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OBJECTIVE Despite its anti-inflammatory and antiatherogenic effects, adiponectin is potentially associated with adverse clinical outcomes, such as all-cause mortality. As plasma adiponectin levels are strongly influenced by single nucleotide polymorphisms [...]

Variants in the CDH13 gene have been identified as determinants of blood levels of adiponectin, an insulin-sensitizing adipokine. However, their association with other metabolic risk factors remains unclear. We examined variants at CDH13 in relation to total and high-molecular-weight (HMW) adiponectin using data from a genome-wide association study performed in 2,434 Singaporean Chinese with replication in up to 3,290 Japanese and 1,610 Koreans. The top signal rs4783244 in CDH13 showed strong associations with total adiponectin (standardized β [β] = -0.34, 95% CI -0.38 to -0.30, P = 2.0 x [10.sup.-70]), HMW adiponectin (β = HMW-to-total adiponectin ratio (β = -0.44, 95% CI -0.49 to -0.40, P = 3.2 x [10.sup.-83]). In the replication study, this single nucleotide polymorphism explained 4.1% of total and 6.5% of HMW adiponectin levels. No association was observed between rs4783244 and metabolic traits associated with insulin resistance before adjustment for HMW adiponectin levels. After adjustment for HMW adiponectin levels, the minor allele was associated with lower BMI (β = -0.15, 95% CI -0.19 to -0.11, P = 3.5 x [10.sup.-14]), homeostasis model assessment-insulin resistance index (β = -0.16, 95% CI -0.20 to -0.12, P = 9.2 x [10.sup.-16]), and triglycerides (β = -0.16, 95% CI -0.19 to -0.12, P = 1.3 x [10.sup.-16]) and with higher HDL (β = 0.16, 95% CI 0.12 to 0.19, P = 2.1 x [10.sup.-17]). CDH13 variants strongly influence plasma total and HMW adiponectin levels in East Asian populations but appear to alter adiponectin sensitivity, resulting in better metabolic health than expected based on circulating adiponectin levels., Adiponectin is a protein abundantly secreted by adipose tissue with anti-inflammatory (1) and insulin-sensitizing properties (2). Blood levels of diponectin are inversely associated with obesity (3), insulin resistance (4), and [...]

Resistin is an adipokine secreted from adipocytes in mice. We previously reported that a single nucleotide polymorphism (SNP) -420 (rs1862513) in the human resistin gene (RETN), is correlated with plasma resistin. Decorin is a multifunctional proteoglycan, and its isoform, lacking 14 amino acids from the N terminal region of mature core decorin, recently was identified as a resistin receptor in mice. To examine whether SNPs in the vicinity of the human decorin gene (DCN) are associated with plasma resistin, we cross-sectionally analyzed six tag SNPs selected around DCN in the same linkage disequilibrium block in 2,078 community-dwelling Japanese subjects. Plasma resistin was associated with the rs7139228, rs7956537, rs516115, and rs3138167 genotypes in DCN. A multiple regression analysis revealed that the genotype of rs7308752 (G/G) or rs516115 (C/C) was associated with decreased plasma resistin after adjusted for age, sex, BMI, and the RETN SNP rs1862513. The effect of rs7139228 and rs1862513 seemed to be additive without synergistic interaction. Therefore, plasma resistin was associated with some tag SNPs around DCN in the general Japanese population. The possibility that human decorin is a human resistin receptor should be pursued., Insulin resistance is a feature of type 2 diabetes (T2DM). Resistin, which antagonizes insulin action, is an adipokine secreted from adipocytes in mice (1,2). The overexpression of the resistin gene [...]

OBJECTIVE--The present study was conducted to confirm possible associations between candidate genes from genomewide association studies and type 2 diabetes in Japanese diabetic patients and a community-based general population. A total of 11 previously reported single-nucleotide polymorphisms (SNPs) from the TCF7L2, CDKAL1, HHEX, IGF2BP2, CDKN2A/B, SLC30A8, and KCNJ11 genes were analyzed. RESEARCH DESIGN AND METHODS--Candidate SNPs were genotyped in 506 type 2 diabetic patients and 402 control subjects and meta-analyzed with six previous association studies in Japanese patients. Associations with fasting plasma insulin levels were investigated in a general population sample (n = 1,963, 61 ± 13 years). RESULTS--In our case-control subjects, susceptibility to type 2 diabetes was replicated in TCFTL2 (rs12255372), CDKAL1 (rs7756992, rs7754840), HHEX (rs7923837), IGF2BP2 (rs4402960 and rs1470579), CDKN2A/B (rs10811661), and SLC30A8 (rs13266634). In addition to these polymorphisms, meta-analysis confirmed the association of type 2 diabetes susceptibility with KCNJ11 rs5219, TCF7L2 rs7903146, and HHEX rs1111875. The TCF7L2 rs12255372 polymorphism showed the highest odds ratio (OR) for type 2 diabetes (OR 1.714 [1.298-2.263]). Odds ratio of other polymorphisms ranged from 1.13 to 1.41. The risk allele of CDKAL1 rs7756992 was significantly associated with lower insulin levels in type 2 diabetic patients after adjustment for other confounding factors. CONCLUSIONS--Type 2 diabetes susceptibility of seven candidate genes was confirmed in Japanese. Conservation of susceptible loci for type 2 diabetes was independent of ethnic background., A great number of studies in various populations have suggested an association between several single-nucleotide polymorphisms (SNPs) and type 2 diabetes. For example, transcription factor 7-like 2 (TCF7L2) is a [...]

OBJECTIVE--Resistin, secreted from adipocytes, causes insulin resistance in rodents. We previously reported that the G/G genotype of a resistin gene promoter single nucleotide polymorphism (SNP) at -420 increases type 2 [...]

To clarify heterogeneity in Japanese adult-onset type 1 diabetes, we analyzed the HLA-DR and -DQ haplotypes, depending on the clinical phenotype, and compared them with those in childhood-onset type 1 diabetes (CO). The patients in a previously reported Ehime Study were divided into subgroups by the mode of onset of diabetes: 68 acute-onset type 1 diabetic patients (AO) and 28 slowly progressive type 1 diabetic patients (SO). HLA haplotypes were compared with those of 80 CO patients and 190 control subjects. Two major susceptible HLA haplotypes in the Japanese, DRB1*0405-DQB1 DQB1 (DR4) and DRB1 *0901-DQB1*0303 (DR9), were significantly increased in the AO and CO groups, but only DR9 was increased in the SO group. AO subjects had a higher frequency of DR9 than CO subjects. Accordingly, the DR9:DR4 frequency increased with increasing age of onset. Another susceptible haplotype, DRB1*0802-DQB1*0302 (DR8), was involved only in the CO group. Analysis of haplotype combinations revealed that DR4 and DR9 had significant dosage effects on the AO and CO groups (P < 0.0001), but only DR9 had such an effect in the SO group (P < 0.03). These results suggest differences in the contribution of HLA class II haplotypes to susceptibility of type 1 diabetes depending on the clinical phenotype and also indicate that HLA class Il haplotypes may be associated with the onset age of type 1 diabetes., Type 1 diabetes is the result of a destruction of pancreatic β-cells and leads to complete insulin deficiency (1,2). Although type 1 diabetes is frequently considered to be a childhood [...]

FOXC2, a forkhead/winged helix transcription factor, represents a promising candidate gene for type 2 diabetes since transgenic mice that specifically overexpress this gene in adipocytes are lean and insulin sensitive. To determine whether there are single nucleotide polymorphisms (SNPs) in this gene that are associated with type 2 diabetes, sequences of the coding and ~1 kb of 5' flanking regions in 24 Japanese type 2 diabetic subjects were initially analyzed using PCR direct sequencing, and the regions containing the identified polymorphisms were then examined. In 200 control subjects, three frequent SNPs were found (g. -512C>T [32.3%] and -350G>T [13.0%] in the 5' flanking region and +1548C>T [10.0%] in the 3' flanking region). Linkage disequilibria were found between all three pairs of these SNPs. Of the eight possible haplotypes defined by these SNPs, only four were found. When the frequencies of these SNPs and the four common haplotypes between 195 type 2 diabetic and 200 control subjects were compared, no association was evident. The +898C>T (Pro300Ser), +907C>A (Leu303Met), 1167_1169delCCA (389delHis), and +1251C>A (Ala417Ala) identified in the coding region were rare, although +907C >A could be higher in type 2 diabetic subjects (1.5%) than in control subjects (0.3%). Thus, the SNPs identified in the FOXC2 gene are unlikely to have major effects on susceptibility to Japanese type 2 diabetes., Type 2 diabetes is characterized by insulin resistance in insulin target tissues and an impaired insulin secretion from pancreatic β-cells (1). The gene mutations identified thus far account for specific [...]

Phosphodiesterase (PDE)-3B, a major PDE isoform in adipocytes, plays a pivotal role in the antilipolytic action of insulin. Insulin-induced phosphorylation and activation of PDE3B is phosphatidylinositol 3-kinase (PI3-K) and Akt dependent, but the precise mechanism of PDE3B activation is not fully understood. We have identified 14-3-3 β, a critical scaffolding molecule in signal transduction, as a protein that interacts with PDE3B using the yeast two-hybrid system. The interaction between PDE3B and 14-3-3 β was then confirmed in vitro. The glutathione S-transferase (GST)-tagged 14-3-3 β interacts with endogenous PDE3B of rat adipocytes, and this interaction is enhanced when adipocytes are treated with insulin. Coimmunoprecipitation experiments reveal that endogenous PDE3B also associates with endogenous 14-3-3 β in rat adipocytes, and this interaction is enhanced by insulin. Two different P13-K inhibitors, wortmannin and Ly294002, block this induction, suggesting that PI3-K is required. Synthetic 15 amino acid peptides of rat PDE3B containing phosphorylated Ser-279 or -302 inhibit this interaction, indicating that the insulin-regulated phosphorylation of these serine residues is involved. Because insulin receptor substrate-1 also associates with 14-3-3, the dimeric 14-3-3 β could function as a scaffolding protein in the activation of PDE3B by insulin., Cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP or cGMP, the second messengers in various biological processes, and thereby regulate the concentration of these molecules in cells. There are [...]

OBJECTIVE -- To characterize the clinical, autoimmune, and genetic features in Japanese adult-onset diabetic patients with GAD autoantibodies. RESEARCH DESIGN AND METHODS -- GAD autoantibodies (GADab) were screened in 4,980 [...]

Resistin is a novel polypeptide specifically secreted from adipocytes, and its serum levels are increased in obese diabetic mice. Resistin antagonizes insulin and could account for insulin resistance. To determine [...]

Phosphodiesterase (PDE) 3B is a key enzyme in the mediation of the anti-lipolytic action of insulin in adipocytes, and activation of this molecule results in a reduced output of free [...]

Phosphodiesterase (PDE) 3B is a key enzyme in the mediation of the anti-lipolytic action of insulin in adipocytes, and activation of this molecule results in a reduced output of free [...]

Phosphodiesterase (PDE) 3B is a key enzyme in the mediation of the antilipolytic action of insulin in adipocytes, and activation of this molecule results in a reduced output of free [...]

Lysosomal acid lipase (LAL) regulates intracellular cholesterol level by hydrolyzing cholesteryl esters and triglycerides from low density lipoprotein (LDL) particles taken up through the LDL receptor. Dyslipidemia is closely related [...]

Phosphodiesterase(PDE)3B is a key enzyme for mediating anti-lipolytic action of insulin in adipocytes. Activation of PDE3B results in reduced output of free fatty acid (FFA) from adipocytes. Elevation of serum [...]