealed that iAs-induced glucose intolerance manifests as a result of pancreatic β-cell dysfunction. To define the mechanisms responsible for this β-cell defect, the MIN6-K8 mouse β-cell line was exposed to environmentally relevant doses of iAs.

Impaired glucagon secretion in patients with fulminant type 1 diabetes mellitus.

Purpose: Fulminant type 1 diabetes mellitus (FT1DM), characterized by rapid and almost complete destruction of pancreatic β-cells, is a newly identified subtype of type 1 diabetes mellitus. Although, the pathophysiology of this condition remains still unclear, histological evidence suggests that not only β-cells but also α-cells of pancreatic islets are reduced in number in FT1DM. However, the ability of glucagon secretion in patients with this condition has remained largely uncharacterized.

Somatostatin Is Only Partly Required for the Glucagonostatic Effect of Glucose but Is Necessary for the Glucagonostatic Effect of K Channel Blockers.

The mechanisms of control of glucagon secretion are largely debated. In particular, the paracrine role of somatostatin (SST) is unclear. We studied its role in the control of glucagon secretion by glucose and K channel blockers, using perifused islets and the in situ perfused pancreas.

Functional adenosine triphosphate-sensitive potassium channel is required in high-carbohydrate diet-induced increase in β-cell mass.

Aims/introduction: A high-carbohydrate diet is known to increase insulin secretion and induce obesity. However, whether or not a high-carbohydrate diet affects β-cell mass (BCM) has been little investigated.

Materials And Methods: Both wild-type (WT) mice and adenosine triphosphate-sensitive potassium channel-deficient (Kir6.

Ectopic overexpression of Kir6.1 in the mouse heart impacts on the life expectancy.

We recently reported the reduced ATP-sensitive potassium (K) channel activities in the transgenic mouse heart overexpressing the vascular type K channel pore-forming subunit (Kir6.1). Although dysfunction of cardiac K channel has been nominated as a cause of cardiomyopathy in human, these transgenic mice looked normal as wild-type (WT) during the experiment period (~20 weeks).

Activation of GLP-1 receptor signalling alleviates cellular stresses and improves beta cell function in a mouse model of Wolfram syndrome.

Aims/hypothesis: Loss of functional beta cells results in a gradual progression of insulin insufficiency in Wolfram syndrome caused by recessive WFS1 mutations. However, beta cell dysfunction in Wolfram syndrome has yet to be fully characterised, and there are also no specific treatment recommendations. In this study, we aimed to characterise beta cell secretory defects and to examine the potential effects of a glucagon-like peptide-1 (GLP-1) receptor agonist on diabetes in Wolfram syndrome.

Inhibition of SNAT5 Induces Incretin-Responsive State From Incretin-Unresponsive State in Pancreatic β-Cells: Study of β-Cell Spheroid Clusters as a Model.

β-Cell-β-cell interactions are required for normal regulation of insulin secretion. We previously found that formation of spheroid clusters (called K20-SC) from MIN6-K20 clonal β-cells lacking incretin-induced insulin secretion (IIIS) under monolayer culture (called K20-MC) drastically induced incretin responsiveness. Here we investigated the mechanism by which an incretin-unresponsive state transforms to an incretin-responsive state using K20-SC as a model.

Characteristics of repaglinide effects on insulin secretion.

The dynamics of insulin secretion stimulated by repaglinide, a glinide, and the combinatorial effects of repaglinide and incretin were investigated. At 4.4 mM glucose, repaglinide induced insulin secretion with a gradually increasing first phase, showing different dynamics from that induced by glimepiride, a sulfonylurea.

Arsenic exposure induces glucose intolerance and alters global energy metabolism.

Environmental pollutants acting as endocrine-disrupting chemicals (EDCs) are recognized as potential contributors to metabolic disease pathogenesis. One such pollutant, arsenic, contaminates the drinking water of ~100 million people globally and has been associated with insulin resistance and diabetes in epidemiological studies. Despite these observations, the precise metabolic derangements induced by arsenic remain incompletely characterized.

Essential roles of aspartate aminotransferase 1 and vesicular glutamate transporters in β-cell glutamate signaling for incretin-induced insulin secretion.

Incretins (GLP-1 and GIP) potentiate insulin secretion through cAMP signaling in pancreatic β-cells in a glucose-dependent manner. We recently proposed a mechanistic model of incretin-induced insulin secretion (IIIS) that requires two critical processes: 1) generation of cytosolic glutamate through the malate-aspartate (MA) shuttle in glucose metabolism and 2) glutamate transport into insulin granules by cAMP signaling to promote insulin granule exocytosis. To directly prove the model, we have established and characterized CRISPR/Cas9-engineered clonal mouse β-cell lines deficient for the genes critical in these two processes: aspartate aminotransferase 1 (AST1, gene symbol Got1), a key enzyme in the MA shuttle, which generates cytosolic glutamate, and the vesicular glutamate transporters (VGLUT1, VGLUT2, and VGLUT3, gene symbol Slc17a7, Slc17a6, and Slc17a8, respectively), which participate in glutamate transport into secretory vesicles.

Electrophysiological analyses of transgenic mice overexpressing KCNJ8 with S422L mutation in cardiomyocytes.

Genetic analysis of KCNJ8 has pointed a mutation (S422L) as a susceptible link to J wave syndrome (JWS). In vitro expression study indicated that the ATP-sensitive K (K) channel with the S422L mutation has the gain-of-function with reduced sensitivity to ATP. However, the electrophysiological impact of KCNJ8 has not been elucidated in vivo.