Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Variants in mitochondrial DNA (mtDNA) could be associated with type 2 diabetes because ATP plays a critical role in the production and release of insulin. Diabetes can be precipitated both by mtDNA mutations and by exposure to mitochondrial poisons. The risk of inheriting diabetes from an affected mother is greater than that from an affected father, but this is not explained by maternally inherited diabetes and/or deafness (MIDD) caused by the 3243G : C mtDNA point mutation, which accounts for less than 0.5% of cases of diabetes. A common mtDNA variant (the 16189 variant) is positively correlated with blood fasting insulin, but there are no definitive studies demonstrating that it is associated with diabetes. We demonstrated a significant association between the 16189 variant and type 2 diabetes in a population-based case-control study in Cambridgeshire, UK (n=932, odds ratio=1.61 (1.0-2.7, P=0.048), which was greatly magnified in individuals with a family history of diabetes from the father's side (odds ratio=infinity; P<0.001).
Hum Mol Genet 2002 Jun 15
PMID:Type 2 diabetes is associated with a common mitochondrial variant: evidence from a population-based case-control study. 1204 11

The aim of this study was to test if a beta-cell defect is associated to deterioration of glucose tolerance early during the natural history of the type 2 diabetes mellitus. In 41 overweight women, with macrosomic infants in their antecedent deliveries, measures of insulin response and insulin sensitivity were derived from a short (45 min) iv glucose test. The early (EIR) and the late (LIR) phase insulin responses and the insulin sensitivity index (Si) were calculated. According the response to 75 g oral glucose test the subjects were divided into two groups: Impaired glucose tolerance (IGT; n = 12), and normal glucose tolerance (NGT; n = 29). EIR was reduced in IGT group (14.9 +/- 3.6 vs 37.0 +/- 4.0; p < 0.002). Glucose tolerance during oral glucose tolerance test (OGTT), correlated inversely to EIR (r = -0.45; n = 41; p < 0.01). A strong correlation of EIR to LIR (r = 0.88; n = 41; p < 0.001) but no correlation between glucose tolerance and Si was found.
J Cell Mol Med
PMID:Beta-cell dysfunctions and insulin resistance in subjects with increased risk for type 2 diabetes mellitus. 1206 62

Lipid peroxides were identified among the factors that contribute to the atherosclerotic plaque formation in the arterial wall. We hypothesised that a correlation may exist between the content of antioxidant constituents in the serum and the gravity of atherosclerosis. To this purpose, we have determined the serum total peroxyl radical- trapping potential (TRAP), which is the combined capacity of all antioxidants to neutralize free radicals in serum and followed its variation in hyperlipemic animals in correlation with the stage of atherosclerosis. In addition, we compared TRAP values in the sera of coronary heart disease (CHD) patients, with or without type II diabetes mellitus. Results showed that after 18 weeks of hyperlipemic diet, the mean TRAP values measured in sera isolated from hyperlipemic hamsters exhibited an about 44% decrease, in good agreement with the increase of serum cholesterol and triglycerides. In the 3 groups of CHD patients, TRAP values decreased with about 10% in sera of stable angina patients, 20% in unstable patients, as compared with normal subjects. The lowest TRAP values were detected in the sera of patients with acute myocardial infarction. The results obtained for different experimental animals and for CHD patients sera indicate that the TRAP method, as adapted in our laboratory, is a reliable and reproducible assay, fit to be used in clinical studies as an ex vivo measurable parameter that correlates with the stage of the atherosclerosis.
J Cell Mol Med
PMID:The total peroxyl radical trapping potential in serum - an assay to define the stage of atherosclerosis. 1206 87

The genetic causes of type 2 diabetes are not well understood. The disease has been linked to chromosome 20q12-q13.1 a region which harbors the transcription factor HNF4alpha. Mutations in the coding region of HNF4alpha cause maturity onset diabetes of the young, an autosomal dominant form of diabetes, but do not account for the linkage to this region. An enhancer element has recently been characterized 6 kb 5' of the HNF4alpha P1 promoter containing binding sites for the transcription factors HNF1, HNF4, HNF3, and C/EBP, which are overlapped by glucocorticoid consensus sites. We hypothesized that variation in the enhancer element disrupts HNF4alpha expression in the liver and increases susceptibility to type 2 diabetes. We screened for variants of the enhancer element in 39 white UK young onset diabetic subjects, giving >95% power to identify variants with minor allele frequencies of >5%. No variants of the enhancer element were found in this population. We conclude that variation in the HNF4alpha enhancer element is not a common cause of susceptibility to type 2 diabetes.
Mol Genet Metab 2002 Jun
PMID:The role of the HNF4alpha enhancer in type 2 diabetes. 1208 13

Mutations in the HNF4alpha gene have been correlated with maturity-onset diabetes of the young, which is characterized mainly by pancreatic beta-cell dysfunction and is also associated with mild liver abnormalities. HNF4alpha D126Y and D126H mutations were found in a patient with early-onset type 2 diabetes, and the R324H mutation was found in a common type 2 diabetic nephropathic patient. We investigated whether these mutations, which have not yet been functionally characterized, impair HNF4alpha function in three cell models: HEK 293 embryonal kidney cells, HepG2 hepatoma cells, and betaTC3 pancreatic beta-cells. The R324H mutation had no effect on HNF4alpha function with either the HNF1alpha and L-type pyruvate kinase (LPK) promoters, but the D126Y and D126H mutations impaired HNF4alpha transcriptional activities in all tested cell lines. These impairments by D126Y and D126H mutations, which are located in the T box, are not due to a loss of dimerization but to a loss of DNA binding. Interestingly, the strongest functional consequences of these mutations were observed on the HNF1alpha promoter in betaTC3 cells. Given the key role of the transcription factor HNF1alpha in pancreatic beta-cell function, it can be inferred that impairment of HNF4alpha function by these mutations affects metabolic pathways in pancreatic beta-cells and contributes to development of diabetes. Moreover, the HNF4alpha-mediated activation of the apolipoprotein CIII promoter in HepG2 cells was significantly impaired by D126Y and D126H mutations. These results support clinical findings that liver function can also be impaired in diabetic patients having HNF4alpha mutations.
J Mol Med (Berl) 2002 Jul
PMID:Mutations in hepatocyte nuclear factor 4alpha (HNF4alpha) gene associated with diabetes result in greater loss of HNF4alpha function in pancreatic beta-cells than in nonpancreatic beta-cells and in reduced activation of the apolipoprotein CIII promoter in hepatic cells. 1211 Sep 48

Obesity-linked type 2 diabetes is a disease of insulin resistance combined with pancreatic beta-cell dysfunction. Although a role for beta-cell mass in the pathogenesis of obesity-linked type 2 diabetes has recently gained prominence, the idea is still being developed. It is proposed that in early obesity an increase in beta-cell mass and function might compensate for peripheral insulin resistance. However, as time and/or the severity of the obesity continue, there is decay in such adaptation and the beta-cell mass becomes inadequate. This, together with beta-cell dysfunction, leads to the onset of type 2 diabetes. It is becoming evident that elements in insulin and insulin growth factor (IGF)-1 signal-transduction pathways are key to regulating beta-cell growth. Current evidence indicates that interference of insulin signaling in obesity contributes to peripheral insulin resistance. This article examines whether a similar interference of IGF-1 signaling in the beta-cell could hinder upregulation of beta-cell mass and/or function, resulting in a failure to compensate for insulin resistance.
Trends Mol Med 2002 Aug
PMID:Pancreatic beta-cell growth and survival--a role in obesity-linked type 2 diabetes? 1212 23

Both type 2 diabetes (T2DM) and familial combined hyperlipidemia have been mapped to human chromosome 1q21-q24. This region includes the retinoid X receptor gamma (RXRgamma), which is a strong candidate for both glucose and lipid metabolism. Retinoid X receptors form heterodimers with a variety of nuclear receptors, including peroxisome-proliferator-activated receptors alpha and gamma (PPARalpha and PPARgamma), and are synergistic targets for drugs that alter glucose and lipid metabolism. We hypothesized that RXRgamma variation could explain the linkage of diabetes and lipid disorders to this region. We screened each of the 10 exons, the flanking intronic sequences, the 3' untranslated region, and the 5' flanking region. We identified 14 variants, none of which altered the coding sequence. Of the 10 variants examined in a diabetes case-control study, three showed nominal (p < 0.05) associations with T2DM. We subsequently typed four variants in all members of the 63 multiplex families used in our previous linkage analysis. No individual variant showed excess transmission to offspring with T2DM using a transmission disequilibrium test and only a single rare haplotype showed evidence of an association with T2DM. Likewise, neither individual variants nor haplotypes were associated with either fasting or post-challenge glucose in non-diabetic subjects. In contrast, three of the four variants were associated with fasting free fatty acid (FFA) levels (p = 0.024-0.00044) and two variants were associated with triglyceride levels (p < 0.05). These findings were supported by the association of several haplotypes with FFA and triglyceride levels. RXRgamma haplotypes were also associated with several measures of pancreatic beta-cell function, consistent with the proposed role of lipid metabolism in insulin secretion. These data suggest that RXRgamma may contribute to disordered lipid metabolism in members of familial T2DM kindreds, but this gene is unlikely to explain the linkage of T2DM with this region.
Mol Genet Metab 2002 May
PMID:Mutation screening and association of human retinoid X receptor gamma variation with lipid levels in familial type 2 diabetes. 1465 62

The insulin sensitizer drug, rosiglitazone, has been shown to have a protective effect on pancreatic islet cell structure and function in animal models of type 2 diabetes. The identification of new molecular targets associated both with islet cell dysfunction and protection is a crucial research goal. In the present study, a proteomics approach has been used to identify such targets. Obese C57Bl/6J lep/lep mice and lean littermates were given the insulin sensitizer drug BRL49653, rosiglitazone. It normalized the impaired glucose tolerance in lep/lep mice but had no significant effect on glucose tolerance in the lean mice. Pancreatic islet polypeptides were arrayed by a two-dimensional gel electrophoresis system that separated more than 2500 individual spots. Three overexpressed and six underexpressed proteins were significant (p < 0.05) between lep/lep and lean mice, and four were modulated significantly (p < 0.05) by the rosiglitazone treatment of the obese mice. The identity of these differentially expressed proteins was made using mass spectrometric analysis and provided evidence that differential expression of actin-binding proteins may be an important aspect of defective islet function. Rosiglitazone increased carboxypeptidase B expression in both lep/lep and normal mice suggesting that this might be an independent effect of rosiglitazone that contributes to improved insulin processing.
Mol Cell Proteomics 2002 Jul
PMID:Effect of rosiglitazone on the differential expression of diabetes-associated proteins in pancreatic islets of C57Bl/6 lep/lep mice. 1223 79

Type 2 diabetes mellitus results from a complex interaction between nutritional excess and multiple genes. Whereas pancreatic beta-cells normally respond to glucose challenge by rapid insulin release (first phase insulin secretion), there is a loss of this acute response in virtually all of the type 2 diabetes patients with significant fasting hyperglycemia. Our previous studies demonstrated that irreversible intracellular accumulation of a glucose metabolite, protein O-linked N-acetylglucosamine modification (O-GlcNAc), is associated with pancreatic beta-cell apoptosis. In the present study, we show that streptozotocin (STZ), a non-competitive chemical blocker of O-GlcNAcase, induces an insulin secretory defect in isolated rat islet cells. In contrast, transgenic mice with down-regulated glucose to glucosamine metabolism in beta-cells exhibited an enhanced insulin secretion capacity. Interestingly, the STZ blockade of O-GlcNAcase activity is also associated with a growth hormone secretory defect and impairment of intracellular secretory vesicle trafficking. These results provide evidence for the roles of O-GlcNAc in the insulin secretion and possible involvement of O-GlcNAc in general glucose-regulated hormone secretion pathways.
Mol Cell Endocrinol 2002 Aug 30
PMID:Streptozotocin, an O-GlcNAcase inhibitor, blunts insulin and growth hormone secretion. 1224 36

Adiponectin (ACRP30), an adipocyte-secreted protein encoded by the APM1 gene, is known to modulate insulin sensitivity and glucose homeostasis, those effects protecting obese mice from diabetes. Plasma adiponectin levels correlate well with insulin sensitivity in humans, and are decreased in both type 2 diabetes (T2D) and obesity. We screened for single-nucleotide polymorphisms (SNPs) the APM1 gene coding and 5' sequences in 40 French Caucasians: 12 SNPs and 4 rare non-synonymous mutations of exon 3 were detected. The 10 most frequent SNPs were genotyped in 1373 T2D and obese French Caucasian subjects and in all subjects available from 148 T2D multiplex families. The screening for rare mutations of exon 3 was extended to 1246 T2D and obese French subjects and to the members of the 148 T2D multiplex families. A haplotype including SNPs -11391 and -11377, both located in the 5' sequences, was associated with adiponectin levels (P<0.0001) and with T2D (P=0.004). The presence of at least one non-synonymous mutation in exon 3 showed evidence of association with adiponectin levels (P=0.0009) and with T2D (P=0.005). We failed to detect an association with insulin resistance indexes. Although family-based association analysis with T2D did not reach significance, our results suggest that an at-risk haplotype of common variants located in the promoter and rare mutations in exon 3 contribute to the variation of the adipocyte-secreted adiponectin hormone level, and may be part of the genetic determinants for T2D in the French Caucasian population.
Hum Mol Genet 2002 Oct 01
PMID:Single-nucleotide polymorphism haplotypes in the both proximal promoter and exon 3 of the APM1 gene modulate adipocyte-secreted adiponectin hormone levels and contribute to the genetic risk for type 2 diabetes in French Caucasians. 1235 86


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