Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Loss of beta-cell mass and function raises a concern regarding the application of sulfonylureas for the treatment of type 2 diabetes because previous studies have shown that agents that cause closure of inwardly rectifying K(+) sulfonylurea receptor subtype of ATP-sensitive potassium channels, such as tolbutamide and glibenclamide, induce apoptosis in beta-cell lines and rodent islets. Therefore, we investigated the effect of the new insulin secretagogues, repaglinide and nateglinide, and the sulfonylurea, glibenclamide, on beta-cell apoptosis in human islets. Human islets from six organ donors were cultured onto extracellular matrix-coated plates and exposed to glibenclamide, repaglinide, or nateglinide. The doses of the three compounds were chosen according to detected maximal effects, i.e. efficacy. Exposure of human islets for 4 h to 0.1 and 10 microm glibenclamide induced a 2.09- and 2.46-fold increase in beta-cell apoptosis, respectively, whereas repaglinide (0.01 and 1 microm) did not change the number of apoptotic beta-cells. At low concentration (10 microm), nateglinide did not induce beta-cell apoptosis. However, at high concentration of 1000 microm, it induced a 1.49-fold increase in the number of apoptotic beta-cells. Prolonged exposure for 4 d of the islets to the secretagogues induced beta-cell apoptosis. The increase was of 3.71- and 4.4-fold at 0.1 and 10 microm glibenclamide, 2.37- and 3.8-fold at 0.01 and 1 microm repaglinide, and of 3.2- and 4.6-fold at 10 and 1000 microm nateglinide, respectively. Glibenclamide at 0.1-10 nm (doses that were less efficient on insulin secretion) did not induce beta-cell apoptosis after 4 h incubation as well as 0.1 nm after 4 d incubation. However, 1 and 10 nm glibenclamide for 4 d induced a 2.24- and 2.53-fold increase in beta-cell apoptosis, respectively. Taken together, closure of the inwardly rectifying K(+) sulfonylurea receptor subtype of ATP-sensitive potassium channels induces beta-cell apoptosis in human islets and may precipitate the decrease in beta-cell mass observed in patients with type 2 diabetes.
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PMID:Sulfonylurea induced beta-cell apoptosis in cultured human islets. 1548 97

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.
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PMID:Sulfonylurea and non-sulfonylurea hypoglycemic agents: pharmachological properties and tissue selectivity. 1556 85

To study whether the 3c/t polymorphism of the sulfonylurea receptor 1 (SUR1) gene exon16 increased the risk of type 2 diabetes mellitus in type 2 diabetes mellitus pedigrees in Han population in south area of China. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used in 46 type 2 diabetes mellitus pedigrees. The polymorphism in SUR1 was tested and analyzed by Mantel-Haenszel chi(2) test. Frequencies of SUR1-3c/t polymorphism had no significant difference between type 2 diabetes mellitus and normal relatives (genotypes chi(2)=3.224, P=0.199; frequency of allele chi(2)=1.250, P=0.264). In all subjects, type 2 diabetes mellitus and normal relatives, SUR1-3c/t genotypes were listed (cc: 29.3%, 30.2%, 28.3%; ct: 50.7%, 53.8%, 47.2%; tt: 20%, 16.0%, 24.5% respectively). The frequencies of c were 54.7%, 57.1% and 51.9% respectively. The frequency of c is lower than Han population in northern China. The results show that SUR1 exon16-3c/t polymorphism is not associated with type 2 diabetes mellitus in the population.
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PMID:[Study on the relationship between sulfonylurea receptor 1 gene polymorphism and type 2 diabetes mellitus]. 1562 59

Pancreatic beta-cell adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channels play a pivotal role in linking glucose metabolism to regulated insulin secretion. K(ATP) channels are hetero-octameric complexes comprising two subunits Kir6.2 and sulfonylurea receptor 1 (SUR1). Changes in the intracellular concentration of nucleotides (ATP) cause alterations in the resting and opening state of the K(ATP) channels. Loss-of-function mutations in the genes encoding the two subunits of K(ATP) channels lead to the most common form of congenital hyperinsulinism (CHI). This causes persistent and severe hypoglycemia in the neonatal and infancy period. CHI can cause mental retardation and epilepsy if not treated properly. On the other hand, now there is evidence of an association between polymorphisms in the Kir6.2 gene and type 2 diabetes mellitus, mutations in the Kir6.2 gene and neonatal diabetes mellitus, and mutations in the SUR1 gene and diabetes mellitus. Interestingly, for reasons that are unclear at present, mice knockout models of K(ATP) channels are different from the human phenotype of CHI. This article is a review focusing on how abnormalities in the pancreatic beta-cell K(ATP) channels can lead to severe hypoglycemia on the one hand and diabetes mellitus on the other.
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PMID:From congenital hyperinsulinism to diabetes mellitus: the role of pancreatic beta-cell KATP channels. 1596 39

We have identified Kruppel-like factor 7 (KLF7) as a new candidate for conferring susceptibility to type 2 diabetes. To ascertain the possible involvement of KLF7 in the pathogenesis of type 2 diabetes, we examined the functional roles of KLF7 in various types of cells. In human adipocytes overexpressing KLF7, the expression of adiponectin and leptin was decreased compared with that in control cells, whereas expression of IL-6 was increased. In the insulin-secreting cell line (HIT-T15 cells), the expression and glucose-induced secretion of insulin were significantly suppressed in KLF7-overexpressed cells compared with control cells, accompanied by the reduction in the expression of glucose transporter 2, sulfonylurea receptor 1, Kir6.2, and pancreatic-duodenal homeobox factor 1. We also found that the overexpression of KLF7 resulted in the decrease of hexokinase 2 expression in smooth muscle cells, and of glucose transporter 2 expression in the HepG2 cells. These results suggest that KLF7 may contribute to the pathogenesis of type 2 diabetes through an impairment of insulin biosynthesis and secretion in pancreatic beta-cells and a reduction of insulin sensitivity in peripheral tissues. Therefore, we suggest that KLF7 plays an important role in the pathogenesis of type 2 diabetes, and may be a useful target for new drugs to aid in the prevention and treatment of this disease.
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PMID:Overexpression of Kruppel-like factor 7 regulates adipocytokine gene expressions in human adipocytes and inhibits glucose-induced insulin secretion in pancreatic beta-cell line. 1633 72

Because impaired insulin secretion is characteristic of type 2 diabetes in Asians, including Japanese, the genes involved in pancreatic beta-cell function are candidate susceptibility genes for type 2 diabetes. We examined the association of variants in genes encoding several transcription factors (TCF1, TCF2, HNF4A, ISL1, IPF1, NEUROG3, PAX6, NKX2-2, NKX6-1, and NEUROD1) and genes encoding the ATP-sensitive K(+) channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) with type 2 diabetes in a Japanese cohort of 2,834 subjects. The exon 16 -3c/t variant rs1799854 in ABCC8 showed a significant association (P = 0.0073), and variants in several genes showed nominally significant associations (P < 0.05) with type 2 diabetes. Although the E23K variant rs5219 in KCNJ11 showed no association with diabetes in Japanese (for the K allele, odds ratio [OR] 1.08 [95% CI 0.97-1.21], P = 0.15), 95% CI around the OR overlaps in meta-analysis of European populations, suggesting that our results are not inconsistent with the previous studies. This is the largest association study so far conducted on these genes in Japanese and provides valuable information for comparison with other ethnic groups.
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PMID:Association studies of variants in the genes involved in pancreatic beta-cell function in type 2 diabetes in Japanese subjects. 1687 4

The sulfonylurea receptors (SURs) ABCC8/SUR1 and ABCC9/SUR2 are members of the C-branch of the transport adenosine triphosphatase superfamily. Unlike their brethren, the SURs have no identified transport function; instead, evolution has matched these molecules with K(+) selective pores, either K(IR)6.1/KCNJ8 or K(IR)6.2/KCNJ11, to assemble adenosine triphosphate (ATP)-sensitive K(+) channels found in endocrine cells, neurons, and both smooth and striated muscle. Adenine nucleotides, the major regulators of ATP-sensitive K(+) (K(ATP)) channel activity, exert a dual action. Nucleotide binding to the pore reduces the activity or channel open probability, whereas Mg-nucleotide binding and/or hydrolysis in the nucleotide-binding domains of SUR antagonize this inhibitory action to stimulate channel openings. Mutations in either subunit can alter this balance and, in the case of the SUR1/KIR6.2 channels found in neurons and insulin-secreting pancreatic beta cells, are the cause of monogenic forms of hyperinsulinemic hypoglycemia and neonatal diabetes. Additionally, the subtle dysregulation of K(ATP) channel activity by a K(IR)6.2 polymorphism has been suggested as a predisposing factor in type 2 diabetes mellitus. Studies on K(ATP) channel null mice are clarifying the roles of these metabolically sensitive channels in a variety of tissues.
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PMID:ABCC8 and ABCC9: ABC transporters that regulate K+ channels. 1689 43

Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target the peroxisome proliferator-activated receptor (PPARgamma) improving insulin resistance (thiazolidinediones). Our work shows that sulfonylureas and glinides additionally bind to PPARgamma and exhibit PPARgamma agonistic activity. This activity was predicted in silico by virtual screening and confirmed in vitro in a binding assay, a transactivation assay, and by measuring the expression of PPARgamma target genes. Among the measured compounds, gliquidone and glipizide (two sulfonylureas), as well as nateglinide (a glinide), exhibit PPARgamma agonistic activity at concentrations comparable with those reached under pharmacological treatment. The most active of these compounds, gliquidone, is shown to be as potent as pioglitazone at inducing PPARgamma target gene expression. This dual mode of action of sulfonylureas and glinides may open new perspectives for the molecular pharmacology of antidiabetic drugs, because it provides evidence that drugs can be designed that target both the sulfonylurea receptor and PPARgamma. Targeting both receptors could increase pancreatic insulin secretion and improve insulin resistance. Glinides, sulfonylureas, and other acidified sulfonamides may be promising leads in the development of new PPARgamma agonists. In addition, we provide a unified concept of the PPARgamma binding ability of seemingly disparate compound classes.
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PMID:Sulfonylureas and glinides exhibit peroxisome proliferator-activated receptor gamma activity: a combined virtual screening and biological assay approach. 1708 35

To investigate the effects of sulfonylurea receptor 1 (SUR1) exon 33 (TCC-->GCC, S1369A) polymorphism on responsiveness to gliclazide. About 115 patients with type 2 diabetes were treated with gliclazide for 8 weeks. SUR1 genotypes were tested by Taqman-PCR. After gliclazide treatment, there was association between T/G polymorphism and decrease of HbA1c. G carriers were more sensitive to gliclazide and the decrease of HbA1c was more significant than TT genotype (TT, 0.76%+/-1.70%; TG+GG, 1.60%+/-1.39%, P=0.044). The polymorphism of SUR1S1369A was associated with the therapeutic efficacy of gliclazide.
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PMID:Association of sulfonylurea receptor 1 genotype with therapeutic response to gliclazide in type 2 diabetes. 1711 80

Epidemiological data collected over the last few decades have demonstrated the significant role of acute (especially postprandial) hyperglycaemia in the development of macrovascular complications in patients with type 2 diabetes. However, the influence of SUR1 exon 16-3c/t polymorphism on impaired insulin secretion during acute hyperglycaemic episodes has not yet been evaluated. We studied 40 type 2 diabetic patients. Single nucleotide polymorphism in the sulfonylurea receptor gene was examined by means of PCR-RLFP. In every patient, fasting insulin, proinsulin, C-peptide and 1,5-anhydro-d-glucitol concentrations were assayed as markers of insulin secretion, peripheral resistance to insulin, and acute hyperglycaemia. The distribution of SUR1 exon 16-3c/t polymorphism was tt 35%, tc -40%, and cc -25%. By means of analysis of covariance, it was revealed that 1,5-anhydro-d-glucitol plasma levels are associated with SUR1 exon 16-3c/t polymorphism. However, the HOMA(IR) score influenced 1,5-anhydro-d-glucitol levels in plasma at a higher level of statistical power than the genetic variant. Our results suggest that SUR1 exon 16-3c/t polymorphism is only a partial determinant of acute hyperglycaemia-cardiovascular risk factor in type 2 diabetes.
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PMID:Impact of the sulfonylurea receptor 1 (SUR1) exon 16-3c/t polymorphism on acute hyperglycaemia in type 2 diabetic patients. 1720 85


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