Showing papers by "Kazuo Hara published in 2006"

Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome

Abstract: Adiponectin is an adipokine that is specifically and abundantly expressed in adipose tissue and directly sensitizes the body to insulin. Hypoadiponectinemia, caused by interactions of genetic factors such as SNPs in the Adiponectin gene and environmental factors causing obesity, appears to play an important causal role in insulin resistance, type 2 diabetes, and the metabolic syndrome, which are linked to obesity. The adiponectin receptors, AdipoR1 and AdipoR2, which mediate the antidiabetic metabolic actions of adiponectin, have been cloned and are downregulated in obesity-linked insulin resistance. Upregulation of adiponectin is a partial cause of the insulin-sensitizing and antidiabetic actions of thiazolidinediones. Therefore, adiponectin and adiponectin receptors represent potential versatile therapeutic targets to combat obesity-linked diseases characterized by insulin resistance. This Review describes the pathophysiology of adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome.

Measurement of the High–Molecular Weight Form of Adiponectin in Plasma Is Useful for the Prediction of Insulin Resistance and Metabolic Syndrome

Abstract: OBJECTIVE —The high–molecular weight (HMW) form of adiponectin, an adipocyte-derived insulin-sensitizing hormone, has been reported to be the most active form of this hormone. We investigated whether measurement of plasma HMW adiponectin levels, using our newly developed enzyme-linked immunosorbent assay system for selective measurement of human HMW adiponectin level, may be useful for the prediction of insulin resistance and metabolic syndrome. RESEARCH DESIGN AND METHODS —A total of 298 patients admitted for diabetes treatment or coronary angiography served as study subjects. Receiver operator characteristic (ROC) curves for the HMW ratio (HMWR; ratio of plasma level of HMW adiponectin to that of total adiponectin) and plasma total adiponectin levels were plotted to predict the presence of insulin resistance and metabolic syndrome. RESULTS —The area under the ROC curve (AUC) of the HMWR values to predict the presence of insulin resistance was significantly larger than that of plasma total adiponectin level in total subjects (0.713 [95% CI 0.620–0.805] vs. 0.615 [0.522–0.708], P = 0.0160). The AUC for the HMWR values to predict the presence of metabolic syndrome was significantly larger than that for plasma total adiponectin levels in men (0.806 [0.747–0.865] vs. 0.730 [0.660–0.800], P = 0.0025) and in women (0.743 [0.659–0.828] vs. 0.637 [0.532–0.742], P = 0.0458). CONCLUSIONS —The HMWR value has better predictive power for the prediction of insulin resistance and metabolic syndrome than plasma total adiponectin level.

A Proposal for the Cutoff Point of Waist Circumference for the Diagnosis of Metabolic Syndrome in the Japanese Population

Abstract: Over the past 2 decades, there has been a dramatic increase in the number of subjects with the metabolic syndrome in Japan as well as in Western countries. Because subjects with the metabolic syndrome have an elevated risk of development of type 2 diabetes and cardiovascular diseases (1–3), there is an urgent need to establish strategies to prevent an epidemic of this syndrome. In particular, a practical and sensitive screening system must be established to detect the metabolic syndrome. At present, there are two internationally recognized definitions of the metabolic syndrome, namely those of the World Health Organization (4) and the National Cholesterol Education Program’s Adult Treatment Panel III (NCEP III) (5). In an attempt to establish a unified definition for the metabolic syndrome, the International Diabetes Federation (IDF) has very recently announced a new definition of the metabolic syndrome that is expected to be suitable for use in clinical practice worldwide (6). The IDF defines metabolic syndrome as the presence of central obesity plus any two of the following four factors (raised triglyceride level, reduced HDL cholesterol, raised blood pressure, and raised fasting plasma glucose). The IDF recommended that the cutoff level used for the waist circumference to define central obesity should be different among different ethnic groups (7). In fact, the new IDF definition has proposed ethnicity-specific cutoff values for waist circumference, namely, 94 and 80 cm for European men and women, respectively, and 85 and 90 …

Association Studies of Variants in the Genes Involved in Pancreatic β-Cell Function in Type 2 Diabetes in Japanese Subjects

Abstract: Because impaired insulin secretion is characteristic of type 2 diabetes in Asians, including Japanese, the genes involved in pancreatic β-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.

A Polymorphism in the AMPKα2 Subunit Gene Is Associated With Insulin Resistance and Type 2 Diabetes in the Japanese Population

Abstract: AMP-activated protein kinase (AMPK) acts as a fuel gauge for glucose and lipid metabolism. The gene encoding the α2 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.

Hepatocyte Nuclear Factor-4α P2 Promoter Haplotypes Are Associated With Type 2 Diabetes in the Japanese Population

Abstract: Hepatocyte nuclear factor (HNF)-4alpha is a transcription factor known as a key molecule in the development and functions of the beta-cells. In a previously performed genome-wide scan of Japanese type 2 diabetic sibpairs, we observed linkage of type 2 diabetes to chromosome 20q12-q13, a region in which the HNF4A gene is located. Recent studies have reported associations between type 2 diabetes and polymorphisms in the P2 promoter region specific to beta-cells. In this study, we attempted to assess whether the HNF4A gene plays a role in the genetic susceptibility to type 2 diabetes in the Japanese population by analyzing polymorphisms and haplotypes of the HNF4A gene. Linkage disequilibrium across the P2 promoter region was preserved in the Japanese population, consistent with previous reports. Although none of the individual polymorphisms examined showed any significant association with type 2 diabetes, we found very strong evidence of the association between type 2 diabetes and the haplotype consisting of two polymorphisms in the P2 promoter region of the HNF4A gene (P = 3.82 x 10(-4)). In contrast, there was no association between type 2 diabetes and haplotypes consisting of polymorphisms not located in the P2 promoter region, suggesting that the type 2 diabetes susceptibility loci are localized in the P2 promoter region of the HNF4A gene. The association was replicated using two additional cohorts (P = 1.51 x 10(-4) and 0.019, respectively). The results of the present analysis revealed that the HNF4A gene might be a type 2 diabetes susceptibility gene common to different ethnic groups. The study also suggested the possible existence of an as-yet-unidentified but functional polymorphism in the P2 promoter region of the HNF4A gene that directly influences susceptibility to type 2 diabetes.