ATP-dependent potassium channels and type 2 diabetes mellitus

Pancreatic beta cells, unique cells that secrete insulin in response to an increase in glucose levels, play a significant role in glucose homeostasis. Glucose-stimulated insulin secretion (GSIS) in pancreatic beta cells has been extensively explored. In this mechanism, glucose enters the cells and subsequently the metabolic cycle. During this process, the ATP/ADP ratio increases, leading to ATP-sensitive potassium (K ATP ) channel closure, which initiates depolarization that is also dependent on the activity of TRP nonselective ion channels. Depolarization leads to the opening of voltage-gated Na 1 channels (Nav) and subsequently voltage-dependent Ca 21 channels (Cav).The increase in intracellular Ca 21 triggers the exocytosis of insulin-containing vesicles. Thus, electrical activity of pancreatic beta cells plays a central role in GSIS. Moreover, many growth factors, incretins, neurotransmitters, and hormones can modulate GSIS, and the channels that participate in GSIS are highly regulated. In this review, we focus on the principal ionic channels (K ATP , Nav, and Cav channels) involved in GSIS and how classic and new proteins, hormones, and drugs regulate it. Moreover, we also discuss advances on how metabolic disorders such as metabolic syndrome and diabetes mellitus change channel activity leading to changes in insulin secretion.

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“…This residue substitution is located in the N-terminal domain of the Kir6.2 subunit (Bonfanti et al, 2015).…”

Section: Pancreatic K Atp Channelopathiesmentioning

confidence: 99%

Modulation of Ionic Channels and Insulin Secretion by Drugs and Hormones in Pancreatic Beta Cells

et al. 2016

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“…Mutations in KCNJ11 or ABCC8 genes could decrease or abolish the metabolic sensitivity of β cell K ATP channel function, leading to a constant depolarization of the cell membrane and a persistent insulin secretion even at very low plasma glucose concentrations [10]. E.g., single nucleotide polymorphism (SNP) E23K (i.e., rs5219) of KCNJ11 gene is associated with T2D risk (reviewed in [11]), is shown to result in a decrease or loss of sensitivity of K ATP channel to the inhibitory effect of ATP [12] and/or an enhancement of activation by free fatty acids [13]. Further, mutations in ABCC8 gene could cause hyperinsulinemic hypoglycemia [10].…”

Section: Introductionmentioning

confidence: 99%

KCNJ11, ABCC8 and TCF7L2 polymorphisms and the response to sulfonylurea treatment in patients with type 2 diabetes: a bioinformatics assessment

et al. 2017

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BackgroundType 2 diabetes (T2D) is a worldwide epidemic with considerable health and economic consequences. Sulfonylureas are widely used drugs for the treatment of patients with T2D. KCNJ11 and ABCC8 encode the Kir6.2 (pore-forming subunit) and SUR1 (regulatory subunit that binds to sulfonylurea) of pancreatic β cell KATP channel respectively with a critical role in insulin secretion and glucose homeostasis. TCF7L2 encodes a transcription factor expressed in pancreatic β cells that regulates insulin production and processing. Because mutations of these genes could affect insulin secretion stimulated by sulfonylureas, the aim of this study is to assess associations between molecular variants of KCNJ11, ABCC8 and TCF7L2 genes and response to sulfonylurea treatment and to predict their potential functional effects.MethodsBased on a comprehensive literature search, we found 13 pharmacogenetic studies showing that single nucleotide polymorphisms (SNPs) located in KCNJ11: rs5219 (E23K), ABCC8: rs757110 (A1369S), rs1799854 (intron 15, exon 16 -3C/T), rs1799859 (R1273R), and TCF7L2: rs7903146 (intron 4) were significantly associated with responses to sulfonylureas. For in silico bioinformatics analysis, SIFT, PolyPhen-2, PANTHER, MutPred, and SNPs3D were applied for functional predictions of 36 coding (KCNJ11: 10, ABCC8: 24, and TCF7L2: 2; all are missense), and HaploReg v4.1, RegulomeDB, and Ensembl’s VEP were used to predict functions of 7 non-coding (KCNJ11: 1, ABCC8: 1, and TCF7L2: 5) SNPs, respectively.ResultsBased on various in silico tools, 8 KCNJ11 missense SNPs, 23 ABCC8 missense SNPs, and 2 TCF7L2 missense SNPs could affect protein functions. Of them, previous studies showed that mutant alleles of 4 KCNJ11 missense SNPs and 5 ABCC8 missense SNPs can be successfully rescued by sulfonylurea treatments. Further, 3 TCF7L2 non-coding SNPs (rs7903146, rs11196205 and rs12255372), can change motif(s) based on HaploReg v4.1 and are predicted as risk factors by Ensembl’s VEP.ConclusionsOur study indicates that a personalized medicine approach by tailoring sulfonylurea therapy of T2D patients according to their genotypes of KCNJ11, ABCC8, and TCF7L2 could attain an optimal treatment efficacy.

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“…KCNJ11 is coding for a K ATP channel KIR6.2 which is known to play a role in insulin secretion in pancreatic β-cells, and insulin and leptin signal transduction in the brain ( Table 1) [55][56][57][58][59]. This polymorphism has been thoroughly investigated with regard to T2D and obesity in many populations (reviewed in detail in [60]). From a functional point of view, the Lys amino acid residue was shown to increase the probability of spontaneous K ATP opening and decrease the potassium channel's sensitivity towards ATP-inhibitory activity, resulting in an inhibited insulin secretion in pancreatic beta-cells [60][61].…”

Section: Leptin (Lep)mentioning

confidence: 99%

“…This polymorphism has been thoroughly investigated with regard to T2D and obesity in many populations (reviewed in detail in [60]). From a functional point of view, the Lys amino acid residue was shown to increase the probability of spontaneous K ATP opening and decrease the potassium channel's sensitivity towards ATP-inhibitory activity, resulting in an inhibited insulin secretion in pancreatic beta-cells [60][61].…”

Section: Leptin (Lep)mentioning

confidence: 99%

Genetic Determination of Serum Levels of Diabetes-Associated Adipokines

Schleinitz¹

2016

Rev Diabet Stud

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■ AbstractAdipose tissue secretes an abundance of proteins. Some of these proteins are known as adipokines and adipose-derived hormones which have been linked with metabolic disorders, including type 2 diabetes, and even with cancer. Variance in serum adipokine concentration is often closely associated with an increase (obesity) or decrease (lipodystrophy) in fat tissue mass, and it is affected by age, gender, and localization of the adipose tissue. However, there may be genetic variants which, in consequence, influence the serum concentration of a certain adipokine, and thereby promote metabolic disturbances or, with regard to the "protective" allele, exert beneficial effects. This review focuses on the genetic determination of serum levels of the following adipokines: adiponectin, chemerin, leptin, progranulin, resistin, retinol binding protein 4, vaspin, adipsin, apelin, and omentin. The article reports on the latest findings from genome-wide association studies (GWAS) and candidate gene studies, showing variants located in/nearby the adipokine genes and other (non-receptor) genes. An extra chapter highlights adipokine-receptor variants. Epigenetic studies on adipokines are also addressed.

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ATP-dependent potassium channels and type 2 diabetes mellitus

Cited by 38 publications

References 101 publications

Modulation of Ionic Channels and Insulin Secretion by Drugs and Hormones in Pancreatic Beta Cells

Modulation of Ionic Channels and Insulin Secretion by Drugs and Hormones in Pancreatic Beta Cells

KCNJ11, ABCC8 and TCF7L2 polymorphisms and the response to sulfonylurea treatment in patients with type 2 diabetes: a bioinformatics assessment

Genetic Determination of Serum Levels of Diabetes-Associated Adipokines

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