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)

It has been proposed that variation in calpain 10 (CAPN10) contributes to the risk of type 2 diabetes (T2D). A previous survey of CAPN10 in ethnically diverse populations revealed an intronic region with a significant excess of polymorphism levels relative to inter-species sequence divergence, suggesting that this region was the target of long-standing balancing selection. Based on the thrifty genotype hypothesis, variation that increases risk to T2D in contemporary humans at one time conferred a survival advantage in ancestral populations. Thus, the signature of positive natural selection in a T2D candidate gene could identify a genomic region containing variation that influences disease susceptibility. Here, we investigate this hypothesis by re-sequencing the CAPN10 region with unusual polymorphism levels in T2D cases and controls (n=91) from a Mexican American (MA) population, and by using networks to infer the evolutionary relationships between the major haplotypes. Haplotype tag SNPs (htSNPs) were then selected in each population sample and in MA cases and controls. By placing the htSNPs on the haplotype network, we investigate how cross-population differences in CAPN10 genetic architecture may affect the detection of the disease association. Interestingly, despite the small scale of our case-control study, we observe a nearly significant signal of association between T2D and variation in the putative target of balancing selection. Finally, we use phylogenetic shadowing across 10 primate species to search for conserved non-coding elements that may affect the expression and function of CAPN10. These elements are postulated to be the targets of long-standing balancing selection.
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PMID:Haplotype structure and phylogenetic shadowing of a hypervariable region in the CAPN10 gene. 1590 97

The clinical picture of type 2 diabetes mellitus (T2DM) is formed by impairment in insulin secretion and resistance to insulin action. As a result of intensive efforts of the scientists around the world mutations and polymorphisms in a number of genes were linked with monogenic and polygenic forms of T2DM. Two major strategies were used in this research: genome scanning and the candidate gene approach. Monogenic forms, despite their rarity, constitute a field where substantial progress has been made in the dissection of the molecular background of T2DM. Monogenic forms of T2DM with profound defect in insulin secretion include subtypes of maturity onset diabetes of the young (MODY), maternally inherited diabetes with deafness (MIDD) caused by mitochondrial mutations, and rare cases resulting from insulin gene mutations. The majority of proteins associated with MODY are transcription factors, such as hepatocyte nuclear factor 4alpha (HNF-4alpha), HNF-1alpha, insulin promoter factor-1 (IPF-1), HNF-1beta, and NEUROD1. They influence expression of the other genes through regulation of mRNA synthesis. Only MODY2 form is associated with glucokinase, a key regulatory enzyme of the beta cell. There are striking differences in the clinical picture of MODY associated with glucokinase and MODY associated with transcription factors. Three monogenic forms of T2DM characterized by severe insulin resistance are the consequence of mutations in the PPARgamma, ATK2, and insulin receptor genes. Patients with monogenic T2DM, particularly with MODY, sometimes, develop discrete extra-pancreatic phenotypes; for example, lipid abnormalities or a variety of cystic renal diseases. Efforts aiming to identify genes responsible for more common, polygenic forms of T2DM were less effective. These forms of T2DM have a middle/late age of onset and occur with both impaired insulin secretion and insulin resistance. Their clinical picture is created by the interaction of environmental and genetic factors, such as frequent polymorphisms of many genes, not just of one. These polymorphisms may be localized in the coding or regulatory parts of the genes and are present, although with different frequencies, in T2DM patients as well as in healthy populations. Sequence differences in a few genes have been associated, so far, with complex, polygenic forms of T2DM, for example, calpain 10, PPARgamma, KCJN11, and insulin. In addition, some evidence exists that genes, such as adiponectin, IRS-1, and some others may also influence the susceptibility to T2DM. It is expected that in the nearest future more T2DM susceptibility genes will be identified.
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PMID:Genetics of type 2 diabetes mellitus. 1595 69

Type 2 diabetes mellitus is a disorder of glucose homeostasis involving complex gene and environmental interactions that are incompletely understood. Mammalian homologs of nematode sex determination genes have recently been implicated in glucose homeostasis and type 2 diabetes mellitus. These are the Hedgehog receptor Patched and Calpain-10, which have homology to the nematode tra-2 and tra-3 sex determination genes, respectively. Here, we have developed Fem1b knockout (Fem1b-KO) mice, with targeted inactivation of Fem1b, a homolog of the nematode fem-1 sex determination gene. We show that the Fem1b-KO mice display abnormal glucose tolerance and that this is due predominantly to defective glucose-stimulated insulin secretion. Arginine-stimulated insulin secretion is also affected. The Fem1b gene is expressed in pancreatic islets, within both beta cells and non-beta cells, and is highly expressed in INS-1E cells, a pancreatic beta-cell line. In conclusion, these data implicate Fem1b in pancreatic islet function and insulin secretion, strengthening evidence that a genetic pathway homologous to nematode sex determination may be involved in glucose homeostasis and suggesting novel genes and processes as potential candidates in the pathogenesis of diabetes mellitus.
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PMID:Abnormal glucose homeostasis and pancreatic islet function in mice with inactivation of the Fem1b gene. 1602 93

Calpain-10 (CAPN10) is the first diabetes gene to be identified through a genome scan. Many investigators, but not all, have subsequently found associations between CAPN10 polymorphism and type 2 diabetes (T2D) as well as insulin action, insulin secretion, aspects of adipocyte biology and microvascular function. However, this has not always been with the same single nucleotide polymorphism (SNP) or haplotype or the same phenotype, suggesting that there might be more than one disease-associated CAPN10 variant and that these might vary between ethnic groups and the phenotype under study. Our understanding of calpain-10 physiological action has also been greatly augmented by our knowledge of the calpain family domain structure and function, and the relationship between calpain-10 and other calpains is discussed here. Both genetic and functional data indicates that calpain-10 has an important role in insulin resistance and intermediate phenotypes, including those associated with the adipocyte. In this regard, emerging evidence would suggest that calpain-10 facilitates GLUT4 translocation and acts in reorganization of the cytoskeleton. Calpain-10 is also an important molecule in the beta-cell. It is likely to be a determinant of fuel sensing and insulin exocytosis, with actions at the mitochondria and plasma membrane respectively. We postulate that the multiple actions of calpain-10 may relate to its different protein isoforms. In conclusion, the discovery of calpain-10 by a genetic approach has identified it as a molecule of importance to insulin signaling and secretion that may have relevance to the future development of novel therapeutic targets for the treatment of T2D.
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PMID:Calpain-10: from genome search to function. 1602 16

Evidence for a genetic basis for type 2 diabetes and the metabolic syndrome has been derived from studies of families, twins and populations with genetic admixture. Identification of genes associated with disease pathogenesis is now underway using techniques such as genome scanning by positional cloning and the candidate gene approach. Genome scanning in several different ethnic groups has identified chromosome regions harbouring type 2 diabetes susceptibility genes such as the novel gene, calpain 10 (CAPN10). The hepatic nuclear factor 4alpha (HNF4alpha) gene partly explains the linkage peak on chromosome 20, while the upstream transcription factor (USF1) is associated with familial combined hyperlipidaemia (FCHL) and maps close to the type 2 diabetes associated 1q peak. Peroxisome proliferator-activated receptor gamma (PPARgamma) was identified as a candidate gene based on its biology. A Pro12Ala variant of this gene has been associated with an increased risk of type 2 diabetes. Many genes accounting for monogenic forms of diabetes have been identified--such as maturity onset diabetes of the young (MODY); glucokinase (GCK) and HNF1alpha mutations being the most common causes of MODY. GCK variants result in 'mild' diabetes or impaired glucose tolerance (IGT) and relatively few cardiovascular complications, while HNF1alpha-associated MODY is more typical of type 2 diabetes, frequently being treated with sulphonylureas or insulin and resulting in microvascular complications. Testing for single gene disorders associated with type 2 diabetes and obesity may determine cause, prognosis and appropriate treatment; however, for the more common polygenic diseases this is not the case. In type 2 diabetes, molecular genetics has the potential to enhance understanding of disease pathogenesis, and help formulate preventative and treatment strategies.
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PMID:Searching for genes in diabetes and the metabolic syndrome. 1603 91

Patients with metabolic syndrome are at increased risk of developing cardiovascular disease. The combinations of the haplotype created by the alleles of three single nucleotide polymorphisms (SNPs): SNP-43, -19, and -63 of the Calpain-10 gene (CAPN10), have been reported to be associated with the risk of type 2 diabetes in many populations. The aim of this study was to examine the association of the CAPN10 polymorphism with metabolic syndrome in patients with type 2 diabetes in Korea. Overall, 382 patients with type 2 diabetes were enrolled in this study. All the subjects were genotyped according to CAPN10 SNP-43, -19, and -63. The restriction fragment length polymorphism method was used for the three SNPs. The baseline presence of components of metabolic syndrome was determined. Two hundred and sixty-five (69.4%) patients had metabolic syndrome. Patients with the 111/121 haplotype combination showed a higher risk of hypertension than the other haplotype combinations (odd ratio (OR)=2.334, P=0.010). Patients with the 111/121 haplotype combination had a significantly high risk of metabolic syndrome (OR=1.927, P=0.042). The results of this study suggest that a novel 111/121 haplotype combination created by the CAPN10 SNP-43, -19, and -63 increases the susceptibility to the metabolic syndrome in patients with type 2 diabetes.
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PMID:Haplotype combination of Calpain-10 gene polymorphism is associated with metabolic syndrome in type 2 diabetes. 1654 86

Type 2 diabetes is a complex polygenic metabolic disorder of epidemic proportions. This review provides a brief overview of the susceptibility genes in type 2 diabetes that primarily affect pancreatic 3 cells, with emphasis on their function and most relevant polymorphisms. We focus on calpain 10, the only susceptibility gene identified thus far through a positional cloning approach in subjects with diabetes.
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PMID:Genes of type 2 diabetes in beta cells. 1663 98

Genetic variations in the Calpain-10 gene, CAPN10, have been reported to be associated with the risk of type 2 diabetes mellitus (T2DM) in Mexican-Americans and Northern Europeans whereas these variations are not associated with T2DM in other populations. The aim of this study was to determine whether there is an association between specific CAPN10 diplotype (SNP-43, -19, and -63) and T2DM in the Korean population. Overall, 454 Korean patients with T2DM (male 230, female 224) and 236 non-diabetic controls (male 124, female 112) with no family history of diabetes were enrolled in this study. All the subjects were genotyped according to CAPN10 SNP-43, -19, and -63. The restriction fragment length polymorphism method was used for the three SNPs. There were eight estimated haplotype allelic variations. After adjusting for gender and age, the 111 haplotype was associated with a high risk of T2DM (P <0.0001). The 111/121 diplotype was associated with a high risk of T2DM (odds ratio =2.580, 95% confidence interval =1.602-4.155, P =0.001). The high-risk haplotype (112/121) in Mexican-Americans was not significant in our study population. In conclusion, we found that a novel 111/121 diplotype in Calpain-10 gene is associated with T2DM in the Korean population.
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PMID:A novel 111/121 diplotype in the Calpain-10 gene is associated with type 2 diabetes. 1672 85

Type 2 diabetes mellitus (T2DM) can lead to death without treatment and it has been predicted that the condition will affect 215 million people worldwide by 2010. T2DM is a multifactorial disorder whose precise genetic causes and biochemical defects have not been fully elucidated, but at both levels, calpains appear to play a role. Positional cloning studies mapped T2DM susceptibility to CAPN10, the gene encoding the intracellular cysteine protease, calpain 10. Further studies have shown a number of noncoding polymorphisms in CAPN10 to be functionally associated with T2DM while the identification of coding polymorphisms, suggested that mutant calpain 10 proteins may also contribute to the disease. Here we review recent studies, which in addition to the latter enzyme, have linked calpain 5, calpain 3, and its splice variants, calpain 2 and calpain 1 to T2DM-related metabolic pathways along with T2DM-associated phenotypes, such as obesity and impaired insulin secretion, and T2DM-related complications, such as epithelial dysfunction and diabetic cataract.
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PMID:Calpains and their multiple roles in diabetes mellitus. 1715 22

Calpains are a family of non-lysosomal cytoplasmatic cysteine proteases. Since calpain 10 (CAPN10), a member of the calpain family of proteases, has been found to represent a putative diabetes susceptibility gene, it was argued that calpains may be involved in the development of type 2 diabetes. The functional role of calpains in insulin signaling and/or insulin action is, however, not clear. We investigated the effects of the calpains 1 and 2 inhibitor PD151746 on insulin signaling and insulin action in human hepatoma G2 cells (HepG2). HepG2 cells were incubated without (-PD) or with (+PD) 5.33 micromol/l PD151746 for different times and then stimulated with 100 nmol/l insulin for 0 (t(0)), 5 (t(5)), 15 (t(15)), 30 (t(30)), 45 (t(45)), and 60 (t(60)) min. After solubilization of the cells, insulin receptor kinase activity, tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1), IRS-1-associated phosphatidylinositol-3 kinase (PI3-kinase), PI3-kinase activity, Thr(308) phosphorlyation of Akt, amount of protein tyrosine phosphatase-epsilon (PTPepsilon), and glycogen synthase activity were determined. Incubation with PD151746 resulted in a significant reduction of insulin-stimulated glycogen synthesis compared with cells not pre-incubated with the calpain inhibitor (-PD: t(0), 4.90 +/- 1.20%; t(5), 5.90 +/- 1.02%; t(15), 5.29 +/- 0.95%; t(30), 5.60 +/- 1.10%; t(45), 5.52 +/- 0.90%; t(60), 5.67 +/- 0.97%;+PD: t(0), 4.56 +/- 1.10%; t(5), 6.16 +/- 1.05%; t(15), 7.52 +/- 1.09%; t(30), 7.68 +/- 1.10%; t(45), 8.28 +/- 0.89%; t(60), 7.69 +/- 0.98%; P < 0.05). Incubation with PD151746 significantly increased the protein amount of PTPepsilon in the cells after 12 h (-PD: t(1), 0.85 +/- 0.18 RU (Relative unit); t(8), 0.87 +/- 0.18 RU; t(12), 0.9 +/- 0.13 RU; +PD: t(1), 0.92 +/- 0.21 RU; t(8), 1.1 +/- 0.15 RU; t(12), 1.34 +/- 0.16 RU; P < 0.05). Calpain inhibition with PD151746 had no effect on the insulin stimulation of the investigated insulin signaling parameters. These results in HepG2 cells suggest that calpains play a role in the hepatic regulation of insulin-stimulated glycogen synthesis independent of the PI3-kinase/Akt signaling pathway.
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PMID:Calpain inhibition impairs glycogen syntheses in HepG2 hepatoma cells without altering insulin signaling. 1740 Aug 2


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