UMLS:C0011860 - FACTA Search

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Query: UMLS:C0011860 (type 2 diabetes)
57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

ATP-sensitive K+ (KATP) channels play a key role in stimulus-secretion coupling in pancreatic beta-cells. Recent studies have shown that the beta-cell KATP channel comprises two subunits: a novel member of the inwardly rectifying K+ channel family, designated BIR and expressed at highest levels in pancreatic islets, and the sulfonylurea receptor (SUR). Moreover, the genes encoding these two proteins are adjacent to one another on human chromosome 11. Genetic factors contribute to the development of NIDDM, and it seems likely that mutations in genes encoding proteins involved in insulin secretion or action may contribute to NIDDM susceptibility. The present study examined the contribution of the linked BIR and SUR genes to the development of NIDDM. These genes were localized to the same yeast artificial chromosome as two microsatellite DNA polymorphisms, D11S902 and D11S921. These microsatellite DNA polymorphisms were typed in 140 Japanese NIDDM-affected sib pairs. There was no evidence for linkage between these markers and NIDDM, suggesting that genetic variation in the BIR and SUR genes does not play a major role in susceptibility to NIDDM in Japanese.
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PMID:Identification of microsatellite markers near the human genes encoding the beta-cell ATP-sensitive K+ channel and linkage studies with NIDDM in Japanese. 854 73

Considerable data support a genetic basis to susceptibility for NIDDM, but previous analysis of candidate genes has failed to identify a major susceptibility locus. Among regions with multiple potential candidates is chromosome 11, which includes the apolipoprotein C3 cluster, muscle glycogen phosphorylase, two insulin-dependent diabetes loci, the sulfonylurea receptor, and ataxia telangiectasia. To test linkage, we initially typed 19 markers at 10- to 15-cM intervals along chromosome 11. Analyses carried out under parametric models in members of 16-19 families of northern European ancestry detected possible linkage of NIDDM to D11S916. Nonparametric methods detected possible linkage to NIDDM at D11S901, which was 5- 10 cM distant, and at D11S935, which was approximately 30 cM distant. Both D11S916 and D11S901 were near the IDDM4 locus. To further test linkage, we typed five additional markers within 5 cM of D11S916 in the initial 19 families. We also tested markers from the linked region in a second set of recently sampled additional families. Two additional markers (D11S527 and D11S534) showed possible linkage in the initial 19 families, but none of the markers were linked to NIDDM in a separate set of families from the same ethnic background. The best evidence for linkage in the combined data set of the initial 19 families and 26 additional families was at D11S534 under parametric analysis (Z = 1.20) and at D11S935 under nonparametric analysis (affected pedigree number, P = 0.0013). Our findings suggest marginal evidence for a diabetes susceptibility locus in the region between D11S901 and D11S935, with the best evidence for a locus at or near D11S935. Replication of these findings in other populations will be necessary to distinguish false-positive linkage from a true NIDDM susceptibility locus.
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PMID:Linkage studies of NIDDM with 23 chromosome 11 markers in a sample of whites of northern European descent. 859 45

NIDDM is a common heterogeneous disorder, the genetic basis of which has yet to be determined. The sulfonylurea receptor (SUR) gene, now known to encode an integral component of the pancreatic beta-cell ATP-sensitive potassium channel, IKATP, was investigated as a logical candidate for this disorder. The two nucleotide-binding fold (NBF) regions of SUR are known to be critical for normal glucose regulation of insulin secretion. Thus, single-strand conformational polymorphism analysis was used to find sequence changes in the two NBF regions of the SUR gene in 35 NIDDM patients. Eight variants were found; and three were evaluated in two Northern European white populations (Utah and the U.K.): 1) a missense mutation in exon 7 (S1370A) was found with equal frequency in patients (n = 223) and control subjects (n = 322); 2) an ACC-->ACT silent variant in exon 22 (T761T) was more common in patients than in control subjects (allele frequencies 0.07 vs. 0.02, P = 0.0008, odds ratio (OR) 3.01, 95% CI 1.54-5.87); and 3) an intronic t-->c change located at position -3 of the exon 24 splice acceptor site was also more common in patients than in control subjects (0.62 vs. 0.46, P < 0.0001, OR 1.91, 95% Cl 1.50-2.44). The combined genotypes of exon 22 C/T or T/T and intron 24 -3c/-3c occurred in 8.9% of patients and 0.5% of control subjects (P < 0.0001, OR 21.5, 95% CI 2.91-159.6). These results suggest that defects at the SUR locus may be a major contributor to the inherited basis of NIDDM in Northern European Caucasians.
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PMID:Sequence variants in the sulfonylurea receptor (SUR) gene are associated with NIDDM in Caucasians. 863 61

Sulfonylureas are widely used to treat non-insulin dependent diabetes mellitus. These drugs exert their hypoglycaemic effects by stimulating insulin secretion from the pancreatic beta-cell. Their primary mechanism of action is to close ATP-sensitive K-channels in the beta-cell plasma membrane, and so initiate a chain of events which results in insulin release. Recent studies have shown that the beta-cell ATP-sensitive K-channel is a complex of two proteins: a pore-forming subunit (Kir6.2) and a drug-binding subunit (SUR1) which functions as the receptor for sulfonylureas. This review summarizes recent advances in our understanding of the molecular mechanism of sulfonylurea action, focusing on the relationship between the sulfonylurea receptor and the K-ATP channel. Earlier studies are also re-examined in the light of new findings.
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PMID:Mechanisms of the glycaemic effects of sulfonylureas. 891 83

Signals derived from the metabolism of glucose in pancreatic beta-cells lead to insulin secretion via the closure of ATP-sensitive K+ channels (KATP). The cloning of the gene encoding the beta-cell inward rectifier Kir6.2 (Bir), a subunit of the beta-cell KATP channel, provided the opportunity to look for mutations in this gene that might contribute to the impaired insulin secretion of NIDDM. By single-strand conformational polymorphism (SSCP) analysis on 35 Northern-European Caucasian patients with NIDDM, six sequence variants were detected: Glu10gag-->Lys10aag (E1OK), Glu23gag-->Lys23aag (E23K), Leu270ctg-->Val270gtg (L270V), Ile337atc-->Val337gtc (I337V), and two silent mutations. Allelic frequencies for the missense variants were compared between the NIDDM group (n = 306) and nondiabetic control subjects (n = 175) and did not differ between the two groups. Pairwise allelic associations indicated significant linkage disequilibrium between the variants in Kir6.2 and between them and a nearby pancreatic beta-cell sulfonylurea receptor (SUR1) missense variant (S1370A), but these linkage disequilibria did not differ between the NIDDM and control groups. The results of these studies thus revealed that mutations in the coding region of Kir6.2 1) were not responsible for the previously noted association of the SUR1 variants with NIDDM (Inoue H et al., Diabetes 45:825-831, 1996) and 2) did not contribute to the impaired insulin secretion characteristic of NIDDM in Caucasian patients.
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PMID:Sequence variants in the pancreatic islet beta-cell inwardly rectifying K+ channel Kir6.2 (Bir) gene: identification and lack of role in Caucasian patients with NIDDM. 903 9

Non-insulin-dependent diabetes mellitus (NIDDM) is a clinically and genetically heterogeneous disorder. Recent advances in molecular genetics have allowed recognition of the genes involved in some subtypes of NIDDM with a well-defined mode of inheritance and a strong association with genetic factors. Thus, maturity-onset diabetes of the young (MODY), an autosomal dominant form of NIDDM, was shown to be caused by, or associated with, mutations in at least four genes. A maternally transmitted form of diabetes, often associated with deafness, was shown to be due to mutations in mitochondrial DNA. Despite these successes, little is known about susceptibility genes to the common polygenic forms of NIDDM. Studies of genes involved in insulin secretion or insulin action have been successful to a certain extent by showing the implication of the IRS-1 gene, the Rad gene, the glucagon receptor gene, or the sulfonylurea receptor (SUR) gene (among others) in a low percentage of cases of NIDDM in particular populations. However, the majority of susceptibility genes to NIDDM are still to be described. The aim of this review was to consider the strategies that can be used to identify the genetic determinants of NIDDM, and to summarise the significant results of recent literature.
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PMID:Genetic determinants of non-insulin-dependent diabetes mellitus: strategies and recent results. 905 62

The sulfonylurea receptor (SUR) is a key component in glucose-stimulated insulin secretion. Obesity and NIDDM are frequently associated and share some metabolic abnormalities, suggesting that they might also share some susceptibility genes. Thus, the SUR encoding gene is a plausible candidate for a primary pancreatic beta-cell defect and thus for hyperglycemia and weight gain. Through association and linkage studies, we have investigated the potential role of the SUR gene in families with NIDDM and in two independent sets of morbidly obese families. The exon 22 T-allele at codon 761 was more common in patients with NIDDM (7.7%) and morbid obesity (7.8%) than in control subjects (1.8%, P = 0.030 and P = 0.023, respectively). This variant was associated with morbid obesity (odds ratio 3.71, P = 0.017) and NIDDM (odds ratio 2.20, P = 0.04; association dependent on BMI). Although the frequencies for intron 24 variant were similar in all groups, morbidly obese patients homozygous for the c-allele had a more deleterious form of obesity. Sib-pair linkage studies with NIDDM in French Caucasian families gave no evidence for linkage to the SUR locus. However, in one set of the obese families, we found an indication for linkage with a SUR-linked microsatellite marker (D11S419, P = 0.0032). We conclude that in Caucasians, the SUR locus may contribute to the genetic susceptibility to NIDDM and obesity.
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PMID:Genetic studies of the sulfonylurea receptor gene locus in NIDDM and in morbid obesity among French Caucasians. 907 12

The sulfonylurea receptor 1 (SUR1) is an essential regulatory subunit of the beta-cell ATP-sensitive K+ channel (K[ATP]). The possible role of SUR1 gene mutation(s) in the development of NIDDM remains controversial as both a positive association and negative linkage results have been reported. Therefore, we examined the SUR1 gene at the single nucleotide level with single strand conformation polymorphism analysis in 100 Japanese NIDDM patients. We identified a total of five amino acid substitutions and 17 silent mutations by examining all 39 exons of this gene. Two rare novel mutations, D811N in exon 20 and R835C in exon 21, were identified in the first nucleotide-binding fold (NBF), a functionally important region of SUR1, in one patient each, both heterozygotes. To analyze possible functional alterations, we reconstituted the mutant K(ATP) by coexpressing beta-cell inward rectifier (BIR) (Kir 6.2), a channel subunit of K(ATP), and mutant SUR1 in HEK293T and COS-7 cells. As demonstrated by the patch clamp technique and rubidium (Rb+) efflux studies, neither mutation alters the properties of channel activities. Two other rare missense mutations, R275Q in exon 6 and V560M in exon 12, were also identified. The R275Q substitution was not found in 67 control subjects, and V560M was present in three control subjects. Neither of these substitutions appeared to cosegregate with NIDDM in the probands' families. A previously reported S1370A substitution located in the second NBF was also common in the Japanese subjects (allelic frequency 0.37), and was found at an equal frequency in nondiabetic control subjects. In conclusion, SUR1 mutations impairing K(ATP) function do not appear to be major determinants of NIDDM susceptibility in Japanese.
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PMID:Identification and functional analysis of sulfonylurea receptor 1 variants in Japanese patients with NIDDM. 951 57

The high-affinity sulfonylurea receptor (SUR1) is, as a subunit of the ATP-sensitive potassium channel, an important regulator of insulin secretion in the pancreatic beta-cell. The aim of this study was to examine if genetic variability of the SUR1 gene was associated with NIDDM or altered pancreatic beta-cell function. Mutational analysis of all the 39 SUR1 exons, including intron-exon boundaries, in 63 NIDDM patients revealed two missense variants, five silent variants in the coding region, and four intron variants. The two missense variants (Asp673Asn and Ser1369Ala) and two sequence variants (ACC-->ACT, Thr759Thr and a c-->t intron variant in position -3 of the exon 16 splice acceptor site) were examined for association with NIDDM and for a possible influence on insulin and C-peptide secretion after intravenous glucose and tolbutamide loads in a random sample of unrelated, healthy, young Danish Caucasians. The Asp673Asn variant in exon 14 was only identified in one NIDDM patient, and the allelic frequency of the Ser1369Ala was similar among 247 control subjects (0.38 [95% CI 0.34-0.42]) and 406 NIDDM patients (0.40 [0.37-0.43]). The allelic frequency of the silent exon 18 Thr775Thr variant was 0.051 (0.035-0.067) in NIDDM patients (n=392) and 0.027 (0.013-0.041) in control subjects (n=246; chi2=4.99, P=0.03). The allelic frequency of the intron variant was similar among NIDDM patients (0.45 [0.42-0.48]) and control subjects (0.44 [0.40-0.48]). Of 386 NIDDM patients, 17 had the combined genotype exon 18 C/T and intron -3c/-3t (0.044 [0.024-0.064]), whereas 3 of 243 control subjects had the same combined genotype (0.012 [0-0.026]; chi2=4.87, P=0.03; odds ratio: 3.69 [1.07-12.71]). Of 380 unrelated, healthy, young Danish Caucasians, 10 (0.026 [0.010-0.042]) had the combined at-risk genotype. These subjects had, on average, a 50% reduction in serum C-peptide and a 40% reduction in serum insulin responses upon tolbutamide injection (P=0.002 and P=0.05, respectively) but normal serum C-peptide and insulin responses upon glucose injection. In conclusion, a silent polymorphism in exon 18 of the SUR1 gene is associated with NIDDM in a Danish Caucasian population. In combination with an intron variant, the association is higher, and young, healthy carriers of the intragenic combination have reduced serum C-peptide and insulin responses to a tolbutamide load.
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PMID:Decreased tolbutamide-stimulated insulin secretion in healthy subjects with sequence variants in the high-affinity sulfonylurea receptor gene. 956 93

Defining the genetic basis of Type II or non-insulin dependent diabetes mellitus (NIDDM) will accelerate our progress toward understanding its etiology and will provide new therapeutic targets for treatment of this common disease. Here we present a brief overview of the history of the search for diabetes genes and report current strategies employed by our laboratory and by others in this effort. Isolation and subsequent mapping of candidate genes involved in insulin production and action has been a major effort in this field. Our lab has focused on pancreatic islet beta-cell genes, since the insulin lack of NIDDM is often the result of resistance to the action of insulin that is superimposed on a limited ability to produce insulin. A number of islet genes have been evaluated, including those involved in glucose metabolism, islet K+ channel genes, and transcription factors. For each gene, human cDNAs and genomic clones have been isolated and simple sequence repeat polymorphisms (SSRPs) identified. The SSRPs were used to map the genes by linkage in CEPH pedigrees, or sequence-tagged sites (STSs) were used to map the genes to radiation hybrids (RH) or to YAC clones containing SSRPs. The SSRPs have then been used as markers for linkage analyses in families with NIDDM. Mutation screening by single-strand conformational polymorphism analysis and by sequencing has revealed variants that have been tested in association studies. A strategy was devised to generate novel expressed sequence tags (ESTs) from human pancreatic islet genes by differential display of islet mRNA. In the first phase of this project we identified 42 cDNAs that were preferentially expressed in pancreatic islets relative to exocrine tissue. When compared to sequences in GenBank, novel genes were represented by 69%. Enhanced islet expression was confirmed by Northern analysis of RNA. Sequence-tagged sites were synthesized for a number of islet ESTs and used to map these genes to human chromosomes. This strategy provides an effective means to selectively identify and map genes transcribed in human pancreatic islets and to identify novel islet candidate genes for NIDDM. Positional cloning of NIDDM genes in families of various racial groups is being conducted by a number of labs. Although regions of genetic susceptibility are being identified, finding the genes within these regions will be difficult because of the polygenic nature of the disease As an alternative strategy, we have begun to map genes responsible for monogenic disorders of carbohydrate metabolism. Familial hyperinsulinism (HI, OMIM #256450) is a rare recessive disease associated with neonatal hyperinsulinism and life-threatening hypoglycemia. To determine the molecular basis for HI, we mapped the gene in multiplex families to chromosome 11p14-15.1. A candidate gene, the sulfonylurea receptor (SUR1), was mapped to the region and shown to harbor mutations in HI patients. Analysis of 21 identified mutations has revealed the role of SUR1 as a nucleotide regulator of the islet ATP-sensitive K+ channel. The challenge for the future will be to utilize the information provided by the Human Genome Project (i.e., the complete nucleotide sequence and expression maps of the genome) to find diabetes-predisposing genes. Our immediate goals include collecting families with NIDDM for phenotyping and for DNA analysis and continuing to identify suitable candidate genes to be studied in these families.
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PMID:Genetics of type II diabetes. 976 9

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