The role of TRPM2 in pancreatic β-cells and the development of diabetes

TRPM2 is a Ca²⁺-permeable non-selective cation channel that can be activated by adenosine dinucleotides, hydrogen peroxide, or intracellular Ca²⁺. The protein is expressed in a wide variety of cells, including neurons in the brain, immune cells, endocrine cells, and endothelial cells. This channel is also well expressed in β-cells in the pancreas. Insulin secretion from pancreatic β-cells is the primary mechanism by which the concentration of blood glucose is reduced. Thus, impairment of insulin secretion leads to hyperglycemia and eventually causes diabetes. Glucose is the principal stimulator of insulin secretion. The primary pathway involved in glucose-stimulated insulin secretion is the ATP-sensitive K⁺ (K_ATP) channel to voltage-gated Ca²⁺ channel (VGCC)-mediated pathway. Increases in the intracellular Ca²⁺ concentration are necessary for insulin secretion, but VGCC is not sufficient to explain [Ca²⁺]_i increases in pancreatic β-cells and the resultant secretion of insulin. In this review, we focus on TRPM2 as a candidate for a [Ca²⁺]_i modulator in pancreatic β-cells and its involvement in insulin secretion and development of diabetes. Although further analyses are needed to clarify the mechanism underlying TRPM2-mediated insulin secretion, TRPM2 could be a key player in the regulation of insulin secretion and could represent a new target for diabetes therapy.     

Calcium signaling in pancreatic β-cells in health and in Type 2 diabetes

Changes in cytosolic free Ca²⁺ concentration ([Ca²⁺]_c) play a crucial role in the control of insulin secretion from the electrically excitable pancreatic β-cell. Secretion is controlled by the finely tuned balance between Ca²⁺ influx (mainly through voltage-dependent Ca²⁺ channels, but also through voltage-independent Ca²⁺ channels like store-operated channels) and efflux pathways. Changes in [Ca²⁺]_c directly affect [Ca²⁺] in various organelles including the endoplasmic reticulum (ER), mitochondria, the Golgi apparatus, secretory granules and lysosomes, as imaged using recombinant targeted probes. Because most of these organelles have specific Ca²⁺ influx and efflux pathways, they mutually influence free [Ca²⁺] in the others. In this article, we review the mechanisms of control of [Ca²⁺] in various compartments and particularly the cytosol, the endoplasmic reticulum ([Ca²⁺]_ER), acidic stores and mitochondrial matrix ([Ca²⁺]_mito), focusing chiefly on the most important physiological stimulus of β-cells, glucose. We also briefly review some alterations of β-cell Ca²⁺ homeostasis in Type 2 diabetes.     

Validity and reliability of a self-reported measure of medication adherence in patients with Type 2 diabetes mellitus in Singapore

Diabet. Med. 29, e338-e344 (2012) ABSTRACT: Aims A reliable and valid measure is essential for the assessment of medication adherence. Until now, no patient-reported medication adherence measure has been validated in Singapore. The aim of this study was to validate a modified 4-item Morisky-Green-Levine Medication Adherence Scale in patients with Type?2 diabetes in Singapore. Methods A cross-sectional survey was conducted in a sample of outpatients with Type?2 diabetes in Singapore from September to December in 2009. Respondents completed either an English or Chinese version of the modified 4-item Morisky-Green-Levine Medication Adherence Scale. The scale scores ranged from 0 to 4, with higher scores indicating better medication adherence. Reliability was assessed using Cronbach's alpha. Content validity was assessed by expert review. Construct validity was examined using factor analysis and hypothesis testing. Results Of the 294 respondents who completed the modified Morisky-Green-Levine Medication Adherence Scale, 13.3, 21.4, 35.7 and 29.6% had a score of 0-1, 2, 3 and 4, respectively. The internal consistency of the scale was moderate (Cronbach's alpha?=?0.62). Principal component analysis showed that the four items loaded onto one factor (eigenvalue?=?1.95). Respondents with higher scores were older (P?相似文献   

Prevalence and clinical characteristics of diabetic peripheral neuropathy in hospital patients with Type 2 diabetes in Korea

Diabet. Med. 29, e290-e296 (2012) ABSTRACT: Aims Diabetic peripheral neuropathy is a common complication of diabetes. This cross-sectional study investigated the prevalence and clinical characteristics of this neuropathy in patients with Type?2 diabetic mellitus treated at hospitals in Korea. Methods Questionnaires and medical records were used to collect data on 4000 patients with Type?2 diabetes from the diabetes clinics of 40 hospitals throughout Korea. Diabetic peripheral neuropathy was diagnosed based on a review of medical records or using the Michigan Neuropathy Screening Instrument score and monofilament test. Results The prevalence of neuropathy was 33.5% (n?=?1338). Multivariate analysis revealed that age, female sex, diabetes duration, lower glycated haemoglobin, treatment with oral hypoglycaemic agents or insulin, presence of retinopathy, history of cerebrovascular or peripheral arterial disease, presence of hypertension or dyslipidaemia, and history of foot ulcer were independently associated with diabetic peripheral neuropathy. Of the patients with neuropathy, 69.8% were treated for the condition and only 12.6% were aware of their neuropathy. Conclusion There was a high prevalence of peripheral neuropathy in patients with Type?2 diabetes in Korea and those patients were far more likely to have complications or co-morbidities. The proper management of diabetic peripheral neuropathy deserves attention from clinicians to ensure better management of diabetes in Korea.     

Association of a variant in exon 31 of the sulfonylurea receptor 1 (SUR1) gene with type 2 diabetes mellitus in French Caucasians

The sulfonylurea receptor (SUR1) of the pancreatic beta-cell ATP-sensitive potassium channel plays a key role in glucose-induced insulin secretion. The A-allele of a single nucleotide polymorphism (SNP) in exon 31 of the SUR1 gene (AGG-->AGA; Arg1273Arg) has previously been shown to be associated with hyperinsulinemia in nondiabetic Mexican-American subjects. Here, we have investigated the association of this SNP with type 2 diabetes mellitus (T2DM) in French Caucasian subjects. We have observed an increased frequency of the A allele (37.1% vs 27.6%, P=0.0048; odds ratio 1.54), of the AA genotype (15.7% vs 9.8%; P=0.025), and of the combined AA/AG genotypes (58.5% vs 45.5%, P=0.0098; odds ratio 1.69) in patients compared with controls. This association is stronger in the subgroup of patients with age of diagnosis of diabetes equal to or less than 45 years: A allele 43.2% (P=0.0003 compared with controls; odds ratio 1.99), AA genotype 21.4% (P=0.0032), and combined AA/AG genotypes 65.1% (P=0.0022; odds ratio 2.23). Unexpectedly, the G allele is strongly associated with arterial hypertension in obese diabetic subjects (GG vs AA odds ratio 19.97). In conclusion, we have observed an association of an SNP in exon 31 of the SUR1 gene with T2DM. These data reinforce the hypothesis that insulin secretion defects in T2DM might be at least partially related to allelic variations in the SUR1 gene.     

The role of autophagy in pancreatic β-cell and diabetes

Pancreatic β-cells play a key role in glucose homeostasis in mammals. Although large-scale protein synthesis and degradation occur in pancreatic β-cells, the mechanism underlying dynamic protein turnover in β-cells remains largely unknown. We found low-level constitutive autophagy in β-cells of C57BL/6 mice fed a standard diet; however, autophagy was markedly upregulated in mice fed a high-fat diet. β-cells of diabetic db/db mice contained large numbers of autophagosomes, compared with non-diabetic db/misty controls. The functional importance of autophagy was analyzed using β-cell-specific Atg7 knockout mice. Autophagy-deficient mice showed degeneration of β-cells and impaired glucose tolerance with reduced insulin secretion. While a high-fat diet stimulated β-cell autophagy in control mice, it induced a profound deterioration of glucose intolerance in β-cell autophagy-deficient mutants, partly because of the lack of a compensatory increase in β-cell mass. These results suggest that the degradation of unnecessary cellular components by autophagy is essential for maintenance of the architecture and function of β-cells. Autophagy also serves as a crucial element of stress responses to protect β-cells under insulin resistant states. Impairment of autophagic machinery could thus predispose individuals to type 2 diabetes.     

Altered islet composition and disproportionate loss of large islets in patients with type 2 diabetes

Human islets exhibit distinct islet architecture with intermingled alpha- and beta-cells particularly in large islets. In this study, we quantitatively examined pathological changes of the pancreas in patients with type 2 diabetes (T2D). Specifically, we tested a hypothesis that changes in endocrine cell mass and composition are islet-size dependent. A large-scale analysis of cadaveric pancreatic sections from T2D patients (n = 12) and non-diabetic subjects (n = 14) was carried out combined with semi-automated analysis to quantify changes in islet architecture. The method provided the representative islet distribution in the whole pancreas section that allowed us to examine details of endocrine cell composition in individual islets. We observed a preferential loss of large islets (>60 µm in diameter) in T2D patients compared to non-diabetic subjects. Analysis of islet cell composition revealed that the beta-cell fraction in large islets was decreased in T2D patients. This change was accompanied by a reciprocal increase in alpha-cell fraction, however total alpha-cell area was decreased along with beta-cells in T2D. Delta-cell fraction and area remained unchanged. The computer-assisted quantification of morphological changes in islet structure minimizes sampling bias. Significant beta-cell loss was observed in large islets in T2D, in which alpha-cell ratio reciprocally increased. However, there was no alpha-cell expansion and the total alpha-cell area was also decreased. Changes in islet architecture were marked in large islets. Our method is widely applicable to various specimens using standard immunohistochemical analysis that may be particularly useful to study large animals including humans where large organ size precludes manual quantitation of organ morphology.     

The Role of Cohesiveness in the Permeability of the Spatial Assemblies of FG Nucleoporins

Nuclear pore complexes (NPCs) conduct selective, bidirectional transport across the nuclear envelope. The NPC passageway is lined by intrinsically disordered proteins that contain hydrophobic phenylalanine-glycine (FG) motifs, known as FG nucleoporins (FG nups), that play the key role in the NPC transport mechanism. Cohesive interactions among the FG nups, which arise from the combination of hydrophobic, electrostatic, and other forces, have been hypothesized to control the morphology of the assemblies of FG nups in the NPC, as well as their permeability with respect to the transport proteins. However, the role of FG nup cohesiveness is still vigorously debated. Using coarse-grained polymer theory and numerical simulations, we study the effects of cohesiveness on the selective permeability of in vitro FG nup assemblies in different geometries that have served as proxies for the morphological and transport properties of the NPC. We show that in high-density FG nup assemblies, increase in cohesiveness leads to the decrease in their permeability, in accordance with the accepted view. On the other hand, the permeability of low-density assemblies is a nonmonotonic function of the cohesiveness, and a moderate increase in cohesiveness can enhance permeability. The density- and cohesiveness-dependent effects on permeability are explained by considering the free-energy cost associated with penetrating the FG nup assemblies. We discuss the implications of these findings for the organization and function of the NPC.     

The involvement of peroxidases in soybean seedlings’ defense against infestation of cowpea aphid

Changes in the level of hydrogen peroxide (H₂O₂) and activity of peroxidases towards phenolic substrates (EC 1.11.1.7) such as pyrogallol (PPX), syringaldazine (SPX) and guaiacol (GPX), and cytosolic ascorbate peroxidase (cAPX, EC 1.11.1.11) in response to infestation of cowpea aphid (Aphis craccivora Koch) were analyzed in soybean (Glycine max (L.) Merr. cv. “Nam Dan”) at the V3 stage (first two trifoliate leaves fully developed, third trifoliate leaf unrolled) for 96 h post-infestation (hpi). Influence of A. craccivora at a varied population size (10, 20 and 30 individuals per each soybean plant) caused a burst of H₂O₂ generation in the aphid-infested leaves at 12 hpi. Paralleling the H₂O₂ accumulation, peroxidase activity in all the infested plants remarkably increased and was significantly higher than that observed in controls (uninfested plants). The cascade of enzymes induced was continuously overlapped by the early enhancement of SPX within 6–24 hpi, an expression of cAPX (12–48 hpi) followed by an accumulation of GPX (24–72 hpi) and PPX (24–96 hpi). The differential induction of SPX, GPX, PPX and cAPX resulted in a rapid reduction of H₂O₂ content in aphid-infested leaves, and the activity of peroxidase was closely correlated with the intensity of A. craccivora infestation around the defined points of time at which the activity of each enzyme reached the maximum level. The increase in activity of peroxidases matched their function as controlling accumulation of H₂O₂ and detoxifying this reactive oxygen product when soybean plants were challenged with cowpea aphid. Furthermore, peroxidases could directly deter cowpea aphid feeding through other functions such as the anti-nutritive and/or toxicological defenses and/or limiting the penetration of aphid stylets into plant tissues via participating to strengthen and reinforce the cell wall barrier. These results indicated that peroxidases may be some elements of the defense system that increased the resistance of G. max cv. “Nam Dan” to infestation of A. craccivora.     

The control of hepatic glycogen metabolism in an in vitro model of sepsis

Culturing hepatocytes with a combination of LPS, TNF-α, IL-1β and IFN-γ resulted in an inhibition of glucose output from glycogen and prevented the repletion of glycogen in freshly cultured cells. The reduced glycogen mobilisation correlated with the lower cell glycogen content and reduced rate of glycogen synthesis from [U-¹⁴C]glucose rather than alterations in either total phosphorylase or phosphorylase a activity. There was no change in the percentage of glycogen exported as glucose nor the production of lactate plus pyruvate indicating that redistribution of the Gluc-6-P cannot explain the failure of the liver to export glucose. Although changes in glycogen mobilisation correlated with NO production, inhibition of NO synthase by inclusion of L-NMMA in the culture medium failed to prevent the inhibition of either glycogen accumulation or mobilisation by the proinflammatory cytokines, precluding the involvement of NO in this response. LPS plus cytokine treatment had no effect on total glycogen synthase activity although the activity ratio was lowered, indicative of increased phosphorylation. The inhibition of glycogen synthesis correlated with a fall in the intracellular concentrations of Gluc-6-P and UDP-glucose and in the absence of measured changes in kinase activity, it is suggested that the fall in Gluc-6-P reduces both substrate supply and glycogen synthase phosphatase activity. The fall in Gluc-6-P coincided with a reduction in total glucokinase and hexokinase activity within the cells, but no significant change in either the translocation of glucokinase or glucose-6-phosphatase activity. This demonstrates direct cytokine effects on glycogen metabolism independent of changes in glucoregulatory hormones.     

The localization of the relaxed form of plasminogen activator inhibitor type 2 in human gingival tissues

The plasminogen activating system is important in extracellular proteolysis. Plasmin degrades tissues and activates proteases. Plasminogen activators (tissue type; t-PA and urokinase type; u-PA) and plasminogen activator inhibitors (PAI-1, PAI-2) are found in high concentrations in gingival crevicular fluid (GCF). Previous findings indicate the significance of PAI-2 in gingival inflammation. When PAI-2 inhibits a plasminogen activator its conformation relaxes and neoepitopes can be detected with a monoclonal antibody (#2H5). Our aim was to study if and where in the gingival region PAI-2 has acted as an inhibitor. Methodological studies were performed on GCF with western blotting. Frozen sections of human gingiva were studied immunohistochemically. The methodological studies showed that our antibody #2H5 selectively detects relaxed low molecular weight non-glycosylated PAI-2. Total PAI-2 and relaxed PAI-2 were found in all gingival epithelia with a honeycomb-like staining. Relaxed PAI-2 showed the most pronounced staining in the cell layers near the surface of the epithelium and no staining in the suprabasal layers, while total PAI-2 was found throughout the epithelium, often more pronounced suprabasally. The results showed that PAI-2 indeed has acted as an inhibitor of a protease in gingival tissues, primarily in the epithelia. The results also suggest primarily an intracellular localization and thus the interaction of PAI-2 with a protein other than t-PA.     

Type 2 diabetes caused by reductive redox potential?

<正>Reactive oxygen species arise(ROS)in the mitochondria as byproducts of respiration and oxidase activity and have important roles in many physiological and pathophysiological conditions.The current literature indicate that excessive levels of ROS can cause oxidative stress and that lots of evidences link ROS and oxidative stress to the pathogenesis of type 2 diabetes mellitus(T2DM)and development of complications.Several studies have shown elevated extraand intracellular glucose concentrations result in oxidative stress both in animal models of diabetes and in diabetic patients[1].And ROS can contribute to the development and progression of diabetes and related complications by directly damaging DNA,proteins,and lipids or indirectly activating a number of cellular stress-sensitive pathways to induce damage to tissues such as isletβcells[2].     

The Role of Viral Infection in Pest Control: A Mathematical Study

In this paper, we propose a mathematical model of viral infection in pest control. As the viral infection induces host lysis which releases more virus into the environment, on the average ‘κ’ viruses per host, κ∈(1,∞), so the ‘virus replication parameter’ is chosen as the main parameter on which the dynamics of the infection depends. There exists a threshold value κ ₀ beyond which the infection persists in the system. Still for increasing the value of κ, the endemic equilibrium bifurcates towards a periodic solution, which essentially indicates that the viral pesticide has a density-dependent ‘numerical response’ component to its action. Investigation also includes the dependence of the process on predation of natural enemy into the system. A concluding discussion with numerical simulation of the model is also presented.