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

Time course of the surface electrical activity was studied in left ventricular trabeculae of Wistar rats made diabetic using streptozotocin. The action potentials were recorded in Tyrode's solution at 32 degrees C, their duration considerably increased in diabetes. By the 8th week, the prolongation was 64% at 25% of repolarization; 112% at 50% and 118% at 75%. Insulin treatment reduced the prolongation of the action potentials although a complete restoration was not achieved. 0.1 mM La3+ moderately shortened the electrical activity both in control and in diabetic trabeculae. Three mM 4-aminopyridine made the time course of control action potentials very similar to the diabetic ones while the action potentials from the diabetic animals were prolonged further to a smaller extent. Whole-cell clamp experiments in isolated ventricular myocytes (20-23 degrees C) showed a considerable decrease and a somewhat accelerated inactivation of the transient outward current (Ito) in diabetes. The steady-state inactivation and the rate of recovery from inactivation of Ito did not change. No alterations in the magnitude and voltage dependence of inward rectifier (IK1) were found around the resting membrane potential. The diabetes-related suppression of Ito explains the decreased repolarization rate of action potentials.
 ...
PMID:Action potentials and potassium currents in rat ventricular muscle during experimental diabetes. 143 14

1. The whole-cell voltage-clamp technique was applied to ventricular myocytes isolated from normal and streptozotocin-induced diabetic rat hearts to investigate the contribution of the calcium current and of the calcium-independent potassium currents to diabetes-induced alterations of the action potential. 2. In single calcium-tolerant isolated myocytes diabetes induced a lengthening of the action potential similar to that previously described in intact ventricular muscles. 3. Only L-type calcium current was present both in normal and diabetic cells. Inactivation of ICa was described in both preparations by two exponentials, whose time constants were not modified by diabetes. 4. Calcium current density-voltage relationships and steady-state inactivation curves were not significantly affected by diabetes. 5. Potassium background inward rectifier current was not modified by diabetes. 6. Calcium-independent outward potassium current inactivated, in both cell types, according to a biexponential process whose time constants were not affected by diabetes. 7. The transient outward potassium current density was significantly reduced by diabetes whereas neither the voltage dependence of the inactivation nor the time dependence of recovery from inactivation was modified. 8. A 4-aminopyridine-insensitive potassium current was also reduced by diabetes. 9. Our results show that in isolated ventricular myocytes the lengthening of the action potential induced by diabetes results mainly from a decrease of the transmembrane calcium-independent potassium permeability.
 ...
PMID:Calcium and potassium currents in ventricular myocytes isolated from diabetic rats. 830 34

The ATP-sensitive potassium channel of insulin-secreting pancreatic beta-cells is a complex of Kir6.2, a member of the inwardly rectifying potassium channel superfamily, and the sulfonylurea receptor. We have isolated cDNA clones encoding rat Kir6.2. Co-expression of rat Kir6.2 and sulfonylurea receptor in human embryonic kidney cells generated a potassium current with the properties of the beta-cell ATP-sensitive potassium channel. A quantitative reverse transcriptase-polymerase chain reaction assay indicated that Kir6.2 and sulfonylurea receptor mRNAs were abundantly expressed in rat islets and that expression of Kir6.2 mRNA was reduced by >70% in islets from Zucker diabetic fatty male rats, whereas there was no significant change in sulfonylurea receptor mRNA levels. Thus, decreased expression of Kir6.2 could contribute to the beta-cell dysfunction which characterizes diabetes mellitus in this animal model.
 ...
PMID:Rat inwardly rectifying potassium channel Kir6.2: cloning electrophysiological characterization, and decreased expression in pancreatic islets of male Zucker diabetic fatty rats. 860

This study examined the effects of protons on cardiac ion channel function in early stages of diabetes mellitus. Transient outward (I(to)) and inward rectifier K+ (IK1) currents were recorded by the whole cell, voltage-clamp technique in ventricular myocytes isolated from hearts of streptozotocin-induced diabetic and control rats. Proton concentration was controlled by independently varying the pH of buffered external or pipette (pHp) solutions. External acidification did not alter I(to) in diabetic rat myocytes when initiated after intracellular dialysis with standard pHp 7.2, but when these cells were dialyzed with acidic pHp (6.6 or 6.0), I(to) density was significantly reduced. Low pHp also reduced I(to) density more in cells from diabetic rats than in controls, whereas alkaline pHp had no effect on either group of cells compared with standard pHp 7.2. In control myocytes dialyzed with pHp 6.0, block of Na+/H+ exchange with 5-(N,N-dimethyl)-amiloride (DMA) or Na(+)-free external solution further reduced I(to) density compared with pHp 6.0 alone, whereas these treatments had less effect on acid-dialyzed cells from diabetic rats. Dialysis with pHp to 6.0 did not alter IK1 in either group of cells compared with standard pHp 7.2, but when done in the presence of DMA or Na(+)-free conditions, IK1 density in both groups was significantly reduced by nearly the same amount. We conclude that intracellular protons inhibit I(to) channels in ventricular myocytes from diabetic and control rats, but that for a given acid load, inhibition is markedly greater in diabetics. This difference may be explained by a diabetes-induced decrease in Na+/H+ exchange that limits proton extrusion during intracellular acidosis. Moreover, acidosis may differentially suppress I(to) and IK1, suggesting that these K+ channels exhibit dissimilar sensitivities to intracellular protons.
 ...
PMID:Intracellular protons inhibit transient outward K+ current in ventricular myocytes from diabetic rats. 894 36

The purpose of this study was to examine the mechanisms of alterations in cardiac K+ channel function in early stages of experimental diabetes mellitus induced by streptozotocin. Transient outward (Ito) and inward rectifier (IK1) K+ currents were recorded by the whole cell voltage-clamp technique in ventricular myocytes isolated from hearts of 2- to 4-wk diabetic and age-matched control rats. Ito density in myocytes from diabetic rats was approximately 30% less than control (at +60 mV; P < 0.01) under basal recording conditions in the presence of 18 mM external glucose, whereas IK1 density was not different between groups. When external glucose concentration was decreased to 5 mM for 4-6 h, basal Ito density was not changed in either group of myocytes. To further examine the possible metabolic basis of reduced Ito density in myocytes from diabetic rats, we separately tested three structurally different compounds that affect substrate utilization in cardiac myocytes: insulin (0.1 microM), dichloroacetate (1.5 mM), and L-carnitine (10 mM). Each compound completely normalized Ito density in myocytes from diabetic rats treated in vitro for 4-6 h. The same agents had no effect on Ito density in control myocytes, nor was IK1 altered in either group of cells. These data provide the first evidence to support the hypothesis that there is a metabolic basis for decreased Ito density in diabetic rat ventricular myocytes in early stages of this model. Furthermore, our data suggest that depressed glucose metabolism in the diabetic heart may be a key factor underlying changes in Ito channel function, because agents that increase glucose utilization normalize Ito density within a short time period.
 ...
PMID:Metabolic basis of decreased transient outward K+ current in ventricular myocytes from diabetic rats. 894 40

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

Kir6.2 is an inwardly rectifying potassium channel that is expressed in pancreatic beta-cells and cardiac and skeletal muscle. Expressed together with the high-affinity sulphonylurea receptor, it reconstitutes a sulphonylurea- and also ATP-sensitive potassium channel resembling the native beta-cell channel. The objective of this study was to search for mutations in the Kir6.2 gene that might be associated with NIDDM or related to altered insulin secretion, insulin action, or glucose metabolism in healthy subjects. Using polymerase chain reaction-single-strand conformation polymorphism analysis (PCR-SSCP) on genomic DNA from 69 Danish NIDDM patients and 66 matched control subjects, we report the finding of three missense polymorphisms in otherwise conserved codons and three silent polymorphisms in the gene encoding Kir6.2: codon 23 (GAG/AAG), Glu-->Lys; codon 190 (GCT/GCC), Ala-->Ala; codon 267 (CTC/CTG), Leu-->Leu; codon 270 (CTG/GTG), Leu-->Val; codon 337 (ATC/GTC), Ile-->Val; codon 381 (AAG/AAA), Lys-->Lys. The codon 23 and codon 337 amino acid polymorphisms were always coupled. The allelic frequencies of the polymorphisms were similar in NIDDM patients and control subjects. The amino acid polymorphisms were not associated with altered insulin secretion after intravenous glucose or tolbutamide injections or with altered glucose effectiveness in a phenotype study of 346 young healthy subjects. However, carriers of the maximal load of amino acid variants, the compound homozygous codon 23/337 and heterozygous codon 270, had on average a 62% higher insulin sensitivity index (P = 0.006), compared with noncarriers. We conclude that a combination of common Kir6.2 amino acid variants may contribute to the genetic background behind the large variation of the insulin sensitivity index in the general population.
Diabetes 1997 Mar
PMID:Amino acid polymorphisms in the ATP-regulatable inward rectifier Kir6.2 and their relationships to glucose- and tolbutamide-induced insulin secretion, the insulin sensitivity index, and NIDDM. 903 10

Kir6.2, a member of the inward rectifier K+ channel family, is a component of the ATP-sensitive K+ (K[ATP]) channel considered to play a key role in glucose-induced insulin secretion. We studied the distribution of Kir6.2 in mouse pancreas at the cellular level. The sites of Kir6.2 mRNA expression were determined by in situ hybridization histochemistry with a digoxigenin (DIG)-labeled antisense cRNA probe. The hybridization signal was unevenly present throughout the islets of Langerhans, while no distinct signal was detected in exocrine acinar cells. This distribution was confirmed by another cRNA probe complementary to a different region of Kir6.2 mRNA. In situ hybridization and immunofluorescence staining of serial sections with the anti-insulin, the anti-glucagon, and the anti-somatostatin antibodies showed Kir6.2 mRNA to be present in alpha-, beta-, and delta-cells. Furthermore, immunofluorescence staining with antibody raised against Kir6.2 revealed that Kir6.2 protein is localized within the pancreatic islets and is not found in exocrine pancreas. Kir6.2 was further shown to be located together with insulin, glucagon, or somatostatin. The positive staining of Kir6.2 appeared concentrated along the contour of each islet cell, suggesting that Kir6.2 is at the plasma membrane of islet cells. These results suggest that Kir6.2, as a component of K(ATP) channels, is an important molecule in the regulation of all the release of insulin, glucagon, and somatostatin.
Diabetes 1997 Sep
PMID:Localization of the ATP-sensitive K+ channel subunit Kir6.2 in mouse pancreas. 928 44

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

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.
Diabetes 1998 Mar
PMID:Identification and functional analysis of sulfonylurea receptor 1 variants in Japanese patients with NIDDM. 951 57


1 2 3 4 5 Next >>