scholarly journals KCNJ11: Genetic Polymorphisms and Risk of Diabetes Mellitus

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Polin Haghvirdizadeh ◽  
Zahurin Mohamed ◽  
Nor Azizan Abdullah ◽  
Pantea Haghvirdizadeh ◽  
Monir Sadat Haerian ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Secretion ◽  
Katp Channel ◽  
Pancreatic Beta Cells ◽  
Current Evidence ◽  
Nucleotide Polymorphisms ◽  
Sulfonylurea Receptor ◽  
Risk Variants ◽  
Kcnj11 Gene ◽  
Dm Type 2

Diabetes mellitus (DM) is a major worldwide health problem and its prevalence has been rapidly increasing in the last century. It is caused by defects in insulin secretion or insulin action or both, leading to hyperglycemia. Of the various types of DM, type 2 occurs most frequently. Multiple genes and their interactions are involved in the insulin secretion pathway. Insulin secretion is mediated through the ATP-sensitive potassium (KATP) channel in pancreatic beta cells. This channel is a heteromeric protein, composed of four inward-rectifier potassium ion channel (Kir6.2) tetramers, which form the pore of the KATP channel, as well as sulfonylurea receptor 1 subunits surrounding the pore. Kir6.2 is encoded by the potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11) gene, a member of the potassium channel genes. Numerous studies have reported the involvement of single nucleotide polymorphisms of the KCNJ11 gene and their interactions in the susceptibility to DM. This review discusses the current evidence for the contribution of common KCNJ11 genetic variants to the development of DM. Future studies should concentrate on understanding the exact role played by these risk variants in the development of DM.

scholarly journals KCNJ11: Genetic Polymorphisms and Risk of Diabetes Mellitus

2014 ◽  
Vol 2014 ◽  
pp. 1-9
Author(s):  
Polin Haghvirdizadeh ◽  
Zahurin Mohamed ◽  
Nor Azizan Abdullah ◽  
Pantea Haghvirdizadeh ◽  
Monir Sadat Haerian ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Secretion ◽  
Katp Channel ◽  
Pancreatic Beta Cells ◽  
Current Evidence ◽  
Nucleotide Polymorphisms ◽  
Sulfonylurea Receptor ◽  
Risk Variants ◽  
Kcnj11 Gene ◽  
Dm Type 2

Diabetes mellitus (DM) is a major worldwide health problem and its prevalence has been rapidly increasing in the last century. It is caused by defects in insulin secretion or insulin action or both, leading to hyperglycemia. Of the various types of DM, type 2 occurs most frequently. Multiple genes and their interactions are involved in the insulin secretion pathway. Insulin secretion is mediated through the ATP-sensitive potassium (KATP) channel in pancreatic beta cells. This channel is a heteromeric protein, composed of four inward-rectifier potassium ion channel (Kir6.2) tetramers, which form the pore of the KATP channel, as well as sulfonylurea receptor 1 subunits surrounding the pore. Kir6.2 is encoded by the potassium inwardly rectifying channel, subfamily J, member 11 (KCNJ11) gene, a member of the potassium channel genes. Numerous studies have reported the involvement of single nucleotide polymorphisms of the KCNJ11 gene and their interactions in the susceptibility to DM. This review discusses the current evidence for the contribution of common KCNJ11 genetic variants to the development of DM. Future studies should concentrate on understanding the exact role played by these risk variants in the development of DM.

Endothelial cell-derived triosephosphate isomerase attenuates insulin secretion from pancreatic beta cells of male rats

Endocrinology ◽  
2020 ◽  
Author(s):  
Bareket Daniel ◽  
Ariela Livne ◽  
Guy Cohen ◽  
Shirin Kahremany ◽  
Shlomo Sasson
Keyword(s):  
Insulin Secretion ◽  
Endothelial Cell ◽  
Beta Cell ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Triosephosphate Isomerase ◽  
Male Rats ◽  
Second Phase ◽  
Dependent Manner ◽  
Sulfonylurea Receptor

Abstract Insulin secretion from pancreatic beta cells is tightly regulated by glucose and paracrine signals within the microenvironment of islets of Langerhans. Extracellular matrix from islet microcapillary endothelial cells (IMEC) affect beta-cell spreading and amplify insulin secretion. This study was aimed at investigating the hypothesis contact-independent paracrine signals generated from IMEC may also modulate beta-cell insulin secretory functions. For this purpose, conditioned medium (CMp) preparations were prepared from primary cultures of rat IMEC and were used to simulate contact-independent beta cell-endothelial cell communication. GSIS assays were then performed on freshly isolated rat islets and the INS-1E insulinoma cell line, followed by fractionation of the CMp, mass-spectroscopic identification of the factor, and mechanism of action characterization. The IMEC-derived CMp markedly attenuated first- and second-phase GSIS in a time- and dose-dependent manner without altering cellular insulin content and cell viability. Size-exclusion fractionation, chromatographic and mass-spectroscopic analyses of the CMp identified the attenuating factor as the enzyme Triosephosphate Isomerase (TPI). An antibody against TPI abrogated the attenuating activity of the CMp while recombinant human TPI (hTPI) attenuated GSIS from beta cells. This effect was reversed in the presence of tolbutamide in the GSIS assay. In silico docking simulation identified regions on TPI dimer that were important for potential interactions with the extracellular epitopes of the sulfonylurea receptor in the complex. This study supports the hypothesis that an effective paracrine interaction exists between IMEC and beta cells and modulates glucose-induced insulin secretion via TPI- sulfonylurea receptor- KATP channel (SUR1-Kir6.2) complex attenuating interactions.

scholarly journals The structure and function of the ATP-sensitive K+ channel in insulin-secreting pancreatic beta-cells

1999 ◽  
Vol 22 (2) ◽  
pp. 113-123 ◽  
Author(s):  
T Miki ◽  
K Nagashima ◽  
S Seino
Keyword(s):  
Molecular Structure ◽  
Insulin Secretion ◽  
Beta Cell ◽  
Beta Cells ◽  
Katp Channel ◽  
Pancreatic Beta Cells ◽  
Pancreatic Beta Cell ◽  
Molecular Genetic ◽  
Katp Channels ◽  
K Channel

ATP-sensitive K+ channels (KATP channels) play important roles in many cellular functions by coupling cell metabolism to electrical activity. The KATP channels in pancreatic beta-cells are thought to be critical in the regulation of glucose-induced and sulfonylurea-induced insulin secretion. Until recently, however, the molecular structure of the KATP channel was not known. Cloning members of the novel inwardly rectifying K+ channel subfamily Kir6.0 (Kir6.1 and Kir6.2) and the sulfonylurea receptors (SUR1 and SUR2) has clarified the molecular structure of KATP channels. The pancreatic beta-cell KATP channel comprises two subunits: a Kir6.2 subunit and an SUR1 subunit. Molecular biological and molecular genetic studies have provided insights into the physiological and pathophysiological roles of the pancreatic beta-cell KATP channel in insulin secretion.

scholarly journals The effect of metformin on fasting and postprandial insulin secretion in obese patients with diabetes mellitus type 2

2007 ◽  
Vol 135 (7-8) ◽  
pp. 447-452 ◽  
Author(s):  
Mira Vukovic ◽  
Mirjana Lapcevic ◽  
Nevena Kalezic ◽  
Branislav Gvozdenovic
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Secretion ◽  
Statistical Significance ◽  
The Body ◽  
Obese Patients ◽  
Peripheral Tissues ◽  
Glucose Output ◽  
Dm Type 2 ◽  
Postprandial Insulin

Introduction The main causes of reduced glucose levels during metformin therapy appear to be an increase in insulin action in peripheral tissues and reduced hepatic glucose output due to inhibition gluconeogenesis. Objective The purpose of the study was to establish the effect of metformin on fasting and postprandial insulin secretion. Method The study carried out was double blind, controlled, comparative, randomized, multicentric, including two groups of out-patient department (OPD) patients. 43 patients were administered metformin (Tefor ICN Canada), and 46 patients were given placebo. Patients enrolled in the study were newly diagnosed with diabetes mellitus (DM) type 2, glycaemia < 12 mmol/l, and had the Body Mass Index (BMI) > 30 kg/m2. Before treatment, blood biochemistry was done: fasting and postprandial glycaemia, glycosylated haemoglobin (HbA1c) value, fasting and postprandial insulinaemia, blood lipids (total cholesterol, total triglycerides, HDL cholesterol, and LDL cholesterol), and gamma glutaryl transferase (GGT) level. BMI was also established. After 42 days of treatment, fasting and postprandial insulinaemia were tested again. Analysis of the effects of therapy, and identification of co-variants for fasting and postprandial insulinaemia, were done by ANOVA two way and ANCOVA method. Results It was shown that metformin accompanied by diet, as compared to placebo accompanied by diet, lowered the fasting insulinaemia value during six weeks of therapy in obese patients with DM type 2 (24.392 mU/l vs. 25.667 mU/l), interacting both with BMI pre-therapy, and interacting with fasting insulinaemia pre-therapy (p<0.001). A significant effect of the interaction of covariants BMI and GGT was defined. As for the effect of therapy on postprandial insulinaemia, it was found that there was a high statistical significance of the effect of BMI interacting with initial values for postprandial insulinaemia before therapy, and interacting with therapy (p<0.01). Adjusted mean values for postprandial insulinaemia after therapy in the placebo group were lower as compared to the metformin group (44.807 mU/l vs. 47.114 mU/l). Conclusion It can be concluded that, as compared to placebo, metformin is more efficient in reducing insulin resistance in obese patients with DM type 2. In addition, as compared to placebo, metformin maintains more efficient productive insulin secretion, indicating that metformin protects the pancreas from beta cell depletion.

scholarly journals Defects in beta cell Ca2+ signalling, glucose metabolism and insulin secretion in a murine model of KATP channel-induced neonatal diabetes mellitus

Diabetologia ◽  
2011 ◽  
Vol 54 (5) ◽  
pp. 1087-1097 ◽  
Author(s):  
R. K. P. Benninger ◽  
M. S. Remedi ◽  
W. S. Head ◽  
A. Ustione ◽  
D. W. Piston ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Secretion ◽  
Glucose Metabolism ◽  
Beta Cell ◽  
Murine Model ◽  
Katp Channel ◽  
Neonatal Diabetes ◽  
Neonatal Diabetes Mellitus

scholarly journals Evaluation of serum c-peptide levels in type 2 diabetics in Punjabi population

2017 ◽  
Vol 4 (4) ◽  
pp. 1026 ◽  
Author(s):  
Hardeep Singh Deep ◽  
Barjinder Pal Singh ◽  
Shalinder Pal Singh
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Insulin Secretion ◽  
Treatment Modality ◽  
Pancreatic Beta Cells ◽  
Diabetic Patients ◽  
C Peptide ◽  
Endogenous Insulin ◽  
Chronic Hyperglycemia

Background: Diabetes mellitus is a chronic metabolic and endocrine disorder characterized by chronic hyperglycemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action or both. It is a major cause of mortality and morbidity worldwide. Human insulin and c-peptide are synthesized as a single polypeptide chain known as Proinsulin in the pancreatic beta cells. Serum insulin measurement gives a wrong value of insulin secretion, because insulin after its secretion into the portal vein, passes through the liver where approximately 50% of the delivered insulin is extracted. The measurement of C-peptide, thus provides a better index of endogenous insulin production and pancreatic beta cell function than insulin measurements.Methods: The present study was conducted on 100 adult patients of type 2 diabetes mellitus presenting in OPD and emergency or admitted in Sri Guru Ram Das Institute of Medical Sciences and Research, Amritsar. Type 1 diabetic patients, pregnant females with diabetes, patients presenting with acute infections, septicaemia, patients with acute or chronic pancreatitis, patients with pancreatic carcinoma were excluded from the study. In this study C-Peptide levels were estimated by DRG C-peptide ELISA method.Results: In our study, 38% patients had adequate insulin reserve (Normal C-peptide levels). Only 2% patients had poor insulin reserve (C-peptide levels below normal). 60% patients had c peptide levels more than normal, indicating insulin resistance. Increase in fasting c-peptide levels were associated with increased fasting plasma glucose (due to insulin resistance). A positive correlation exists in our study with r value of 0.523.Conclusions: As majority of patients with elevated FBS and fasting c-peptide were obese, our study infers that obese are more insulin resistant than non-obese. Since c-peptide levels assess the endogenous insulin reserve, it will also be helpful to alter the treatment modality based on it. So, routine c-peptide testing should be done in patients with poor glycaemic control to modify treatment modality accordingly.

scholarly journals Association of Single Nucleotide Polymorphisms With Insulin Secretion, Insulin Sensitivity, and Diabetes in Women With a History of Gestational Diabetes Mellitus

2021 ◽  
Author(s):  
Rashmi Prasad ◽  
Karl Kristensen ◽  
Anastasia Katsarou ◽  
Nael Shaat
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Insulin Secretion ◽  
Gestational Diabetes ◽  
Gestational Diabetes Mellitus ◽  
Disposition Index ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Impaired Insulin ◽  
History Of

Abstract Aims: This study investigated whether single nucleotide polymorphisms (SNPs) reported by previous genome-wide association studies (GWAS) to be associated with impaired insulin secretion, insulin resistance, and/or type 2 diabetes are associated with disposition index, the homeostasis model assessment of insulin resistance (HOMA-IR), and/or development of diabetes following a pregnancy complicated by gestational diabetes mellitus (GDM).Methods: Seventy-two SNPs were genotyped in 374 women with previous GDM from Southern Sweden. An oral glucose tolerance test was performed 1–2 years postpartum, although data on the diagnosis of diabetes were accessible up to 5 years postpartum. HOMA-IR and disposition index were used to measure insulin resistance and secretion, respectively. Results: The risk A-allele in the rs11708067 polymorphism of the adenylate cyclase 5 gene (ADCY5) was associated with decreased disposition index (beta = -0.90, SE 0.38, p = 0.019). This polymorphism was an expression quantitative trait loci (eQTL) in islets for both ADCY5 and its antisense transcript. The risk C-allele in the rs2943641 polymorphism, near the insulin receptor substrate 1 gene (IRS1), was associated with increased HOMA-IR (beta = 0.36, SE 0.18, p = 0.050), and the T-allele of the rs4607103 polymorphism, near the ADAM metallopeptidase with thrombospondin type 1 motif 9 gene (ADAMTS9), was associated with postpartum diabetes (OR = 2.12, SE 0.22, p = 0.00055). All analyses were adjusted for age, body mass index, and ethnicity.Conclusions: This study demonstrated the genetic susceptibility of women with a history of GDM to impaired insulin secretion and sensitivity and, ultimately, to diabetes development.

ATP-Regulated K+ Channels and Diabetes Mellitus

Physiology ◽  
1990 ◽  
Vol 5 (4) ◽  
pp. 143-147 ◽  
Author(s):  
P Rorsman ◽  
P-O Berggren ◽  
K Bokvist ◽  
S Efendic
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Secretion ◽  
Pancreatic Beta Cells ◽  
Insulin Dependent Diabetes Mellitus ◽  
Dependent Diabetes Mellitus ◽  
K Channel ◽  
K Channels ◽  
Channel Regulation ◽  
Insulin Dependent ◽  
Glucose Stimulated Insulin Secretion

Glucose-stimulated insulin secretion from pancreatic Beta-cells is dependent on closure of ATP-regulated K+ channels. These channels are selectively blocked by hypoglycaemic sulfonylureas, compounds used in treatment of non-insulin-dependent diabetes mellitus (NIDDM). This suggests that NIDDM may result from defective K+-channel regulation.

scholarly journals Nitric oxide opens ATP-sensitive K+ channels through suppression of phosphofructokinase activity and inhibits glucose-induced insulin release in pancreatic beta cells.

1994 ◽  
Vol 104 (6) ◽  
pp. 1079-1098 ◽  
Author(s):  
Y Tsuura ◽  
H Ishida ◽  
S Hayashi ◽  
K Sakamoto ◽  
M Horie ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Insulin Secretion ◽  
Beta Cells ◽  
Katp Channel ◽  
Pancreatic Beta Cells ◽  
Katp Channels ◽  
Channel Activity ◽  
K Channels ◽  
Intracellular Mechanism ◽  
Phosphofructokinase Activity

Nitric oxide (NO) is known to be a potent messenger in the intracellular signal transduction system in many tissues. In pancreatic beta cells, NO has been reported to be formed from L-arginine through NO synthase. To elucidate the effect of NO on insulin secretion and to investigate the intracellular mechanism of its effect, we have used sodium nitroprusside (SNP) as a NO donor. SNP inhibited glucose-induced insulin secretion in a dose-dependent manner, and its effect was reversed by hemoglobin, a known NO scavenger. However, glyceraldehyde-induced insulin secretion was not affected by SNP. Since the closure of ATP-sensitive K+ channels (KATP channel) has been established as a key step in glucose-induced insulin secretion, we have directly assessed the effect of SNP on KATP channel activity using the patch clamp technique. The KATP channel activity reduced by glucose was found to be reversibly activated by the addition of SNP, and this activation was able to be similarly reproduced by applying S-Nitroso-N-acetyl-DL-penicillamine (SNAP), another NO generator. Furthermore, these activating effects were completely eliminated by hemoglobin, in accordance with the reversibility in inhibition of glucose-induced insulin release. However, SNP could not affect the KATP channel suppression by ATP applied to the inside of the plasma membrane. The activation of the KATP channel by NO, therefore, seems to be due to the decreased ATP production attributable to impairment of glucose metabolism in beta cells. Since SNP exhibited no effect on glyceraldehyde-induced KATP channel inhibition, NO may disturb a glycolytic step before glyceraldehyde-3-phosphate. The KATP channel activation by 2-deoxyglucose through presumable ATP consumption due to its phosphorylation by glucokinase was, however, not affected even in the presence of SNP. But in the permeabilized beta cells made by exposure to a low concentration (0.02 U/ml) of streptolysin O (open cell-attached configuration), SNP reopens KATP channels which have been eliminated by fructose-6-phosphate, while this effect was not observed in the KATP channels inhibited by fructose-1,6-bisphosphate. On the other hand, in rat ventricular myocyte KATP channels were not activated by SNP even under a low concentration of glucose. From these observations, the inhibition of phosphofructokinase activity is probably the site responsible for the impairment of glucose metabolism induced by NO in pancreatic beta cells. NO, therefore, seems to be a factor in the deterioration of glucose-induced insulin secretion from pancreatic beta cells through a unique intracellular mechanism.

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