In pancreatic b-cells, closure of the ATP-sensitive K + (K ATP ) channel is an initial process triggering glucosestimulated insulin secretion. In addition, constitutive opening of background nonselective cation channels (NSCCs) is essentially required to effectively evoke depolarization as a consequence of K ATP channel closure. Thus, it is hypothesized that further opening of NSCC facilitates membrane excitability. We identified a class of NSCC that was activated by exendin (ex)-4, GLP-1, and its analog liraglutide at picomolar levels. This NSCC was also activated by increasing the glucose concentration. NSCC activation by glucose and GLP-1 was a consequence of the activated cAMP/EPAC-mediated pathway and was attenuated in TRPM2-deficient mice. The NSCC was not activated by protein kinase A (PKA) activators and was activated by ex-4 in the presence of PKA inhibitors. These results suggest that glucose-and incretinactivated NSCC (TRPM2) works in concert with closure of the K ATP channel to effectively induce membrane depolarization to initiate insulin secretion. The current study reveals a new mechanism for regulating electrical excitability in b-cells and for mediating the action of glucose and incretin to evoke insulin secretion, thereby providing an innovative target for the treatment of type 2 diabetes.It has been long proposed that glucose-stimulated insulin secretion in pancreatic b-cells is initiated by closure of the ATP-sensitive K + (K ATP ) channel, followed by membrane depolarization (1). In theory, closure of the K ATP channel is an important process but is not sufficient to induce the shift of the membrane potential toward a threshold level, as membrane potential is determined by the overall balance of outward and inward currents. Modest constitutive opening of background inward current through nonselective cation channels (NSCCs) is crucial to facilitate depolarization after K ATP channel closure (2). This idea suggests that further regulated opening of a class of NSCCs may bring about greater depolarization. However, whether glucose metabolism regulates NSCC activity remains unclear.The incretin hormones, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP), potentiate insulin secretion in association with increased intracellular Ca 2+ concentrations at insulin-secreting glucose concentrations (3-5). GLP-1 fails to increase insulin secretion from the islets of mice deficient in transmembrane receptor potential (TRP) melastatin 2 (TRPM2) (6,7), a type of NSCC, suggesting that the TRPM2 channel is essential for GLP-1-induced potentiation of glucose-stimulated insulin secretion (8). GLP-1 depolarizes the plasma membrane by the opening of NSCC in b-cells (2). Several types of NSCC (TRPs) are expressed in insulin-secreting cells (9). The aims of the current study were to determine 1) the type of NSCC activation (through TRPM2 or other TRPs) that is crucial for signaling after stimulation of the incretin receptor, 2) whether the NSCC is modulated by glucose

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BackgroundPatients undergoing hemodialysis (HD) often develop cerebral disease complications. Furthermore, cerebral regional saturation of oxygen (rSO2) was previously reported to be significantly lower in HD patients than in healthy subjects. We aimed to identify the factors affecting the cerebral rSO2 in HD patients.MethodsFifty-four HD patients (38 men and 16 women; mean age, 67.7 ± 1.2 years, HD duration, 6.5 ± 1.9 years) were recruited. Cerebral rSO2 was monitored at the forehead before HD using an INVOS 5100C (Covidien Japan, Tokyo, Japan).ResultsThe rSO2 levels were significantly lower in HD patients compared with healthy controls (49.5 ± 1.7% vs. 68.9 ± 1.6%, p <0.001). Multiple regression analysis showed that cerebral rSO2 independently associated with pH (standardized coefficient: -0.35), HD duration (standardized coefficient: -0.33), and serum albumin concentration (standardized coefficient: 0.28). Furthermore, the rSO2 was significantly lower in HD patients with diabetes mellitus (DM), compared with patients without DM (46.8 ± 1.7% vs. 52.1 ± 1.8%, p <0.05).ConclusionsIn HD patients, cerebral rSO2 was affected by multiple factors, including pH, HD duration, and serum albumin concentration. Furthermore, this is the first report describing significantly lower levels of rSO2 in HD patients with DM than in those without DM.

G protein-coupled receptors (GPCRs) are expressed in pancreatic beta-cells. G protein-coupled receptor 40 (GPR40) contributes to medium- or long-chain fatty acid-induced amplification of glucose-stimulated insulin secretion (GSIS), and GPR40 agonists are promising therapeutic targets in type 2 diabetes. Recently, we demonstrated that glucagon-like peptide 1, a ligand of pancreatic GPCR, activates a class of nonselective cation channels (NSCCs) and enhances GSIS. The aim of the current study was to determine whether the GPR40 signal interacts with NSCCs. A GPR40 agonist (fasiglifam) potentiated GSIS at 8.3 and 16.7 mM glucose but not 2.8 mM glucose. The NSCC current was activated by fasiglifam at 5.6 mM glucose with 100 μM tolbutamide (−70 mV), and this activation was prevented by the presence of pyrazole-3 (transient receptor potential canonical; a TRPC3 channel blocker). Inhibitors of phospholipase C or protein kinase C (PKC) inhibited the increases in GSIS and the NSCC current induced by GPR40 stimulation. The present study demonstrates a novel mechanism for the regulation of insulin secretion by GPR40 agonist in pancreatic beta-cells. The stimulation of the GPR40–PLC/PKC–TRPC3 channel pathway potentiates GSIS by the depolarization of the plasma membrane in pancreatic beta-cell.

BackgroundSaturated fatty acids have been shown to cause insulin resistance and low-grade chronic inflammation, whereas unsaturated fatty acids suppress inflammation via G-protein coupled receptor 120 (GPR120) in macrophages. However, the anti-inflammatory effects of unsaturated fatty acids in adipocytes have yet to be elucidated. Hence, the aims of the present study were to evaluate the anti-inflammatory effects of eicosapentaenoic acid (EPA) via GPR120 in adipocytes.MethodsWe used 250 μM palmitate as a representative saturated fatty acid. 3T3-L1 adipocytes were used for in vitro studies. We further evaluated the effect of EPA supplementation in a high-fat/high-sucrose (HFHS) diet-induced adipose tissue inflammatory mouse model.ResultsEPA attenuated palmitate-induced increases in inflammatory gene expression and NF-κB phosphorylation in 3T3-L1 adipocytes. Silencing of GPR120 abolished the anti-inflammatory effects of EPA. In GPR120 downstream signal analysis, EPA was found to decrease palmitate-induced increases in TAK1/TAB1 complex expression. EPA supplementation suppressed HFHS-induced crown-like structure formation in epididymal adipose tissue and altered macrophage phenotypes from M1 to M2 in the stromal vascular fraction. Moreover, the EPA-containing diet attenuated increases in adipose p-JNK and phospho-p65 NF-κB levels.ConclusionsIn conclusion, the findings of the present study demonstrate that EPA suppresses palmitate-induced inflammation via GPR120 by inhibiting the TAK1/TAB1 interaction in adipocytes. EPA supplementation reduced HFHS diet-induced inflammatory changes in mouse adipose tissues. These results demonstrate adipose GPR120 as a potential therapeutic target for decreasing inflammation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12986-017-0188-0) contains supplementary material, which is available to authorized users.

Abstract. In pancreatic β-cells, glucose-induced closure of the ATP-sensitive K + (KATP) channel is an initial process triggering glucose-stimulated insulin secretion (GSIS). This KATP-channel dependent pathway has been believed to be a central mechanism for GSIS. However, since the resting membrane potential of cells is determined by the balance of the net result of current amplitudes in outward and inward directions, it must be taken into consideration that not only KATP channel inhibition but also inward current via the basal opening of non-selective cation channels (NSCCs) plays a crucial role in membrane potential regulation. The basal activity of NSCCs is essential to effectively evoke depolarization in concert with KATP channel closure that is dependent on glucose metabolism. The present study summarizes recent findings regarding the roles of NSCCs in GSIS and GTP-binding protein coupled receptor-(GPCR) operated potentiation of GSIS. Key words: GPCR, Pancreatic β-cells, TRP channel, Insulin secretionTHE CONCEPT that glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells is initiated by closure of the ATP-sensitive K + (KATP) channel as a result of an increase in the intracellular ATP/ADP ratio induced by glucose metabolism upon elevation of glucose concentration in the blood ( Fig. 1; the triggering pathway), was proposed a long time ago [1][2][3]. Inhibition of the KATP channel is followed by membrane depolarization and activation of voltage-dependent Ca 2+ channels (VDCCs) [4,5]. Opening of the VDCCs brings about firing of action potential, cytosolic Ca 2+ increase and initiation of GSIS [6,7]. The triggering pathway is followed by time-dependent increase in insulin secretion that is potentiated by glucose exposure (the second phase, potentiating pathway or KATP-independent pathway) [3,8] However, closure of the KATP channel alone is not sufficient to induce a shift in the membrane potential towards the threshold level and for the triggering pathway that can activate VDCCs, since membrane potential is theoretically determined by the overall balance of outward and inward currents. Modest background inward currents through opening of nonselective cation channels (NSCCs) are crucial for induction of membrane depolarization following KATP channel closure [9,10]. This idea further suggests that regulation of a class of NSCCs may play an important role in producing effective depolarization of the membrane. Several types of NSCCs have been reported to be expressed in pancreatic β-cells, which, in terms of ion selectivity, are permeable to Na + , K + , and Ca 2+ . In contrast to these ion channels, which have not been well studied, the classic-type ion channels; i.e., the voltage-dependent Na + channel, the voltage-dependent K + channel [11,12], the voltage-dependent Ca 2+ channel [13,14] and the KATP channel have attracted a large amount of interest for a long time, because the first three types of these ion channels play an important role in membrane excitability and the KATP

Postprandial hyperglycemia is a risk factor for cardiovascular disease and mortality. Serum 1,5-anhydroglucitol (1,5-AG) level is an useful clinical marker of glucose metabolism which reflects postprandial hyperglycemia more robustly compared to hemoglobin A1c (HbA1c). Relationship between serum 1,5-AG level and cardiovascular disease has been reported; however, comparison between HbA1c and 1,5-AG as markers of cardiovascular disease was not performed. We included 227 consecutive patients who underwent coronary angiography meeting the following inclusion criteria: (1) patients who had no history of coronary artery disease (CAD); (2) patients without acute coronary syndrome; (3) patients without poorly controlled diabetes mellitus; (4) patients without anemia, liver dysfunction, acute, and chronic renal failure and malnutrition; and (5) patients without adhibition of acarbose or Chinese herbal medicine. We measured HbA1c, glycoalbumin, and 1,5-AG. Serum 1,5-AG was significantly lower in patients with CAD (16.6 ± 8.50 vs. 21.1 ± 7.97 μg/ml, P < 0.001). Multivariable logistic regression analysis showed decrease in serum 1,5-AG was independently associated with the presence of denovo CAD (0.93, 95% CI 0.88-0.98, P = 0.006). Serum 1,5-AG was also independently associated with the presence of denovo CAD in patients without diabetes mellitus (0.94, 95% CI 0.88-0.99, P = 0.046). In conclusion, lower serum 1,5-AG was associated with the presence of denovo CAD. Serum 1,5-AG may identify high cardiovascular risk patients for denovo CAD in both diabetic and non-diabetic patients.

In pancreatic β-cells, pharmacological concentrations of catecholamines, including adrenaline, have been used to inhibit insulin release and explore the multiple mechanisms involved. However, the significance of these signaling pathways for physiological adrenergic functions in β-cells is largely unknown. In the process of glucose-induced insulin secretion, opening of background current through nonselective cation channels (NSCCs) might facilitate membrane depolarization by closure of the ATP-sensitive K channels. Here, we examined whether physiological insulinostatic adrenaline action is mediated via the transient receptor potential melastatin 2 (TRPM2) channel, a type of NSCC, in β-cells. Results showed that physiological concentrations of adrenaline strongly suppressed glucose-induced and incretin-potentiated cAMP production and insulin secretion and inhibited NSCCs current and membrane excitability via the α2A-adrenoceptor in wild-type mice; however, insulin secretion was not attenuated in TRPM2-knockout (KO) mice. Administration of yohimbine, an α2-adrenoceptor antagonist, failed to affect glucose tolerance in TRPM2-KO mice, in contrast to an improved glucose tolerance in wild-type mice receiving the antagonist. The current study demonstrated that a physiological concentration of adrenaline attenuates insulin release via coupling of α2A-adrenoceptor to cAMP/TRPM2 signaling, thereby providing a potential therapeutic tool to treat patients with type 2 diabetes.