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)

Type 2 or non-insulin-dependent diabetes mellitus (NIDDM) is the most common form of diabetes worldwide, affecting approximately 4% of the world's adult population. It is multifactorial in origin with both genetic and environmental factors contributing to its development. A genome-wide screen for type 2 diabetes genes carried out in Mexican Americans localized a susceptibility gene, designated NIDDM1, to chromosome 2. Here we describe the positional cloning of a gene located in the NIDDM1 region that shows association with type 2 diabetes in Mexican Americans and a Northern European population from the Botnia region of Finland. This putative diabetes-susceptibility gene encodes a ubiquitously expressed member of the calpain-like cysteine protease family, calpain-10 (CAPN10). This finding suggests a novel pathway that may contribute to the development of type 2 diabetes.
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PMID:Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. 1101 62

Variation in CAPN10, the gene encoding the ubiquitously expressed cysteine protease calpain-10, has been associated with type 2 diabetes in Mexican Americans and in two northern-European populations, from Finland and Germany. We have studied CAPN10 in white subjects of British/Irish ancestry, using both family-based and case-control studies. In 743 sib pairs, there was no evidence of linkage at the CAPN10 locus, which thereby excluded it as a diabetes-susceptibility gene, with an overall sib recurrence risk, lambda(S), of 1.25. We examined four single-nucleotide polymorphisms (SNP-44, -43, -19, and -63) previously either associated with type 2 diabetes or implicated in transcriptional regulation of calpain-10 expression. We did not find any association between SNP-43, -19, and -63, either individually or as part of the previously described risk haplotypes. We did, however, observe significantly increased (P=.033) transmission of the less common C allele at SNP-44, to affected offspring in parents-offspring trios (odds ratio 1.6). An independent U.K. case-control study and a small discordant-sib study did not show significant association individually. In a combined analysis of all U.K. studies (P=.015) and in combination with a Mexican American study (P=.004), the C allele at SNP-44 is associated with type 2 diabetes. Sequencing of the coding region of CAPN10 in a group of U.K. subjects revealed four coding polymorphisms-L34V, T504A, R555C, and V666I. The T504A polymorphism was in perfect linkage disequilibrium with the diabetes-associated C allele at SNP-44, suggesting that the synthesis of a mutant protein and/or altered transcriptional regulation could contribute to diabetes risk. In conclusion, we were not able to replicate the association of the specific calpain-10 alleles identified by Horikawa et al. but suggest that other alleles at this locus may increase type 2 diabetes risk in the U.K. population.
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PMID:Studies of association between the gene for calpain-10 and type 2 diabetes mellitus in the United Kingdom. 1148 85

Polycystic ovary syndrome (PCOS) is associated with an increased risk of impaired glucose tolerance and type 2 diabetes. Recent evidence suggests that variation in the gene encoding the cysteine protease calpain-10 influences susceptibility to type 2 diabetes. The present study was undertaken to determine whether variation in this gene is associated with quantitative traits pertinent to the pathogenesis of PCOS and diabetes. We studied 212 women with PCOS (124 white of European ancestry, 57 African-American, 13 Hispanic, 13 Asian-American, and 5 Middle-Eastern). Each subject was genotyped for 3 DNA polymorphisms in the calpain-10 gene associated with type 2 diabetes (SNP-43, -19, and -63). The white and African-American subjects were examined for association of these polymorphisms with phenotypic features of PCOS and type 2 diabetes. There were not enough individuals in the other groups for similar genotype/phenotype analyses. Nineteen (9%) of the 212 women with PCOS were diabetic and were not included in the genotype/phenotype analyses. Twelve (63%) of these subjects were African-American. Phenotypic traits in nondiabetic white probands did not differ whether analyzed for each individual SNP (SNP-43, -19, -63) or haplotype combination. Nor was there association of SNP-43, -19, or -63 with any of the phenotypic features of type 2 diabetes or PCOS in nondiabetic African-Americans. However, nondiabetic African-Americans with the 112/121-haplotype combination had significantly higher insulin levels, in response to an oral glucose challenge, as reflected in the area under the insulin curve (257,021 +/- 95,384 vs. 136,240 +/- 11,468 pmol/min; P = 0.03), compared with those with other haplotypes. This finding was particularly notable because the 112/121 subjects were less obese. The difference between groups in area under the insulin response curve remained significant (P = 0.002 by analysis of covariance) after adjustment for body mass index. In addition to its association with insulin levels in African-Americans, the 112/121-haplotype combination was associated with an approximate 2-fold increase in risk of PCOS in both African-Americans and whites.
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PMID:Relationship of calpain-10 genotype to phenotypic features of polycystic ovary syndrome. 1193 99

Genetic variation in the gene for a cytosolic cysteine protease, calpain-10, increases the susceptibility to type 2 diabetes apparently by altering levels of gene expression. In view of the importance of altered beta-cell function in the pathophysiology of type 2 diabetes, the present study was undertaken to define the effects on insulin secretion of exposing pancreatic islets to calpain inhibitors for 48 hours. Exposure of mouse islets to calpain inhibitors (ALLN, ALLM, E-64-d, MDL 18270, and PD147631) of different structure and mechanism of action for 48 hours reversibly suppresses glucose-induced insulin secretion by 40% to 80%. Exposure of islets to inhibitors of other proteases, ie, cathepsin B and proteasome, did not affect insulin secretion. The 48-hour incubation with calpain inhibitors also attenuates insulin secretory responses to the mitochondrial fuel alpha-ketoisocaproate (KIC). The same incubation also suppresses glucose metabolism and intracellular calcium ([Ca(2+)](i)) responses to glucose or KIC in islets. In summary, long-term inhibition of islet calpain activity attenuates insulin secretion possibly by limiting the rate of glucose metabolism. A reduction of calpain activity in islet could contribute to the development of beta-cell failure in type 2 diabetes thereby providing a link between genetic susceptibility to diabetes and the pathophysiologic manifestations of the disease.
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PMID:A 48-hour exposure of pancreatic islets to calpain inhibitors impairs mitochondrial fuel metabolism and the exocytosis of insulin. 1275 79

Calpain, a Ca(2+)-requiring cytoplasmic cysteine protease, plays indispensable roles in various cellular functions such as signal transduction, cell growth and differentiation, apoptosis, necrosis, and so on. Although most of the detailed physiological functions of calpains have not yet been elucidated, the importance of calpain is obvious from the increasing numbers of papers describing relationships between human disease states (such as Alzheimer's disease, cataract, and muscular dystrophies) and malfunction of calpain. One of the recent remarkable topics of calpain is that a single nucleotide polymorphism of CAPN10, the gene for calpain 10, is related to type 2 diabetes. However, physiological functions of calpain 10 and its relation to diabetes are still unclear. Among 14 human calpain genes, mutations in CAPN3, the gene for p94/calpain 3a and Lp82/calpain 3b, are the only example that genetically connects the calpain gene and human disease, in this case, limb-girdle muscular dystrophy type 2A (LGMD2A). p94 has unique characteristics such as apparent Ca(2+)-independent activation and very rapid autolytic activity, which are dependent on p94-specific regions, NS, IS1, and IS2. Based on the 3D structures of micro - and m-calpain, molecular functions of p94 in relation to LGMD2A are discussed, with the hope of providing us with some clues to understand calpain functions and its relationships to human diseases.
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PMID:[Calpain and pathology in view of structure-function relationships]. 1284 69

Type 2 diabetes mellitus (T2DM) is characterized by defects in haepatic glucose production, insulin action and insulin secretion, which can also lead to a variety of secondary disorders. The disease can lead to death without treatment and it has been predicted that T2DM will affect 215 million people world-wide by 2010. T2DM is a multifactorial condition 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 non-coding polymorphisms in CAPN10 to be functionally associated with T2DM whilst the identification of coding polymorphisms, suggested that mutant calpain 10 proteins may also contribute to the disease. The presence of both calpain 10 and its mRNA have been demonstrated in tissues from several mammalian species whilst calpain 10 appears to be associated with pathways involved in glucose metabolism, insulin secretion and insulin action. It appears that other calpains may also participate in these pathways and here we present an overview of recent studies on calpains and their putative role in T2DM.
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PMID:Role of calpains in diabetes mellitus: a mini review. 1536 99

Variation in the gene encoding the cysteine protease calpain-10 has been linked and associated with risk of type 2 diabetes. We have examined the effect of three polymorphisms in the calpain-10 gene (SNP-43, Indel-19, and SNP-63) on the development of type 2 diabetes in the Japanese population in a pooled analysis of 927 patients and 929 controls. We observed that SNP-43, Indel-19, and SNP-63 either individually or as a haplotype were not associated with altered risk of type 2 diabetes with the exception of the rare 111/221 haplogenotype (odds ratio (OR) =3.53, P=0.02). However, stratification based on the median age-at-diagnosis in the pooled study population (<50 and > or =50 years) revealed that allele 2 of Indel-19 and the 121 haplotype were associated with reduced risk in patients with later age-at-diagnosis (age-at-diagnosis > or =50 years OR=0.82 and 0.80, respectively; P=0.04 and 0.02). Thus, variation in the calpain-10 gene may affect risk of type 2 diabetes in Japanese, especially in older individuals.
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PMID:Genetic variants in the calpain-10 gene and the development of type 2 diabetes in the Japanese population. 1569 76

Calpain is a Ca(2+)-regulated cytosolic cysteine protease that exists mainly in two isoforms and mediates crucial cellular functions, including rearrangement of cytoskeletal proteins, transport of the glucose transporter GLUT4, and protein cleavage to activate various receptors and pro-enzymes. Unintentional activation or functional loss of intracellular calpain has been implicated in several pathologies, including neurodegenerative diseases, traumatic brain and spinal cord injuries, cataracts and ischemia-associated injuries. Furthermore, polymorphism in the gene encoding calpain-10 has been associated with increased risk of type 2 diabetes. Recent studies have revealed a novel role for calpain in the progression of toxicant-induced liver damage. Evidence suggests that calpain leaking out of necrotic hepatocytes is highly activated in the extracellular milieu and hydrolyzes proteins in the plasma membrane of neighboring cells leading to progression of injury. Experimental intervention with calpain inhibitors substantially mitigates progression of liver injury initiated by toxicants, thereby preventing acute liver failure, and toxicant-induced animal death, pointing to a new potential therapeutic strategy against acute toxicities.
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PMID:Calpain: a death protein that mediates progression of liver injury. 1586 Mar 69

The first type 2 diabetes (T2D) gene to be identified in a genome wide scan followed by positional cloning was CAPN10 encoding the cysteine protease calpain-10. Subsequently, a large number of studies have investigated variation in CAPN10 in relation to T2D. Two CAPN10 single nucleotide polymorphisms (SNPs), the SNP43 (rs3792267) and the SNP44 (rs2975760), have been associated with T2D in some, but not all studies conducted in a wide range of ethnicities. We investigated the two SNPs for association with T2D in a relatively large, homogenous population of Danish whites (n = 1359 T2D cases, n = 4659 normoglycemic and glucose-tolerant control subjects), however, no significant associations of the SNP43 or the SNP44 variant with T2D were found. Neither were the two variants associated with obesity, and no association of either variant with diabetes-related quantitative traits was found in a study involving a population-based sample of 5698 middle-aged subjects. Meta-analyses, however, of the present and previously published studies involving 15,368 (SNP43) or 13,628 (SNP44) subjects yielded odds ratios of 1.09 (95% CI 1.02-1.16, p = 0.007) and 1.15 (1.07-1.23, p = 0.0002), respectively, for association with T2D. In conclusion, in a relatively large study sample of whites we found no consistent evidence of association of the CAPN10 SNP43 or SNP44 with T2D, obesity, or related quantitative traits, although meta-analyses of these two CAPN10 SNPs demonstrated an association with T2D.
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PMID:Variation in CAPN10 in relation to type 2 diabetes, obesity and quantitative metabolic traits: studies in 6018 whites. 1685 2

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


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