ABSTRACT
We carried out a multistage genome-wide association study of type 2 diabetes mellitus in Japanese individuals, with a total of 1,612 cases and 1,424 controls and 100,000 SNPs. The most significant association was obtained with SNPs in KCNQ1, and dense mapping within the gene revealed that rs2237892 in intron 15 showed the lowest Pvalue (6.7 x 10(-13), odds ratio (OR) = 1.49). The association of KCNQ1 with type 2 diabetes was replicated in populations of Korean, Chinese and European ancestry as well as in two independent Japanese populations, and meta-analysis with a total of 19,930 individuals (9,569 cases and 10,361 controls) yielded a P value of 1.7 x 10(-42) (OR = 1.40; 95% CI = 1.34-1.47) for rs2237892. Among control subjects, the risk allele of this polymorphism was associated with impairment of insulin secretion according to the homeostasis model assessment of beta-cell function or the corrected insulin response. Our data thus implicate KCNQ1 as a diabetes susceptibility gene in groups of different ancestries.
Subject(s)
Diabetes Mellitus, Type 2/genetics , KCNQ1 Potassium Channel/genetics , Polymorphism, Single Nucleotide , Asian People/genetics , Chromosome Mapping , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Insulin-Secreting Cells/physiology , White PeopleABSTRACT
Chemerin, a recently discovered adipocytokine plays an important role in obesity and obesity-associated metabolic complications. However, the role of chemerin in the pathogenesis of type 2 diabetes mellitus (T2DM) has not fully been elucidated. We compared the serum chemerin levels and metabolic parameters between 88 control subjects, 86 patients with metabolic syndrome (MS), and 147 patients with T2DM in a Japanese population and further analyzed their correlation. Enzyme-linked immunosorbent assay was used to measure the serum chemerin levels. The chemerin levels were significantly higher in male than in female control subjects (p < 0.005), with significant decreases in patients with T2DM compared with those with MS and control subjects (164.9 ± 6.3 ng/mL vs. 209.8 ± 7.7 and 218.7 ± 7.3 ng/mL; p < 0.0001 vs. p < 0.0001, respectively) but no significant differences in female subjects. The multiple regression analysis revealed that the chemerin levels negatively correlated with the fasting glucose and HbA1c levels in total and male subjects. In the patients with T2DM, the chemerin levels negatively correlated with fasting glucose and high-density lipoprotein cholesterol but positively correlated with body mass index (BMI), and total cholesterol and triglyceride levels. The negative correlation between the chemerin and fasting glucose levels remained significant after adjustment for age, sex, and BMI in the total and male subjects and those with T2DM. These results suggest the role of chemerin in sex dimorphism and a potential link between chemerin levels and T2DM pathogenesis in a Japanese population.
Subject(s)
Chemokines/blood , Diabetes Mellitus, Type 2/blood , Sex Characteristics , Adult , Aged , Asian People , Blood Glucose , Body Mass Index , Female , Glycated Hemoglobin , Humans , Insulin Resistance , Intercellular Signaling Peptides and Proteins , Japan , Male , Middle AgedABSTRACT
Near-infrared (NIR) light control of living cellular activities is a highly desired technique for living cell manipulation because of its advantage of high penetrability towards living tissue. In this study, (π-extended porphyrin)-fullerene linked molecules are designed and synthesized to achieve NIR light control of the membrane potential. A donor-(π-extended porphyrin)-acceptor linked molecule exhibited the formation of the charge-separated state with a relatively long lifetime (0.68 µs) and a moderate quantum yield (27-31%). The hydrophilic trimethylammonium-linked triad molecule successfully altered PC12 cells' membrane potential via photoinduced intramolecular charge separation.
ABSTRACT
Prediction of the disease status is one of the most important objectives of genetic studies. To select the genes with strong evidence of the association with type 2 diabetes mellitus, we validated the associations of the seven candidate loci extracted in our earlier study by genotyping the samples in two independent sample panels. However, except for KCNQ1, the association of none of the remaining seven loci was replicated. We then selected 11 genes, KCNQ1, TCF7L2, CDKAL1, CDKN2A/B, IGF2BP2, SLC30A8, HHEX, GCKR, HNF1B, KCNJ11 and PPARG, whose associations with diabetes have already been reported and replicated either in the literature or in this study in the Japanese population. As no evidence of the gene-gene interaction for any pair of the 11 loci was shown, we constructed a prediction model for the disease using the logistic regression analysis by incorporating the number of the risk alleles for the 11 genes, as well as age, sex and body mass index as independent variables. Cumulative risk assessment showed that the addition of one risk allele resulted in an average increase in the odds for the disease of 1.29 (95% CI=1.25-1.33, P=5.4 x 10(-53)). The area under the receiver operating characteristic curve, an estimate of the power of the prediction model, was 0.72, thereby indicating that our prediction model for type 2 diabetes may not be so useful but has some value. Incorporation of data from additional risk loci is most likely to increase the predictive power.
Subject(s)
Asian People/genetics , Diabetes Mellitus, Type 2/genetics , Genetic Predisposition to Disease , Models, Genetic , Alleles , Genetic Testing , Genome-Wide Association Study , Humans , Japan , Odds Ratio , ROC Curve , Reproducibility of Results , Risk AssessmentABSTRACT
BACKGROUND: In Europeans and populations of European origin, several groups have recently identified novel type 2 diabetes susceptibility genes, including FTO, SLC30A8, HHEX, CDKAL1, CDKN2B, and IGF2BP2, none of which were in the list of functional candidates. OBJECTIVE AND DESIGN: The aim of this study was to replicate in a Japanese population previously identified associations of single nucleotide polymorphisms (SNPs) within 10 candidate loci with type 2 diabetes using a relatively large sample size: 1921 subjects with type 2 diabetes and 1622 normal controls. RESULTS: A total of 15 SNPs were genotyped. Eight SNPs in five loci were found to be associated with type 2 diabetes: rs3802177 [odds ratio (OR) = 1.16 (95% confidence interval (CI) 1.05-1.27); P = 4.5 x 10(-3)] in SLC30A8; rs1111875 [OR = 1.27 (95% CI 1.14-1.40); P = 1.4 x 10(-5)] and rs7923837 [OR = 1.27 (95% CI 1.13-1.43); P = 1.0 x 10(-4)] in HHEX; rs10811661 [OR = 1.27 (95% CI 1.15-1.40); P = 1.9 x 10(-6)] in CDKN2B; rs4402960 [OR = 1.23 (95% CI 1.11-1.36); P = 8.1 x 10(-5)] and rs1470579 [OR = 1.18 (95% CI 1.07-1.31); P = 8.3 x 10(-4)] in IGF2BP2; and rs7754840 [OR = 1.28 (95% CI 1.17-1.41); P = 4.5 x 10(-7)] and rs7756992 [OR = 1.27 (95% CI 1.15-1.40); P = 9.8 x 10(-7)] in CDKAL1. The first and second strongest associations were found at variants in CDKAL1 and CDKN2B, both of which are involved in the regenerative capacity of pancreatic beta-cells. CONCLUSION: Some of these variants represent common type 2 diabetes-susceptibility genes in both Japanese and Europeans.
Subject(s)
Diabetes Mellitus, Type 2/genetics , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Body Mass Index , Cyclin-Dependent Kinase 5/genetics , Cyclin-Dependent Kinase Inhibitor p15/genetics , Genotype , Humans , Insulin Resistance , Insulin-Like Growth Factor Binding Protein 2/genetics , Japan , tRNA MethyltransferasesABSTRACT
AIMS: A missense mutation in the low density lipoprotein receptor-related protein 6 gene (LRP6) was recently shown to be responsible for a disorder characterized by early-onset coronary artery disease as well as diabetes mellitus (DM), hyperlipidemia, hypertension, and osteoporosis. Mice deficient in LRP5, a closely related paralog of LRP6, manifest a marked impairment in glucose tolerance. The aim of the present study was to examine whether common variants of LRP5 and LRP6 are associated with Type 2 DM or dyslipidemia in Japanese individuals. METHODS: Thirteen single nucleotide polymorphisms (SNPs) of LRP6 and nine SNPs of LRP5 were genotyped in a total of 608 Type 2 DM patients and 366 nondiabetic control subjects (initial study). An association analysis was then performed for each SNP and for haplotypes. For some of the SNPs, we provided another sample panel of 576 cases and 576 controls for the replication study. The relation to clinical characteristics was also examined in diabetic subjects. RESULTS: In the initial study, three SNPs of LRP6 were found to be associated with susceptibility to Type 2 DM. However, this association was not detected in the replication panel. None of SNPs in LRP5 were associated with Type 2 DM in the initial panel. Neither LRP6 nor LRP5 was associated with body mass index, HOMA-beta, HOMA-IR or serum lipid concentrations. CONCLUSIONS: We found no evidence for a substantial effect of LRP5 or LRP6 SNPs on susceptibility to type 2 diabetes or clinical characteristics of diabetic subjects in Japanese population.
Subject(s)
Asian People/genetics , Diabetes Mellitus, Type 2/genetics , LDL-Receptor Related Proteins/genetics , Polymorphism, Single Nucleotide , Aged , Aged, 80 and over , Humans , Japan/epidemiology , Low Density Lipoprotein Receptor-Related Protein-5 , Low Density Lipoprotein Receptor-Related Protein-6 , Middle AgedABSTRACT
AMP-activated protein kinase (AMPK) acts as a fuel gauge for glucose and lipid metabolism. The gene encoding the alpha2 isoform of the catalytic subunit of AMPK (PRKAA2) is located at one of the Japanese type 2 diabetes loci mapped by our previous genome scan (1p36-32). PRKAA2 is, therefore, a good candidate gene for insulin resistance and type 2 diabetes. We screened all nine exons, their exon-intron boundaries, and the 5' and 3' flanking regions of PRKAA2 to identify single nucleotide polymorphisms (SNPs), and we genotyped 192 type 2 diabetic patients and 272 nondiabetic subjects to assess possible associations between genotypes or haplotypes and type 2 diabetes. None of the 10 SNPs genotyped was associated with type 2 diabetes, but the haplotype analysis, consisting of six representative SNPs, revealed one haplotype, with the A (minor) allele for rs2051040 and a major allele for the other five SNPs, to be associated with type 2 diabetes (P = 0.009). This finding was confirmed in two larger replication samples (657 case and 360 control subjects, P = 0.021; and 356 case and 192 control subjects from the same area in Japan, P = 0.007) and a significant P value was obtained in the joint haplotype analysis of all samples (1,205 case and 824 control subjects, P = 0.0001). Furthermore, insulin resistance was associated with rs2051040 in nondiabetic subjects, and those with the A (minor) allele had a higher homeostasis model assessment of insulin resistance index than those who did not (initial control subjects [n = 272], P = 0.002; and joint replication control subjects [n = 552], P = 0.037). We speculate that the PRKAA2 gene influences insulin resistance and susceptibility to type 2 diabetes in the Japanese population.
Subject(s)
Chromosomes, Human, Pair 1 , Diabetes Mellitus, Type 2/genetics , Insulin Resistance/genetics , Multienzyme Complexes/genetics , Polymorphism, Single Nucleotide , Protein Serine-Threonine Kinases/genetics , 3' Untranslated Regions , AMP-Activated Protein Kinases , Asian People/genetics , Chromosome Mapping , Genetic Predisposition to Disease , Glucose/metabolism , Homeostasis , Humans , Introns , Japan , Promoter Regions, Genetic , Protein Subunits/genetics , Reference ValuesABSTRACT
The physiological relevance of phosphoinositide 3-kinase (PI 3-K) signaling in the liver to fuel homeostasis was investigated. Systemic infusion of an adenovirus encoding a dominant negative mutant of PI 3-K ((Delta)p85) resulted in liver-specific expression of this protein and in inhibition of the insulin-induced activation of PI 3-K in the liver within 3 days, without affecting insulin signaling in skeletal muscle. Hepatic expression of (Delta)p85 led to hyperinsulinemia and to a marked increase in blood glucose concentration in response to oral glucose intake. The increases in both glycogen and glucose 6-phosphate content, as well as in Akt and glycogen synthase activities in the liver, that were induced by glucose intake were markedly impaired in mice expressing (Delta)p85. Despite an upregulation of mRNAs for gluconeogenic enzymes apparent in the liver of these animals, the fasting blood glucose concentration was increased only slightly, and the serum concentrations of gluconeogenic precursors were reduced. However, administration of pyruvate, a substrate for gluconeogenesis, resulted in an exaggerated increase in blood glucose concentration. In the fasted state, the mass of adipose tissue of the mice was about 1.5 times that in control mice. The mice also exhibited marked decreases in the serum concentrations of FFAs and triglyceride and suppression of insulin-induced PI 3-K activation in adipose tissue, probably due to the associated hyperinsulinemia. PI 3-K activity in the liver is thus essential for normal carbohydrate and lipid metabolism in living animals.
Subject(s)
Glucose Intolerance/etiology , Hyperinsulinism/etiology , Hyperlipidemias/etiology , Phosphoinositide-3 Kinase Inhibitors , Adenoviridae/genetics , Adipose Tissue/drug effects , Adipose Tissue/metabolism , Animals , Gene Transfer Techniques , Glucose/metabolism , Glucose Intolerance/metabolism , Hyperinsulinism/metabolism , Hyperlipidemias/metabolism , Insulin/pharmacology , Lac Operon , Lipid Metabolism , Liver/drug effects , Liver/metabolism , Male , Mice , Mice, Inbred BALB C , Mice, Transgenic , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Mutation , Phosphatidylinositol 3-Kinases/genetics , Signal TransductionABSTRACT
PKClambda is implicated as a downstream effector of PI3K in insulin action. We show here that mice that lack PKClambda specifically in the liver (L-lambdaKO mice), produced with the use of the Cre-loxP system, exhibit increased insulin sensitivity as well as a decreased triglyceride content and reduced expression of the sterol regulatory element-binding protein-1c (SREBP-1c) gene in the liver. Induction of the hepatic expression of Srebp1c and of its target genes involved in fatty acid/triglyceride synthesis by fasting and refeeding or by hepatic expression of an active form of PI3K was inhibited in L-lambdaKO mice compared with that in control animals. Expression of Srebp1c induced by insulin or by active PI3K in primary cultured rat hepatocytes was inhibited by a dominant-negative form of PKClambda and was mimicked by overexpression of WT PKClambda. Restoration of PKClambda expression in the liver of L-lambdaKO mice with the use of adenovirus-mediated gene transfer corrected the metabolic abnormalities of these animals. Hepatic PKClambda is thus a determinant of hepatic lipid content and whole-body insulin sensitivity.
Subject(s)
CCAAT-Enhancer-Binding Proteins/metabolism , DNA-Binding Proteins/metabolism , Insulin/metabolism , Lipid Metabolism , Liver/physiology , Protein Kinase C/metabolism , Animals , Blood Glucose/metabolism , CCAAT-Enhancer-Binding Proteins/genetics , Cells, Cultured , DNA-Binding Proteins/genetics , Gene Expression Regulation , Hepatocytes/cytology , Hepatocytes/metabolism , Humans , Isoenzymes , Liver/chemistry , Male , Mice , Mice, Knockout , Phenotype , Protein Kinase C/genetics , Rats , Sterol Regulatory Element Binding Protein 1 , Tissue Distribution , Transcription Factors/metabolismABSTRACT
MOTIVATION: Preliminary results on the data produced using the Affymetrix large-scale genotyping platforms show that it is necessary to construct improved genotype calling algorithms. There is evidence that some of the existing algorithms lead to an increased error rate in heterozygous genotypes, and a disproportionately large rate of heterozygotes with missing genotypes. Non-random errors and missing data can lead to an increase in the number of false discoveries in genetic association studies. Therefore, the factors that need to be evaluated in assessing the performance of an algorithm are the missing data (call) and error rates, but also the heterozygous proportions in missing data and errors. RESULTS: We introduce a novel genotype calling algorithm (GEL) for the Affymetrix GeneChip arrays. The algorithm uses likelihood calculations that are based on distributions inferred from the observed data. A key ingredient in accurate genotype calling is weighting the information that comes from each probe quartet according to the quality/reliability of the data in the quartet, and prior information on the performance of the quartet. AVAILABILITY: The GEL software is implemented in R and is available by request from the corresponding author at nicolae@galton.uchicago.edu.
Subject(s)
Computational Biology/methods , Genotype , Algorithms , Likelihood Functions , Oligonucleotide Array Sequence Analysis , Programming Languages , Reproducibility of Results , SoftwareABSTRACT
Accumulation of fat in the liver is associated with insulin resistance and type 2 diabetes mellitus. The carnitine palmitoyltransferase (CPT) enzyme system facilitates the transport of long-chain fatty acids into mitochondria, and the gene for the hepatic isoform of CPT1 (CPT1A) is a candidate gene for metabolic disorders such as insulin resistance associated with fatty liver. We have now investigated the contribution of the CPT1A locus to hepatic lipid content (HLC), insulin resistance, and susceptibility to type 2 diabetes mellitus. A total of 324 type 2 diabetic patients and 300 nondiabetic individuals were enrolled in the study. Eighty-seven of the type 2 diabetic patients who had not been treated with insulin or lipid-lowering drugs were evaluated by homeostasis model assessment for insulin resistance and were subjected to nuclear magnetic resonance for determination of HLC. A total of 19 single nucleotide polymorphisms (SNPs) were identified at the CPT1A locus, and linkage disequilibrium analysis revealed a strong linkage disequilibrium block between SNP8 (intron 5) and SNP17 (intron 14). Neither haplotypes nor SNPs of CPT1A were found to be associated either with susceptibility to type 2 diabetes mellitus or with HLC or insulin resistance in type 2 diabetic patients.
Subject(s)
Carnitine O-Palmitoyltransferase/genetics , Diabetes Mellitus, Type 2/enzymology , Fatty Liver/enzymology , Insulin Resistance/genetics , Aged , Carnitine O-Palmitoyltransferase/metabolism , DNA/chemistry , DNA/genetics , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/genetics , Fatty Liver/blood , Fatty Liver/genetics , Female , Haplotypes , Humans , Japan , Linkage Disequilibrium , Lipid Metabolism/genetics , Liver/metabolism , Male , Middle Aged , Polymerase Chain Reaction , Polymorphism, Single Nucleotide , Triglycerides/bloodABSTRACT
A series of porphyrin-fullerene linked molecules has been synthesized to evaluate the effects of substituents and molecular structures on their charge-separation yield and the lifetime of a final charge-separated state in various hydrophilic environments. The selected high-performance molecule effectively achieved depolarization in a plasma cell membrane by visible light as well as two-photon excitation using a near-infrared light laser. Moreover, it was revealed that the depolarization can trigger neuronal firing in rat hippocampal neurons, demonstrating the potential and versatility for controlling cell functions using light.
ABSTRACT
The mechanism by which insulin induces the expression of the sterol regulatory element binding protein 1c (SREBP-1c) and glucokinase genes was investigated in cultured rat hepatocytes. Overexpression of an NH(2)-terminal fragment of IRS-1 that contains the pleckstrin homology and phosphotyrosine binding domains (insulin receptor substrate-1 NH(2)-terminal fragment [IRS-1N]) inhibited insulin-induced tyrosine phosphorylation of IRS-1 as well as the association of IRS-1 with phosphatidylinositol (PI) 3-kinase activity, whereas the tyrosine phosphorylation of IRS-2 and its association with PI 3-kinase activity were slightly enhanced. The equivalent fragment of IRS-2 (IRS-2N) prevented insulin-induced tyrosine phosphorylation of both IRS-1 and IRS-2, although that of IRS-1 was inhibited more efficiently. The insulin-induced increases in the abundance of SREBP-1c and glucokinase mRNAs, both of which were sensitive to a dominant-negative mutant of PI 3-kinase, were blocked in cells in which the insulin-induced tyrosine phosphorylation of IRS-1 was inhibited by IRS-1N or IRS-2N. A dominant-negative mutant of Akt enhanced insulin-induced tyrosine phosphorylation of IRS-1 (but not that of IRS-2) and its association with PI 3-kinase activity, suggesting that Akt contributes to negative feedback regulation of IRS-1. The Akt mutant also promoted the effects of insulin on the accumulation of SREBP-1c and glucokinase mRNAs. These results suggest that the IRS-1-PI 3-kinase pathway is essential for insulin-induced expression of SREBP-1c and glucokinase genes.
Subject(s)
CCAAT-Enhancer-Binding Proteins/genetics , DNA-Binding Proteins/genetics , Gene Expression/drug effects , Glucokinase/genetics , Hepatocytes/metabolism , Insulin/pharmacology , Phosphatidylinositol 3-Kinases/metabolism , Phosphoproteins/metabolism , Protein Serine-Threonine Kinases , Signal Transduction , Transcription Factors , Animals , Feedback , Insulin Receptor Substrate Proteins , Intracellular Signaling Peptides and Proteins , Male , Mutation , Peptide Fragments/pharmacology , Phosphatidylinositol 3-Kinases/genetics , Phosphoproteins/pharmacology , Phosphorylation , Phosphotyrosine/metabolism , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Proto-Oncogene Proteins c-akt , Rats , Rats, Wistar , Sterol Regulatory Element Binding Protein 1ABSTRACT
Adiponectin is an adipose tissue-specific protein and plays an important role in insulin sensitivity. On the other hand, intramyocellular lipid content and hepatic lipid content (HLC) are related to insulin resistance in humans. In the present study, the possible relations between the serum concentration of adiponectin and intracellular triglyceride content in skeletal muscle and in the liver were investigated in individuals with type 2 diabetes mellitus. Fifty Japanese sedentary subjects (34 men, 16 women) with type 2 diabetes who had neither been treated with insulin nor with thiazolidinediones were enrolled in the study. Insulin sensitivity in vivo was evaluated by measurement of the glucose infusion rate during a hyperinsulinemic-euglycemic clamp and of the homeostasis model of assessment-insulin resistance index. The intracellular triglyceride content in skeletal muscle and the liver was determined by nuclear magnetic resonance. The serum adiponectin concentration was inversely correlated with both HLC ( r = -0.39, P < .01) and the homeostasis model of assessment-insulin resistance index ( r = -0.32, P < .05), but it was not significantly related to either intramyocellular lipid content or glucose infusion rate during the hyperinsulinemic-euglycemic clamp in individuals with type 2 diabetes. These results suggest that adiponectin might play an important role in the regulation of HLC and basal insulin sensitivity in individuals with type 2 diabetes.
Subject(s)
Diabetes Mellitus, Type 2/metabolism , Insulin Resistance , Intercellular Signaling Peptides and Proteins/blood , Liver/chemistry , Triglycerides/analysis , Adiponectin , Adult , Aged , Body Mass Index , Female , Humans , Male , Middle Aged , Muscle, Skeletal/chemistryABSTRACT
We describe two sisters with type A insulin resistance. In contrast to common situation for this genetic disorder, the sisters harbored compound heterozygous mutations in the insulin receptor gene associated with mild glucose intolerance. The cases highlight the diversity of clinical phenotypes associated with mutations of the insulin receptor gene.
Subject(s)
Glucose Intolerance/genetics , Insulin Resistance/genetics , Mutation , Receptor, Insulin/genetics , Adolescent , Amino Acid Substitution , Aspartic Acid/genetics , Female , Genetic Carrier Screening , Genetic Variation , Glycine/genetics , Heterozygote , Humans , Phenotype , Phosphotyrosine/metabolism , SiblingsABSTRACT
OBJECTIVE: The E23K variant in the Kir6.2 subunit of the ATP-sensitive K(+) channel (K(ATP) channel) is associated with increased risk of type 2 diabetes. The present study was undertaken to increase our understanding of the mechanisms responsible. To avoid confounding effects of hyperglycemia, insulin secretion and action were studied in subjects with the variant who had normal glucose tolerance. RESEARCH DESIGN AND METHODS: Nine subjects with the E23K genotype K/K and nine matched subjects with the E/E genotype underwent 5-h oral glucose tolerance tests (OGTTs), graded glucose infusion, and hyperinsulinemic-euglycemic clamp with stable-isotope-labeled tracer infusions to assess insulin secretion, action, and clearance. A total of 461 volunteers consecutively genotyped for the E23K variant also underwent OGTTs. Functional studies of the wild-type and E23K variant potassium channels were conducted. RESULTS: Insulin secretory responses to oral and intravenous glucose were reduced by approximately 40% in glucose-tolerant subjects homozygous for E23K. Normal glucose tolerance with reduced insulin secretion suggests a change in insulin sensitivity. The hyperinsulinemic-euglycemic clamp revealed that hepatic insulin sensitivity is approximately 40% greater in subjects with the E23K variant, and these subjects demonstrate increased insulin sensitivity after oral glucose. The reconstituted E23K channels confirm reduced sensitivity to inhibitory ATP and increase in open probability, a direct molecular explanation for reduced insulin secretion. CONCLUSIONS: The E23K variant leads to overactivity of the K(ATP) channel, resulting in reduced insulin secretion. Initially, insulin sensitivity is enhanced, thereby maintaining normal glucose tolerance. Presumably, over time, as insulin secretion falls further or insulin resistance develops, glucose levels rise resulting in type 2 diabetes.
Subject(s)
Insulin/metabolism , KATP Channels/physiology , Potassium Channels, Inwardly Rectifying/genetics , ATP-Binding Cassette Transporters/genetics , Adult , Amino Acid Substitution , Cross-Sectional Studies , Female , Genetic Variation , Genotype , Glucose Clamp Technique , Glucose Tolerance Test , Humans , Insulin Secretion , Male , Middle Aged , Receptors, Drug/genetics , Reference Values , Sulfonylurea ReceptorsABSTRACT
Mutations of WFS1 gene cause Wolfram syndrome, which is a rare autosomal recessive disorder characterized by juvenile diabetes mellitus, optic atrophy, deafness and diabetes insipidus. The product encoded by WFS1 gene, wolframin, could be involved in ER stress response causing beta-cell loss through impaired cell cycle progression and increased apoptosis. Recently, polymorphisms in the WFS1 gene were strongly associated with type 2 diabetes in Caucasians. The aim of the present study was to examine whether the variants of WFS1 are associated with risk of type 2 diabetes in Japanese individuals. Four single nucleotide polymorphisms, rs6446482, rs12511742, rs1801208 (R456H) and rs734312 (H611R) were genotyped in a total of 536 diabetic patients and 398 nondiabetic control subjects. Among the four variants, rs12511742 showed a marginal association with susceptibility to type 2 diabetes (odds ratio = 1.32, 95% confidence interval = 1.02-1.71, P = 0.033). Carriers of the risk allele at rs12511742 exhibited lower pancreas beta-cell function (P = 0.017). However, this association disappeared after adjustment for sex, age and BMI (Adjusted P = 0.24). Although we found no evidence for a substantial effect of WFS1 polymorphisms on risk of type 2 diabetes or clinical characteristics of diabetic subjects in Japanese population, this gene is still a good candidate for a type 2 diabetes susceptibility gene, potentially, through impaired insulin secretion.
Subject(s)
Asian People/genetics , Diabetes Mellitus, Type 2/epidemiology , Diabetes Mellitus, Type 2/genetics , Genetic Predisposition to Disease/genetics , Membrane Proteins/genetics , Polymorphism, Single Nucleotide/genetics , Genome, Human/genetics , Humans , Japan/epidemiology , Middle AgedABSTRACT
Monocyte chemoattractant protein-1 (MCP-1, also known as CCL2) secreted by adipocytes is a member of the CC chemokine family and plays a pivotal role in the inflammatory process. A polymorphism, the -2518 A/G of MCP-1 gene, has been associated with type 2 diabetes, type 1 diabetes, parameters of insulin resistance and obesity. Therefore, we investigated the effects of MCP-1 single nucleotide polymorphisms (SNPs) on the susceptibility to type 2 diabetes or insulin resistance in the Japanese population. We also assessed the correlation between serum MCP-1 concentration and other clinical characteristics in Japanese type 2 diabetic subjects. The serum MCP-1 concentration was significantly correlated with HOMA-IR and the visceral fat area, but not with BMI. Although there was no association between this SNP and type 2 diabetes, the -2518A/G polymorphism was associated with the serum MCP-1 concentration. In subgroup analysis, Japanese obese diabetic -2518AA carriers had a higher MCP-1 concentration and increased insulin resistance than obese diabetic -2518G carriers. These data indicated that the MCP-1 polymorphism was associated with insulin resistance in Japanese obese diabetic subjects and that MCP-1 was implicated in the pathogenesis of insulin resistance, especially associated with obesity, in humans.
Subject(s)
Asian People/genetics , Chemokine CCL2/blood , Chemokine CCL2/genetics , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/genetics , Insulin Resistance/genetics , Polymorphism, Single Nucleotide/genetics , Aged , Female , Genotype , Humans , Male , Middle Aged , Obesity/blood , Obesity/geneticsABSTRACT
Transcription factor 7-like 2 (TCF7L2) has been shown to be associated with type 2 diabetes mellitus in multiple ethnic groups. Regarding the Asian population, Horikoshi et al. (Diabetologia 50:747-751, 2007) and Hayashi et al. (Diabetologia 50:980-984, 2007) reported that single nucleotide polymorphisms (SNPs) in TCF7L2 were associated with type 2 diabetes in the Japanese population, while contradictory results were reported for Han Chinese populations. The aim of this study was to investigate the associations of the TCF7L2 gene with type 2 diabetes using a relatively large sample size: 2,214 Japanese individuals with type 2 diabetes and 1,873 normal controls. The minor alleles of rs7903146, rs11196205, and rs12255372 showed significant associations with type 2 diabetes (OR=1.48, P=2.7 x 10(-4); OR=1.39, P=4.6 x 10(-4); OR=1.70, P=9.8 x 10(-5), respectively) in the combined sample sets. However, neither rs11196218 nor rs290487 showed a significant association. These results indicate that TCF7L2 is an important susceptibility gene for type 2 diabetes in the Japanese population.