Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Insulin resistance may be a mechanism linking non-insulin-dependent diabetes mellitus (NIDDM) to hypertension and cardiovascular mortality. Microalbuminuria also is an independent risk factor of cardiovascular mortality and of hypertension. Little information is available in the literature on the relationship between microalbuminuria and insulin action. This study investigated the relationships between blood pressure (BP) levels, microalbuminuria, and insulin resistance in NIDDM patients. Seventy-five NIDDM patients attending the outpatient clinic of the Department of Internal Medicine of the University Hospital in Padua, Italy participated in the cross-sectional part of our study. These subjects were divided into four groups on the basis of BP levels and albumin excretion rate (AER): 28 normotensive normoalbuminuric (NIDDM1), 19 hypertensive normoalbuminuric (NIDDM2), 15 normotensive microalbuminuric (NIDDM3), and 13 hypertensive microalbuminuric patients (NIDDM4). We defined microalbuminuria as an AER > 20 micrograms/min. Patients with BP levels > 145/90 mmHg were considered hypertensive. A group of 20 normal subjects served as control subjects. The results from the cross-sectional study indicate that the mean of insulin-induced whole-body glucose utilization, primarily an index of extrahepatic insulin action, was lower at all insulin infusion steps in the group of hypertensive and/or microalbuminuric patients than in the group of normotensive normoalbuminuric patients and control subjects. Hepatic glucose output, an index of insulin action in the liver, was on average less efficiently inhibited in all of the patients than in the control subjects, regardless of the BP levels or the AER.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1994 Mar
PMID:Impaired insulin-induced glucose uptake by extrahepatic tissue is hallmark of NIDDM patients who have or will develop hypertension and microalbuminuria. 831 23

Non-insulin-dependent (type 2) diabetes mellitus (NIDDM) is a common disorder of middle-aged individuals characterized by high blood glucose levels which, if untreated, can cause serious medical complications and lead to early death. Genetic factors play an important role in determining susceptibility to this disorder. However, the number of genes involved, their chromosomal location and the magnitude of their effect on NIDDM susceptibility are unknown. We have screened the human genome for susceptibility genes for NIDDM using non-and quasi-parametric linkage analysis methods in a group of Mexican American affected sib pairs. One marker, D2S125, showed significant evidence of linkage to NIDDM and appears to be a major factor affecting the development of diabetes mellitus in Mexican Americans. We propose that this locus be designated NIDDM1.
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PMID:A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. 932 32

In the first reported positive result from a genome scan for non-insulin-dependent diabetes mellitus (NIDDM), Hanis et al. found significant evidence of linkage for NIDDM on chromosome 2q37 and named the putative disease locus NIDDM1 (Hanis et al. 1996. Nat. Genet. 13:161-166). Their total sample was comprised of 440 Mexican-American affected sib-pairs from 246 sibships. The strongest evidence for linkage was at marker D2S125 and best estimates of lambdas (risk to siblings of probands/population prevalence) using this marker were 1.37 under an additive model and 1.36 under a multiplicative model. We examined this chromosomal region using linkage analysis in a Finnish sample comprised of 709 affected sib-pairs from 472 sibships. We excluded this region in our sample (multipoint logarithm of odds score </= -2) for lambdas >/= 1.37. We discuss possible reasons why linkage to 2q37 was not found and conclude that this region is unlikely to be playing a major role in NIDDM susceptibility in the Finnish Caucasian population.
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PMID:A large sample of finnish diabetic sib-pairs reveals no evidence for a non-insulin-dependent diabetes mellitus susceptibility locus at 2qter. 971 Apr 38

Complex disorders such as diabetes, cardiovascular disease, asthma, hypertension and psychiatric illnesses account for a large and disproportionate share of health care costs, but remain poorly characterized with respect to aetiology. The transmission of such disorders is complex, reflecting the actions and interactions of multiple genetic and environmental factors. Genetic analyses that allow for the simultaneous consideration of susceptibility from multiple regions may improve the ability to map genes for complex disorders, but such analyses are currently computationally intensive and narrowly focused. We describe here an approach to assessing the evidence for statistical interactions between unlinked regions that allows multipoint allele-sharing analysis to take the evidence for linkage at one region into account in assessing the evidence for linkage over the rest of the genome. Using this method, we show that the interaction of genes on chromosomes 2 (NIDDM1) and 15 (near CYP19) makes a contribution to susceptibility to type 2 diabetes in Mexican Americans from Starr County, Texas.
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PMID:Loci on chromosomes 2 (NIDDM1) and 15 interact to increase susceptibility to diabetes in Mexican Americans. 998 76

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

Diabetes mellitus is a group of metabolic disorders characterized by hyperglycemia resulting from defects in insulin secretion, insulin action or both. Genetic factors contribute to the development of diabetes. Some forms such as the condition called maturity-onset diabetes of the young(MODY) result from mutations in a single gene. Other forms such as type 1 or type 2 diabetes are multifactorial in origin with different combinations of genes together with non-genetic factors contributing to the development of hyperglycemia. MODY has been a good model for studying the genetics and pathophysiology of diabetes. This form of diabetes can result from mutations in at least seven different genes: hepatocyte nuclear factor(HNF)-4 alpha/MODY1, glucokinase/MODY2, HNF-1 alpha/MODY3, insulin promoter factor(IPF-1)/MODY4, HNF-1 beta/MODY5, NeuroD1/MODY6 and Islet(Isl)-1/MODY7. Mutations in HNF-1 alpha/MODY3 are the most common cause of MODY in Japanese identified to date accounting for about 15% of cases of MODY. Mutations in the HNF-4 alpha/MODY1, glucokinase/MODY2, HNF-1 beta/MODY5 and Isl-1/MODY7 genes have also been found in Japanese; however, they are rare causes of MODY. Clinical studies indicate that patients with MODY are generally not obese and that all forms of MODY are characterized by pancreatic beta-cell dysfunction. Patients who have mutations in the HNF-1 beta/MODY5 gene have non-diabetic kidney dysfunction including renal cysts. Female carriers may also exhibit abnormalities in the upper vagina and uterus. Genetic approach for type 2 diabetes had done by using non-parameteric linkage analysis such as sibpair analysis which worked well and NIDDM1 and NIDDM2 have been identified to date. The responsible gene for NIDDM1 was recently identified to be Calpain 10, and SNP43 in this gene could explain all of the evidence for linkage in Mexican American type 2 diabetes.
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PMID:[Diabetes mellitus]. 1130 9

Macrovascular disease is a major complication of type 2 diabetes. Epidemiological data suggest that the risk of macrovascular complications may predate the onset of hyperglycemia. Hypertriglyceridemia, low levels of HDL cholesterol, and an atherogenic profile characterize the insulin resistance/metabolic syndrome that is also prevalent among nondiabetic members of familial type 2 diabetic kindreds. To identify the genes for lipid-related traits, we first performed a 10-cM genome scan using 440 markers in 379 members of 19 multiplex families ascertained for two diabetic siblings (screening study). We then extended findings for three regions with initial logarithm of odds (LOD) scores >1.5 to an additional 23 families, for a total of 576 genotyped individuals (extended study). We found heritabilities for all lipid measures in the range of 0.31 to 0.52, similar to those reported by others in unselected families. However, we found the strongest evidence for linkage of triglyceride levels to chromosome 19q13.2, very close to the ApoC2/ApoE/ApoC1/ApoC4 gene cluster (LOD 2.56) in the screening study; the LOD increased to 3.16 in the extended study. Triglyceride-to-HDL cholesterol ratios showed slightly lower LOD scores (2.73, extended family) in this same location. Other regions with LOD scores >2.0 included HDL linkage to chromosome 1q21-q23, where susceptibility loci for both familial type 2 diabetes and familial combined hyperlipidemia have been mapped, and to chromosome 2q in the region of the NIDDM1 locus. Neither region showed stronger evidence for linkage in the extended studies, however. Our results suggest that genes in or near the ApoE/ApoC2/ApoC1/ApoC4 cluster on 19q13.2 may contribute to the commonly observed hypertriglyceridemia and low HDL seen in diabetic family members and their offspring, and thus may be a candidate locus for the insulin resistance syndrome.
Diabetes 2002 Feb
PMID:Quantitative trait linkage analysis of lipid-related traits in familial type 2 diabetes: evidence for linkage of triglyceride levels to chromosome 19q. 1181 65

The calpain-10 gene (CAPN10) has been implicated in type 2 diabetes (T2DM) susceptibility by both linkage and association in a Hispanic population from Starr County Texas. Common intronic variants seem to alter CAPN10 mRNA levels and were associated with insulin resistance but not diabetes in Pima Indians. The role of these variants in Caucasian populations is less clear. We found some evidence for linkage of T2DM to chromosome 2q approximately 20 cM proximal to the NIDDM1/CAPN10 locus. To test the hypothesis that CAPN10 is a diabetes susceptibility locus in Caucasian families at high risk for T2DM, we examined the influence of the three previously implicated CAPN10 variants on both diabetes risk and measures of insulin sensitivity and glucose homeostasis. We genotyped approximately 700 members of 63 families for 3 variants (SNP-43, SNP-19, and SNP-63). We tested each variant separately and as haplotype combinations for altered transmission from parents to affected children (transmission disequilibrium test), and we tested for an effect of each variant individually on measures of glucose and insulin during a glucose tolerance test in nondiabetic family members. Finally, we looked for an effect of each variant on measures of insulin sensitivity (S(I)) and insulin secretion estimated by frequently sampled iv glucose tolerance test and Minimal Model analysis. We could not confirm an increase in risk for T2DM susceptibility for any variant or for any haplotype combination, although we found marginal evidence for an increased risk of the 111/221 haplotype combination (P = 0.036) after ascertainment correction. However, both SNP-19 and SNP-63 increased fasting and/or postchallenge insulin levels, consistent with reduced insulin sensitivity. Furthermore, SNP-19 had modest effects on insulin sensitivity measured by homeostatic model, and on postchallenge glucose. The reduction in insulin sensitivity was confirmed by analysis of the subset of individuals who underwent iv glucose tolerance tests, where SNP-19 significantly altered the insulin sensitivity index. CAPN10 cannot be considered a major diabetes susceptibility gene in our population and seems unlikely to explain the observed linkage findings. However, CAPN10 influences insulin sensitivity and glucose homeostasis in nondiabetic members of kindreds at high risk for T2DM.
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PMID:Role of calpain-10 gene variants in familial type 2 diabetes in Caucasians. 1183 99

The follow-up studies to the original report of association of variation at calpain 10 (CAPN10) with type 2 diabetes in the Mexican-American population of Starr County, Texas, encompass a broad range of science. There are association studies on genetic variation at CAPN10 in different human populations over a range of phenotypes related to type 2 diabetes, physiological studies on the biological functions of calpain proteases, and evolutionary studies on CAPN10 and the NIDDM1 region. We review here the studies published to date on CAPN10, as well as the latest findings from positional cloning studies on a number of other complex disorders. Collectively, these studies provide perspective on the challenges of moving from the linkage mapping and positional cloning studies on which we have been focused to an understanding of the biology shaping the relationship of genotype to phenotype at loci influencing susceptibility to complex disorders like type 2 diabetes.
Diabetes 2004 Feb
PMID:Linkage of calpain 10 to type 2 diabetes: the biological rationale. 1474 61

A positional cloning study of type 2 diabetes in Mexican Americans identified a region, termed "NIDDM1," on chromosome 2q37 with significant linkage evidence. Haplotype combinations at the calpain-10 gene (CAPN10) within this region were shown to increase diabetes risk in several populations. On the basis of the thrifty genotype hypothesis, variants that increase susceptibility to type 2 diabetes under modern lifestyle conditions provided a survival advantage in past environments by increasing the efficiency of energy use and storage. Here, our goal is to make inferences about the evolutionary forces shaping variation in genes in the NIDDM1 region and to investigate the population genetics models that may underlie the thrifty genotype hypothesis. To this end, we surveyed sequence variation in CAPN10 and in an adjacent gene, G-protein-coupled receptor 35 (GPR35), in four population samples from different ethnic groups. These data revealed two distinct deviations from the standard neutral model in CAPN10, whereas GPR35 variation was largely consistent with neutrality. CAPN10 showed a significant deficit of variation in the haplotype class defined by the derived allele at SNP44, a polymorphism that is significantly associated with diabetes in meta-analysis studies. This suggests that this haplotype class was quickly driven to high frequency by positive natural selection. Interestingly, the derived allele at SNP44 is protective against diabetes. CAPN10 also showed a local excess of polymorphism and linkage disequilibrium decay in intron 13. Simulations show that this pattern may be explained by long-standing balancing selection that maintains multiple selected alleles. Alternatively, it is possible that the local mutation and recombination rates changed since the divergence of human and chimpanzee; this scenario does not require the action of natural selection on intron 13 variation.
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PMID:Population genetics of CAPN10 and GPR35: implications for the evolution of type 2 diabetes variants. 1569 18


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