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)

Binding of hypoglycemic sulfonylureas and their analogues to the sulfonylurea receptor in the beta-cell plasma membrane mediates closure of the ATP-sensitive K+-channel (KATP-channel) and thereby stimulation of insulin release. The sulfonylurea receptor is a member of the traffic ATPase family with two intracellular nucleotide binding folds. The receptor binding site for hypoglycemic drugs is located at the cytoplasmic face of the plasma membrane. Mutations in the sulfonylurea receptor gene have been detected which cause familial hyper-insulinism. Non-beta-cell sulfonylurea receptors do not contribute to the therapeutic benefit of sulfonylureas, but might be involved in presumed adverse effects of sulfonylureas in the cardiovascular and the central nervous system.
Exp Clin Endocrinol Diabetes 1996
PMID:Sulfonylurea receptors and mechanism of sulfonylurea action. 875 May 63

The genetic factors involved in type II diabetes are still unknown. To address this problem, we are creating a 10 to 15 cM genetic map on 444 individuals from 32 Mexican American families ascertained on a type II diabetic proband. Using highly polymorphic microsatellite markers and a multipoint variance components method, we found evidence for linkage of plasma glucose concentration 2 hr after oral glucose administration to two regions on chromosome 11: beta-hemoglobin (HBB) and markers D11S899/D11S1324 near the sulfonylurea receptor (SUR) gene. Iod scores at these two loci were 2.77 and 3.37, respectively. The SUR gene region accounted for 44.7% of the phenotypic variance. Evidence for linkage to fasting glucose concentration was also observed for two loci on chromosome 6, one of which is identical to a proposed susceptibility locus for type I diabetes (D6S290). When diabetics were excluded from the analyses, all Iod scores became zero, suggesting that the observed linkages were with the trait diabetes rather than with normal variation in glucose levels. Results were similar whether all diabetics were included in the analyses or only those who were not under treatment with oral antidiabetic agents or insulin.
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PMID:Evidence for linkage of regions on chromosomes 6 and 11 to plasma glucose concentrations in Mexican Americans. 885 47

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.
Diabetes 1997 Mar
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.
Diabetes Metab 1997 Feb
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.
Diabetes 1997 Apr
PMID:Genetic studies of the sulfonylurea receptor gene locus in NIDDM and in morbid obesity among French Caucasians. 907 12

Persistent hyperinsulinemic hypoglycemia of infancy (PHHI), a rare disorder due to defective negative feedback regulation of insulin secretion by low glucose levels, is often familial. Most cases are recessively inherited, and mutations of the sulfonylurea receptor gene (SUR) or the closely linked KIR6.2 gene have been found in several families. Both of these genes encode components of the potassium channels responsible for glucose-regulated insulin release. However, in some families recessive PHHI is not linked to the SUR-KIR6.2 locus, suggesting genetic heterogeneity. We report here a French Canadian kindred with hypoglycemia in five first cousins. All five patients had documented hypoglycemia, and all responded well to diazoxide. In two, inappropriately elevated insulin levels during hypoglycemia were documented. This familial clustering strongly suggests the existence of an autosomal dominant form of PHHI. By preliminary linkage analysis, we tested the possibility of a dominant negative SUR or KIR6.2 mutant. The insulin (INS) and glucokinase (GCK) genes were also tested as additional candidates. Microsatellite markers closely linked to each gene were used, and large negative Lod scores were obtained at the known recombination fractions between all three genes studied and the corresponding marker. We conclude that mutation of a gene other than SUR or KIR6.2 is responsible for the dominant PHHI in this family, and this gene cannot be INS or GCK. We propose that a genome-wide search for this gene is important for elucidating this rare disorder and, more importantly, for determining its potential impact on understanding noninsulin-dependent diabetes mellitus and on the effort to develop bioengineered beta-cells for transplantation.
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PMID:An autosomal dominant form of familial persistent hyperinsulinemic hypoglycemia of infancy, not linked to the sulfonylurea receptor locus. 910 May 95

Hyperinsulinism is the most common cause of hypoglycemia in early infancy. Congenital hyperinsulinism, formerly termed nesidioblastosis, is usually caused by genetic defects in beta-cell regulation, including a severe recessive disorder of the sulfonylurea receptor, a milder dominant form of hyperinsulinism, and a syndrome of hyperinsulinism plus hyperammonemia. Transient neonatal hyperinsulinism may be associated with perinatal asphyxia or small-for-dates birthweight and maternal diabetes. To prevent permanent brain damage from hypoglycemia, the treatment of infants with hyperinsulinism must be prompt and aggressive. A combination of medical therapy with diazoxide or octreotide, a long-acting somatostatin analog, and surgical 95% subtotal pancreatectomy may be required.
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PMID:Hyperinsulinism in infants and children. 913 Sep 25

Cellular engineering studies in our group are directed at creating insulin-secreting cell lines that simulate the performance of the normal islet beta-cell. The strategy described in this article involves the stepwise stable introduction of genes relevant to beta-cell performance into the RIN 1046-38 insulinoma cell line, a process that we term "iterative engineering." RIN cells stably engineered to contain multiple copies of the human insulin gene exhibit a large increase in insulin content, such that they approach the content of human islets assayed in parallel. Analysis by high-performance liquid chromatography demonstrates that these engineered cell lines process human proinsulin to mature insulin with high efficiency. Cell lines that are further engineered to express the GLUT2 and glucokinase genes demonstrate stable expression of the three transgenes for the full lifetime of the lines produced to date (6 months to 1 year in continuous culture). Transplantation of the engineered cell lines into nude rats reveals that stably integrated genes are expressed at constant levels in the in vivo environment over the full duration of experiments performed (48 days). Several endogenous genes expressed in normal beta-cells, including rat insulin, amylin, sulfonylurea receptor, and glucokinase, are stably expressed in the insulinoma lines during these in vivo studies. Endogenous GLUT2 expression, in contrast, is rapidly extinguished during in vivo passage. The loss of GLUT2 is overcome in engineered cell ines in which transporter expression is provided by a stably transfected transgene. These results suggest that a potential advantage of the iterative engineering approach may be to preserve stability of function and phenotype, particularly in the in vivo setting.
Diabetes 1997 Jun
PMID:Novel insulinoma cell lines produced by iterative engineering of GLUT2, glucokinase, and human insulin expression. 916 66

ATP-sensitive potassium (K[ATP]) channels are an essential component of glucose-dependent insulin secretion in pancreatic islet beta-cells. These channels comprise the sulfonylurea receptor (SUR1) and Kir6.2, a member of the inward rectifier K+ channel family. Mutations in the SUR1 subunit are associated with familial hyperinsulinism (HI) (MIM:256450), an inherited disorder characterized by hyperinsulinism in the neonate. Since the Kir6.2 gene maps to human chromosome 11p15.1 (1,2), which also encompasses a locus for HI, we screened the Kir6.2 gene for the presence of mutations in 78 HI probands by single-strand conformation polymorphism (SSCP) and nucleotide sequence analyses. A nonsense mutation, Tyr-->Stop at codon 12 (designated Y12X) was observed in the homozygous state in a single proband. 86Rb+ efflux measurements and single-channel recordings of COS-1 cells co-expressing SUR1 and either wild-type or Y12X mutant Kir6.2 proteins confirmed that K(ATP) channel activity was abolished by this nonsense mutation. The identification of an HI patient homozygous for the Kir6.2/Y12X allele affords an opportunity to observe clinical features associated with mutations resulting in an absence of Kir6.2. These data provide evidence that mutations in the Kir6.2 subunit of the islet beta-cell K(ATP) channel are associated with the HI phenotype and also suggest that the majority of HI cases are not attributable to mutations in the coding region of the Kir6.2 gene.
Diabetes 1997 Nov
PMID:A nonsense mutation in the inward rectifier potassium channel gene, Kir6.2, is associated with familial hyperinsulinism. 935 20

ATP-sensitive K+ (KATP) channels are therapeutic targets for several diseases, including angina, hypertension, and diabetes. This is because stimulation of KATP channels is thought to produce vasorelaxation and myocardial protection against ischemia, whereas inhibition facilitates insulin secretion. It is well known that native KATP channels are inhibited by ATP and sulfonylurea (SU) compounds and stimulated by nucleotide diphosphates and K+ channel-opening drugs (KCOs). Although these characteristics can be shared with KATP channels in different tissues, differences in properties among pancreatic, cardiac, and vascular smooth muscle (VSM) cells do exist in terms of the actions produced by such regulators. Recent molecular biology and electrophysiological studies have provided useful information toward the better understanding of KATP channels. For example, native KATP channels appear to be a complex of a regulatory protein containing the SU-binding site [sulfonylurea receptor (SUR)] and an inward-rectifying K+ channel (Kir) serving as a pore-forming subunit. Three isoforms of SUR (SUR1, SUR2A, and SUR2B) have been cloned and found to have two nucleotide-binding folds (NBFs). It seems that these NBFs play an essential role in conferring the MgADP and KCO sensitivity to the channel, whereas the Kir channel subunit itself possesses the ATP-sensing mechanism as an intrinsic property. The molecular structure of KATP channels is thought to be a heteromultimeric (tetrameric) assembly of these complexes: Kir6.2 with SUR1 (SUR1/Kir6.2, pancreatic type), Kir6.2 with SUR2A (SUR2A/ Kir6.2, cardiac type), and Kir6.1 with SUR2B (SUR2B/Kir6.1, VSM type) [i.e., (SUR/Kir6.x)4]. It remains to be determined what are the molecular connections between the SUR and Kir subunits that enable this unique complex to work as a functional KATP channel.
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PMID:ATP-sensitive K+ channels in pancreatic, cardiac, and vascular smooth muscle cells. 945 9


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