Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

ATP-sensitive K+ channels (K(ATP) channels) control electrical activity in beta-cells and therefore are key players in excitation-secretion coupling. Partial suppression of beta-cell K(ATP) channels in transgenic (AAA) mice causes hypersecretion of insulin and enhanced glucose tolerance, whereas complete suppression of these channels in Kir6.2 knockout (KO) mice leads to hyperexcitability, but mild glucose intolerance. To test the interplay of hyperexcitability and dietary stress, we subjected AAA and KO mice to a high-fat diet. After 3 months on the diet, both AAA and KO mice converted to an undersecreting and markedly glucose-intolerant phenotype. Although Kir6.2 is expressed in multiple tissues, its primary functional consequence in both AAA and KO mice is enhanced beta-cell electrical activity. The results of our study provide evidence that, when combined with dietary stress, this hyperexcitability is a causal diabetic factor. We propose an "inverse U" model for the response to enhanced beta-cell excitability: the expected initial hypersecretion can progress to undersecretion and glucose-intolerance, either spontaneously or in response to dietary stress.
Diabetes 2004 Dec
PMID:Diet-induced glucose intolerance in mice with decreased beta-cell ATP-sensitive K+ channels. 1556 46

The insulin receptor substrate (IRS)-1 is an important component of the insulin signal transduction cascade. Several reports suggest that a Gly-->Arg change in codon 972 is associated with type 2 diabetes and related traits, and a recent meta-analysis reported a modest but nominally significant association with type 2 diabetes (odds ratio [OR] 1.25 in favor of carriers of the Arg allele [95% CI 1.05-1.48). To test the reproducibility of the model in a recent meta-analysis, we examined genotype-phenotype correlation in three large Caucasian samples (not previously reported for this variant) totaling 9,000 individuals (estimated to have >95% power to obtain a P < 0.05 for the OR of 1.25 estimated in the meta-analysis). In our combined sample, comprising 4,279 case and 3,532 control subjects, as well as 1,189 siblings discordant for type 2 diabetes, G972R was not associated with type 2 diabetes (OR 0.96 [0.84-1.10], P = 0.60). Genotype at G972R had no significant effect on various measures of insulin secretion or insulin resistance in a set of Scandinavian samples in whom we had detailed phenotypic data. In contrast, the well-documented associations of peroxisome proliferator-activated receptor gamma P12A and Kir6.2 E23K with type 2 diabetes are both robustly observed in these 9,000 subjects, including an additional (previously unpublished) confirmation of Kir6.2 E23K and type 2 diabetes in the Polish and North American samples (combined OR 1.15 [1.05-1.26], P = 0.001). Despite genotyping 9,000 people and >95% power to reproduce the estimated OR from the recent meta-analysis, we were unable to replicate the association of the IRS-1 G972R polymorphism with type 2 diabetes.
Diabetes 2004 Dec
PMID:Association testing in 9,000 people fails to confirm the association of the insulin receptor substrate-1 G972R polymorphism with type 2 diabetes. 1556 65

ATP-sensitive K+ (K(ATP)) channels play many important roles in cellular functions, including control of membrane excitability of skeletal muscle and neurons, K+ recycling in renal epithelia, cytoprotection in cardiac ischemia, and insulin secretion from pancreatic beta-cells. K(ATP) channels are composed of pore-forming inwardly rectifying potassium channel (Kir6.2 or Kir6.1) subunits and sulfonylurea receptor (SUR1, SUR2A, or SUR2B) subunits. Kir6.2 or Kir6.1 subunits conjoined with a SUR subunit constitute the various tissue-specific K(ATP) channels with distinct pharmacological properties. Both sulfonylureas and non-sulfonylurea hypoglycemic agents are used in treatment of type 2 diabetes mellitus. While the sulfonylurea receptor (SUR) is the target molecule of all of these hypoglycemic agents, the binding sites differ according to the moiety containing in the agent, and alter the pharmachological properties. In addition, chronic exposure of pancreatic beta-cells to the various agents affects the agent-specific sensitivities differently. Here we distinguish differences in pharmacological profile among the various hypoglycemic agents that reflect their chemical composition. We also suggest possible risk in the use of certain hypoglycemic agents in patients with ischemic heart disease.
Diabetes Res Clin Pract 2004 Dec
PMID:Sulfonylurea and non-sulfonylurea hypoglycemic agents: pharmachological properties and tissue selectivity. 1556 85

The ATP-sensitive potassium (KATP) channel couples membrane excitability to cellular metabolism and is a critical mediator in the process of glucose-stimulated insulin secretion. Increasing numbers of KATP channel polymorphisms are being described and linked to altered insulin secretion indicating that genes encoding this ion channel could be susceptibility markers for type-2 diabetes. Genetic variation of KATP channels may result in altered beta-cell electrical activity, glucose homeostasis, and increased susceptibility to type-2 diabetes. Of particular interest is the Kir6.2 E23K polymorphism, which is linked to increased susceptibility to type-2 diabetes in Caucasian populations and may also be associated with weight gain and obesity, both of which are major diabetes risk factors. This association highlights the potential contribution of both genetic and environmental factors to the development and progression of type-2 diabetes. In addition, the common occurrence of the E23K polymorphism in Caucasian populations may have conferred an evolutionary advantage to our ancestors. This review will summarize the current status of the association of KATP channel polymorphisms with type-2 diabetes, focusing on the possible mechanisms by which these polymorphisms alter glucose homeostasis and offering insights into possible evolutionary pressures that may have contributed to the high prevalence of KATP channel polymorphisms in the Caucasian population.
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PMID:Current status of the E23K Kir6.2 polymorphism: implications for type-2 diabetes. 1556 84

Type 2 diabetes is caused by defective insulin secretion and impaired insulin action. We investigated whether common polymorphisms in the SUR1 and Kir6.2 genes are associated with increased risk of type 2 diabetes in 490 subjects with impaired glucose tolerance participating in the Finnish Diabetes Prevention Study. The 1273AGA allele of the SUR1 gene was associated with a 2-fold risk of type 2 diabetes [odds ratio (OR), 2.00; 95% confidence interval (CI), 1.19-3.36; P = 0.009]. This silent polymorphism was in linkage disequilibrium with three promoter polymorphisms (G-2886A, G-1561A, and A-1273G), and they formed a high-risk haplotype having a 2-fold risk of type 2 diabetes (OR, 1.89; 95% CI, 1.09-3.27; P = 0.023). Subjects with both the high-risk haplotype of the SUR1 gene and the 23K allele of the Kir6.2 gene had a 6-fold risk for the conversion to diabetes compared with those without any of these risk genotypes (OR, 5.68; 95% CI, 1.75-18.32; P = 0.004). We conclude that the polymorphisms of the SUR1 gene predicted the conversion from impaired glucose tolerance to type 2 diabetes and that the effect of these polymorphisms on diabetes risk was additive with the E23K polymorphism of the Kir6.2 gene.
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PMID:Polymorphisms of the SUR1 (ABCC8) and Kir6.2 (KCNJ11) genes predict the conversion from impaired glucose tolerance to type 2 diabetes. The Finnish Diabetes Prevention Study. 1557 91

Permanent neonatal diabetes mellitus (PNDM) is a rare condition characterized by severe hyperglycemia constantly requiring insulin treatment from its onset. Complete deficiency of glucokinase (GCK) can cause PNDM; however, the genetic etiology is unknown in most PNDM patients. Recently, heterozygous activating mutations of KCNJ11, encoding Kir6.2, the pore forming subunit of the ATP-dependent potassium (K(ATP)) channel of the pancreatic beta-cell, were found in patients with PNDM. Closure of the K(ATP) channel exerts a pivotal role in insulin secretion by modifying the resting membrane potential that leads to insulin exocytosis. We screened the KCNJ11 gene in 12 Italian patients with PNDM (onset within 3 months from birth) and in six patients with non-autoimmune, insulin-requiring diabetes diagnosed during the first year of life. Five different heterozygous mutations were identified: c.149G>C (p.R50P), c.175G>A (p.V59M), c.509A>G (p.K170R), c.510G>C (p.K170N), and c.601C>T (p.R201C) in eight patients with diabetes diagnosed between day 3 and 182. Mutations at Arg50 and Lys170 residues are novel. Four patients also presented with motor and/or developmental delay as previously reported. We conclude that KCNJ11 mutations are a common cause of PNDM either in isolation or associated with developmental delay. Permanent diabetes of non autoimmune origin can present up to 6 months from birth in individuals with KCNJ11 and EIF2AK3 mutations. Therefore, we suggest that the acronym PNDM be replaced with the more comprehensive permanent diabetes mellitus of infancy (PDMI), linking it to the gene product (e.g., GCK-PDMI, KCNJ11-PDMI) to avoid confusion between patients with early-onset, autoimmune type 1 diabetes.
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PMID:KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes. 1558 May 58

Inwardly rectifying potassium channels (Kir channels) control cell membrane K(+) fluxes and electrical signaling in diverse cell types. Heterozygous mutations in the human Kir6.2 gene (KCNJ11), the pore-forming subunit of the ATP-sensitive (K(ATP)) channel, cause permanent neonatal diabetes mellitus (PNDM). For some mutations, PNDM is accompanied by marked developmental delay, muscle weakness, and epilepsy (severe disease). To determine the molecular basis of these different phenotypes, we expressed wild-type or mutant (R201C, Q52R, or V59G) Kir6.2/sulfonylurea receptor 1 channels in Xenopus oocytes. All mutations increased resting whole-cell K(ATP) currents by reducing channel inhibition by ATP, but, in the simulated heterozygous state, mutations causing PNDM alone (R201C) produced smaller K(ATP) currents and less change in ATP sensitivity than mutations associated with severe disease (Q52R and V59G). This finding suggests that increased K(ATP) currents hyperpolarize pancreatic beta cells and impair insulin secretion, whereas larger K(ATP) currents are required to influence extrapancreatic cell function. We found that mutations causing PNDM alone impair ATP sensitivity directly (at the binding site), whereas those associated with severe disease act indirectly by biasing the channel conformation toward the open state. The effect of the mutation on ATP sensitivity in the heterozygous state reflects the different contributions of a single subunit in the Kir6.2 tetramer to ATP inhibition and to the energy of the open state. Our results also show that mutations in the slide helix of Kir6.2 (V59G) influence the channel kinetics, providing evidence that this domain is involved in Kir channel gating, and suggest that the efficacy of sulfonylurea therapy in PNDM may vary with genotype.
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PMID:Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features. 1558 26

The human ATP-binding cassette (ABC) protein MRP1 causes resistance to many anticancer drugs and is also a primary active transporter of conjugated metabolites and endogenous organic anions, including leukotriene C(4) (LTC(4)) and glutathione (GSH). The sulfonylurea receptors SUR1 and SUR2 are related ABC proteins with the same domain structure as MRP1, but serve as regulators of the K(+) channel Kir6.2. Despite their functional differences, the activity of both SUR1/2 and MRP1 can be blocked by glibenclamide, a sulfonylurea used to treat diabetes. Residues in the cytoplasmic loop connecting transmembrane helices 15 and 16 of the SUR proteins have been implicated as molecular determinants of their sensitivity to glibenclamide and other sulfonylureas. We have now investigated the effect of mutating Tyr(1189) and Tyr(1190) in the comparable region of MRP1 on its transport activity and sulfonylurea sensitivity. Ala and Ser substitutions of Tyr(1189) and Tyr(1190) caused a > or =50% decrease in the ability of MRP1 to transport different organic anions, and a decrease in LTC(4) photolabeling. Kinetic analyses showed the decrease in GSH transport was attributable primarily to a 10-fold increase in K(m). In contrast, mutations of these Tyr residues had no major effect on the catalytic activity of MRP1. Furthermore, the mutant proteins showed no substantial differences in their sensitivity to glibenclamide and tolbutamide. We conclude that MRP1 Tyr(1189) and Tyr(1190), unlike the corresponding residues in SUR1, are not involved in its differential sensitivity to sulfonylureas, but nevertheless, may be involved in the transport activity of MRP1, especially with respect to GSH.
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PMID:Role of two adjacent cytoplasmic tyrosine residues in MRP1 (ABCC1) transport activity and sensitivity to sulfonylureas. 1565 36

Throughout the last decade, molecular genetic studies of non-autoimmune diabetes mellitus have contributed significantly to our present understanding of this disease's complex aetiopathogenesis. Monogenic forms of diabetes (maturity-onset diabetes of the young, MODY) have been identified and classified into MODY1-6 according to the mutated genes that by being expressed in the pancreatic beta-cells confirm at the molecular level the clinical presentation of MODY as a predominantly insulin secretory deficient form of diabetes mellitus. Genomewide linkage studies of presumed polygenic type 2 diabetic populations indicate that loci on chromosomes 1q, 5q, 8p, 10q, 12q and 20q contain susceptibility genes. Yet, so far, the only susceptibility gene, calpain-10 (CAPN10), which has been identified using genomewide linkage studies, is located on chromosome 2q37. Mutation analyses of selected 'candidate' susceptibility genes in various populations have also identified the widespread Pro12Ala variant of the peroxisome proliferator-activated receptor-gamma and the common Glu23Lys variant of the ATP-sensitive potassium channel, Kir6.2 (KCNJ11). These variants may contribute significantly to the risk type 2 diabetes conferring insulin resistance of liver, muscle and fat (Pro12Ala) and a relative insulin secretory deficiency (Glu23Lys). It is likely that, in the near future, the recent more detailed knowledge of the human genome and insights into its haploblocks together with the developments of high-throughput and cheap genotyping will facilitate the discovery of many more type 2 diabetes gene variants in study materials, which are statistically powered and phenotypically well characterized. The results of these efforts are likely to be the platform for major progress in the development of personalized antidiabetic drugs with higher efficacy and few side effects.
Diabetes Obes Metab 2005 Mar
PMID:Genetics of type 2 diabetes mellitus: status and perspectives. 1571 85

Neonatal diabetes can either remit and hence be transient or else may be permanent. These two phenotypes were considered to be genetically distinct. Abnormalities of 6q24 are the commonest cause of transient neonatal diabetes (TNDM). Mutations in KCNJ11, which encodes Kir6.2, the pore-forming subunit of the ATP-sensitive potassium channel (K(ATP)), are the commonest cause of permanent neonatal diabetes (PNDM). In addition to diabetes, some KCNJ11 mutations also result in marked developmental delay and epilepsy. These mutations are more severe on functional characterization. We investigated whether mutations in KCNJ11 could also give rise to TNDM. We identified the three novel heterozygous mutations (G53S, G53R, I182V) in three of 11 probands with clinically defined TNDM, who did not have chromosome 6q24 abnormalities. The mutations co-segregated with diabetes within families and were not found in 100 controls. All probands had insulin-treated diabetes diagnosed in the first 4 months and went into remission by 7-14 months. Functional characterization of the TNDM associated mutations was performed by expressing the mutated Kir6.2 with SUR1 in Xenopus laevis oocytes. All three heterozygous mutations resulted in a reduction in the sensitivity to ATP when compared with wild-type (IC(50) approximately 30 versus approximately 7 microM, P-value for is all <0.01); however, this was less profoundly reduced than with the PNDM associated mutations. In conclusion, mutations in KCNJ11 are the first genetic cause for remitting as well as permanent diabetes. This suggests that a fixed ion channel abnormality can result in a fluctuating glycaemic phenotype. The multiple phenotypes associated with activating KCNJ11 mutations may reflect their severity in vitro.
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PMID:Relapsing diabetes can result from moderately activating mutations in KCNJ11. 1571 50


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