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Investigates the involvement of Pro[sup12] to Ala substitution in insulin secretion impairment in patient with type 2 diabetes in Japan.

Recently, variants of transcription factor 7-like 2 gene (TCF7L2) were reported to confer an increased risk of type 2 diabetes in different samples from European and European-origin populations. We studied whether the single nucleotide polymorphisms (SNPs) in TCF7L2 is associated with type 2 diabetes in the Japanese population. Five SNPs were genotyped in 3 different sample sets. Association with type 2 diabetes was investigated in each, as well as in combined sample sets. Among the 5 SNPs, the SNP rs7903146 was nominally associated with type 2 diabetes in the initial (p=0.08) and 2 replication sample sets (p= 0.05 and 0.06). For the combined sample set, in which we successfully genotyped 1174 type 2 diabetes patients and 823 control subjects, rs7903146 showed a significant association with type 2 diabetes (Odds Ratio (OR) 1.69 [95%C.I. 1.21-2.36], p=0.002). SNP rs7903146 and rs7901695 were in complete linkage disequilibrium. The rest of the 5 SNPs (rs7895340, rs11196205, rs12255372) did not show any significant associations with type 2 diabetes. We found a significant interaction between SNP rs7903146 and BMI (p=0.031). When we restricted the subjects to those with BMI lower than the median, rs7903146 showed a higher OR (2.02 [95%C.I. 1.28-3.21], p=0.0027). In conclusion, the consistent association between rs7903146 in TCF7L2 and type 2 diabetes in different ethnic groups, including the Japanese population, suggests that TCF7L2 is a common susceptibility gene for type 2 diabetes. The SNP rs7903146 may play the most important aetiological role among the previously reported variants. [ABSTRACT FROM AUTHOR]

Type 2 diabetes and the metabolic syndrome, are explosively increasing due to a pandemic of obesity. Numerous studies using animal models have suggested that hypertrophied adipocytes by obesity produce a wide variety of adipokines, which may cause and enhance insulin resistance and atherosclerosis. However, it remains unclear whether these results are recapitulated and what adipokines are causative for the metabolic syndrome in human. In the present study, we have extensively analyzed the expression profiles in adipose tissues of Japanese non-diabetic subjects with various body mass indexes. Fifty-one subjects, who were taken subcutaneous fat samples in the plastic surgery, participated in this study. The isolated RNA from the adipose tissue was applied to an expression analysis using a microarray chip (Affymetrix Human Genome U 133 Plus 2). Together with the clinical data, expression analysis revealed that there are 75 genes whose expression was increased more than 2 fold in overweight (OW) group (BMI≧22) compared to normal weight (NW) group (BMI<22), while 100 genes were decreased in expression more than 2 fold in OW compared to NW. These contain many genes, which seem to encode the secretory proteins including proinflammatory cytokines, Wnt family proteins and TGFβ super-family proteins. Indeed, there were strong correlations between BMI and expression levels of some adipokines, such as leptin, IL-8, IL-18 and MCP-1, whereas an inverse correlation was observed between BMI and adiponectin expression. On the other hand, very interestingly, most of the genes for mitochondrial function, such as electron transport, were decreased in expression in insulin resistant (IR) group (HOMA-IR≧ 1.5) compared to insulin sensitive (IS) group (HOMA-IR< 1.5), although the reduction of each gene expression (IR vs. IS) was too small (20-30%) to reach statistical significance. Since the subjects in the current study are not diabetic or morbidly obese, it is very likely that the moderate mitochondrial dysfunction assumed by the results of microarray data in this study may play a causative role in insulin resistance. Thus, it is important to explore what genetically and environmentally makes this change. Furthermore, some of the adipokines, whose expression was altered at the very early stage of obesity in this study, may also contribute to the development of the metabolic syndrome. [ABSTRACT FROM AUTHOR]

In pancreatic β-cells, pharmacological concentrations of catecholamines, including adrenaline, have been used to inhibit insulin release and explore the multiple mechanisms involved. However, the significance of these signaling pathways for physiological adrenergic functions in β-cells is largely unknown. In the process of glucose-induced insulin secretion, opening of background current through nonselective cation channels (NSCCs) might facilitate membrane depolarization by closure of the ATP-sensitive K + channels. Here, we examined whether physiological insulinostatic adrenaline action is mediated via the transient receptor potential melastatin 2 (TRPM2) channel, a type of NSCC, in β-cells. Results showed that physiological concentrations of adrenaline strongly suppressed glucose-induced and incretin-potentiated cAMP production and insulin secretion and inhibited NSCCs current and membrane excitability via the α2A-adrenoceptor in wild-type mice; however, insulin secretion was not attenuated in TRPM2-knockout (KO) mice. Administration of yohimbine, an α2-adrenoceptor antagonist, failed to affect glucose tolerance in TRPM2-KO mice, in contrast to an improved glucose tolerance in wild-type mice receiving the antagonist. The current study demonstrated that a physiological concentration of adrenaline attenuates insulin release via coupling of α2A-adrenoceptor to cAMP/TRPM2 signaling, thereby providing a potential therapeutic tool to treat patients with type 2 diabetes., (© 2017 by the American Diabetes Association.)

Fasting plasma glucose (FPG) has been recognized as an important indicator for the overall glycemic state preceding the onset of metabolic diseases. So far, most indentified genome-wide association loci for FPG were derived from populations with European ancestry, with a few exceptions. To extend a thorough catalog for FPG loci, we conducted meta-analyses of 13 genome-wide association studies in up to 24,740 nondiabetic subjects with East Asian ancestry. Follow-up replication analyses in up to an additional 21,345 participants identified three new FPG loci reaching genome-wide significance in or near PDK1-RAPGEF4, KANK1, and IGF1R. Our results could provide additional insight into the genetic variation implicated in fasting glucose regulation., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

We performed a genome-wide association study (GWAS) and a multistage meta-analysis of type 2 diabetes (T2D) in Punjabi Sikhs from India. Our discovery GWAS in 1,616 individuals (842 case subjects) was followed by in silico replication of the top 513 independent single nucleotide polymorphisms (SNPs) (P < 10⁻³) in Punjabi Sikhs (n = 2,819; 801 case subjects). We further replicated 66 SNPs (P < 10⁻⁴) through genotyping in a Punjabi Sikh sample (n = 2,894; 1,711 case subjects). On combined meta-analysis in Sikh populations (n = 7,329; 3,354 case subjects), we identified a novel locus in association with T2D at 13q12 represented by a directly genotyped intronic SNP (rs9552911, P = 1.82 × 10⁻⁸) in the SGCG gene. Next, we undertook in silico replication (stage 2b) of the top 513 signals (P < 10⁻³) in 29,157 non-Sikh South Asians (10,971 case subjects) and de novo genotyping of up to 31 top signals (P < 10⁻⁴) in 10,817 South Asians (5,157 case subjects) (stage 3b). In combined South Asian meta-analysis, we observed six suggestive associations (P < 10⁻⁵ to < 10⁻⁷), including SNPs at HMG1L1/CTCFL, PLXNA4, SCAP, and chr5p11. Further evaluation of 31 top SNPs in 33,707 East Asians (16,746 case subjects) (stage 3c) and 47,117 Europeans (8,130 case subjects) (stage 3d), and joint meta-analysis of 128,127 individuals (44,358 case subjects) from 27 multiethnic studies, did not reveal any additional loci nor was there any evidence of replication for the new variant. Our findings provide new evidence on the presence of a population-specific signal in relation to T2D, which may provide additional insights into T2D pathogenesis.

Because impaired insulin secretion is characteristic of type 2 diabetes in Asians, including Japanese, the genes involved in pancreatic beta-cell function are candidate susceptibility genes for type 2 diabetes. We examined the association of variants in genes encoding several transcription factors (TCF1, TCF2, HNF4A, ISL1, IPF1, NEUROG3, PAX6, NKX2-2, NKX6-1, and NEUROD1) and genes encoding the ATP-sensitive K(+) channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) with type 2 diabetes in a Japanese cohort of 2,834 subjects. The exon 16 -3c/t variant rs1799854 in ABCC8 showed a significant association (P = 0.0073), and variants in several genes showed nominally significant associations (P < 0.05) with type 2 diabetes. Although the E23K variant rs5219 in KCNJ11 showed no association with diabetes in Japanese (for the K allele, odds ratio [OR] 1.08 [95% CI 0.97-1.21], P = 0.15), 95% CI around the OR overlaps in meta-analysis of European populations, suggesting that our results are not inconsistent with the previous studies. This is the largest association study so far conducted on these genes in Japanese and provides valuable information for comparison with other ethnic groups.