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Objective The Ala allele of the Pro12Ala polymorphism (rs1801282) of peroxisome proliferator-activated receptor γ (PPARγ) is protective against type 2 diabetes (T2DM). Resistin, secreted from adipocytes, causes insulin resistance in rodents. Resistin gene expression is reduced by the PPARγ ligand. We previously reported that subjects with the G/G genotype of a resistin gene single nucleotide polymorphism (SNP) at –420 (rs1862513) had the highest circulating resistin levels, followed by C/G and C/C. The aim of this study was to determine the relationship among PPARγ Pro12Ala polymorphism, resistin SNP-420, and plasma resistin. Design, patients and measurements We cross-sectionally analysed 2077 community-dwelling subjects attending an annual medical check-up. Genotypes were determined by TaqMan analysis. Fasting plasma resistin was measured using ELISA. Results Plasma resistin appeared to be higher in subjects with the Pro/Pro genotype of PPARγ than those with Pro/Ala and Ala/Ala genotypes (mean ± SE, 11·6 ± 0·2 vs. 10·4 ± 0·5 μg/l). Multiple regression analysis, adjusted for age, gender, BMI, and resistin SNP-420, revealed that the Pro/Pro genotype was a positive predictor of plasma resistin (PPARγ ,  Pro/Pro vs. Pro/Ala + Ala/Ala, unstandardized regression coefficient (β) = 1·03, P = 0·0384). The effects of the Pro/Pro genotype of PPARγ (Pro/Pro vs. Pro/Ala + Ala/Ala) and the G/G genotype of resistin SNP-420 (G/G vs. C/C) on plasma resistin were synergistic (β = 4·76, P = 0·011). Conclusions The PPARγ Pro12Ala Pro/Pro and resistin SNP-420 G/G genotypes were synergistically associated with plasma resistin, when adjusted for age, gender, and BMI, in the Japanese general population. [ABSTRACT FROM AUTHOR]

OBJECTIVE--The present study was conducted to confirm possible associations between candidate genes from genome-wide 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 TCF7L2 (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. Diabetes 58:493-498, 2009 [ABSTRACT FROM AUTHOR]

Objective The c-Jun N-terminal kinase 1 (JNK1, mitogen-activated kinase 8; MAPK8) phosphorylates insulin receptor substrate-1 (IRS-1) at serine 307, which induces insulin resistance. MAPK8 activity is increased in obese insulin-resistant mice, whereas mapk8 (–/–) mice show decreased adiposity and improved insulin sensitivity. The aim of this study was to determine the relationship between single nucleotide polymorphisms (SNPs) of MAPK8 and type 2 diabetes (T2DM). Design, patients and measurements Approximately 2 kb of 5′ flanking and the coding regions were initially sequenced in 24 Japanese T2DM subjects. Identified SNPs were genotyped in 204 T2DM cases and 201 nondiabetic controls. The function of promoter SNP–1066 (g.–1066G > A, rs10857561) was analysed by electrophoretic mobility shift assay (EMSA) and luciferase assay. SNP–1066 was further genotyped in a total of 498 cases and 407 controls, and in 2075 subjects in the general population. Results In 204 cases and 201 controls, 11 identified SNPs were not associated with T2DM. These SNPs were in the same linkage disequilibrium (LD) block. The tag SNP–1066 was not associated with T2DM in a total of 498 cases and 407 controls with the power > 80% when the relative risk is > 1·31. Functionally, transcription factor AP2α specifically recognized G but not A at –1066. MAPK8 promoter activity was unchanged between G and A. In 2075 subjects, neither body mass index (BMI), fasting plasma glucose (FPG), homeostasis model assessment insulin resistance index (HOMA-IR), nor β cell function index (HOMA-β) was associated with SNP–1066. Conclusions The G/G genotype of MAPK8 SNP–1066 did not affect T2DM susceptibility despite specific binding of AP2α. [ABSTRACT FROM AUTHOR]

Objective Resistin, secreted from adipocytes, causes insulin resistance in rodents. We reported that the G/G genotype of a resistin gene promoter single nucleotide polymorphism (SNP) at −420 increases type 2 diabetes (T2DM) susceptibility by enhancing promoter activity. We also showed that serum resistin was positively correlated with G at SNP-420, the duration of T2DM, and HbA1c in T2DM. The aim of this study was to determine the relation between serum resistin and factors related to the metabolic syndrome (MetS) in T2DM. Design, patients and measurements We analysed 238 Japanese T2DM subjects (124 males and 114 females, age 60·2 ± 11·3 years, body mass index (BMI) 24·1 ± 3·9) whose overnight fasting sera were available. Serum resistin was measured using ELISA. Results Serum resistin was higher in subjects with either obesity ( P = 0·041), low HDL ( P = 0·004), high triglycerides (TG) ( P = 0·019), hypertension (HT) ( P = 0·001) or atherosclerosis ( P = 0·012). Simple regression analysis revealed that serum resistin was correlated with lower HDL, TG and high-sensitivity C-reactive protein (hsCRP). Multiple regression analysis (or logistic regression analysis for HT), adjusted for age, gender, BMI and the duration of T2DM, revealed that serum resistin was correlated with lower HDL ( P = 0·008), TG ( P = 0·041), HT ( P = 0·031) and hsCRP ( P = 0·004). Serum resistin was positively correlated with the number of MetS factors, independent of age, gender and the duration of T2DM ( P < 0·001). Adjustment by either thiazolidinedione (TZD) treatment or hsCRP had no effects on these findings. Conclusions Serum resistin was positively correlated with the accumulation of MetS factors in T2DM. [ABSTRACT FROM AUTHOR]

Objective Adiponectin is secreted specifically from adipocytes, and improves insulin sensitivity. Of its isoforms, the high molecular weight (HMW) complex is thought to be the most active. The aim of this study was to determine the relationship between serum total or HMW adiponectin and diabetic microangiopathy. Design, patients and measurements We analysed 198 Japanese patients with type 2 diabetes mellitus (T2DM) whose fasting serum samples were available. Serum total adiponectin and HMW adiponectin were measured using an enzyme-linked immunosorbent assay (ELISA). Results Serum total adiponectin was found to have increased in the advanced stages of diabetic retinopathy (mean ± SE, none, 6·9 ± 0·3; simple, 8·3 ± 1·0; preproliferative, 8·4 ± 0·8; proliferative, 12 ± 1·1 mg/l;anova P = 0·0004) and nephropathy (stage I, 7·0 ± 0·3; II, 7·7 ± 0·5; III, 9·5 ± 0·9; IV, 16 ± 4·5 mg/l, P < 0·0001). Similarly, serum HMW adiponectin had increased in the advanced stages of retinopathy (3·7 ± 0·2, 4·6 ± 0·5, 4·6 ± 0·6 and 6·9 ± 0·8 mg/l, respectively, P = 0·0005) and nephropathy (3·7 ± 0·2, 4·3 ± 0·4, 5·3 ± 0·7 and 7·9 ± 2·2 mg/l, respectively, P = 0·0007). Neither serum total nor HMW adiponectin was correlated with neuropathy. The HMW/total adiponectin ratio was not correlated with microangiopathy. Multiple regression analysis revealed that serum total and HMW adiponectin were independent factors for retinopathy stage ( P = 0·0055 and P = 0·0027, respectively) and nephropathy stage ( P = 0·0003 and P = 0·0018, respectively), when adjusted for age, gender, body mass index (BMI) and the duration of T2DM. This correlation remained significant when serum creatinine (or estimated glomerular filtration rate) and hypertension were added as independent variables. Treatment with thiazolidinediones (TZDs) did not affect these findings. Conclusions Serum total adiponectin and HMW adiponectin were found to be positively correlated with the severity of retinopathy and nephropathy but not with neuropathy in T2DM. [ABSTRACT FROM AUTHOR]

OBJECTIVE--Resistin is an adipocyte-secreted cytokine associated with insulin resistance in mice. We previously reported that the G/G genotype of a resistin single nucleotide polymorphism (SNP) at -420 increases type 2 diabetes susceptibility by enhancing its promoter activity. The aim of the present study was to determine the relevance of SNP -120 in a large number of subjects. RESEARCH DESIGN AND METHODS--We examined 2,610 type 2 diabetic case and 2,502 control subjects. The relation between SNP -420 and the age of type 2 diabetes onset was further analyzed by adding 237 type 2 diabetic subjects with age of onset ≤40 years. RESULTS--When analyzed without considering subject age, the SNP -420 genotype was not associated with type 2 diabetes. Since we reported that the onset of type 2 diabetes was earlier in G/G genotype, we analyzed the data using a trend test for age intervals of 10 years. The frequency of G/G genotype differed among age grades in type 2 diabetes (P = 0.037) and appeared to be higher in younger grades. In type 2 diabetes, G/G genotype was more frequent in subjects aged <40 years than in those aged ≥40 years (G/G vs. C/C, P = 0.003). In a total of 2,430 type 2 diabetic subjects with age of onset <60 years, the trend test showed that the G/G genotype had an increasing linear trend as the age grade of type 2 diabetes onset became younger (P = 0.0379). In control subjects, the frequency of C/G genotype showed an increasing linear trend with increasing age (P = 0.010). CONCLUSIONS--The G/G genotype frequency of resistin SNP -420 appears to be increased in younger-onset type 2 diabetic subjects. Diabetes 56:2834-2838, 2007 [ABSTRACT FROM AUTHOR]

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 diabetes susceptibility by enhancing promoter activity. We report here on the relation between plasma resistin and either SNP -420 genotype or factors related to insulin resistance. RESEARCH DESIGN AND METHODS -- We cross-sectionally analyzed 2,078 community-dwelling Japanese subjects attending a yearly medical checkup. The SNP -420 genotype was determined by TaqMan analysis. Fasting plasma resistin was measured using an enzyme-linked immunosorbent assay kit. RESULTS -- Plasma resistin was associated with the SNP -420 genotype (P < 0.0001), which was highest in G/G followed by C/G and C/C. Plasma resistin was higher in elderly individuals, female subjects, nondrinkers, and subjects with high blood pressure (P < 0.001, 0.003, <0.001, and 0.001, respectively). Simple regression analysis revealed that age, female sex, homeostasis model assessment of insulin resistance (HOMA-IR) index, systolic blood pressure, low HDL cholesterol, and high-sensitivity C-reactive protein (hs-CRP) were positively correlated with plasma resistin (P <0.001, 0.003, <0.001, 0.004, <0.001, and 0.003, respectively). Multiple regression analysis adjusted for age, sex, and BMI revealed that plasma resistin was an independent factor for HOMA-IR, low HDL cholesterol, and hs-CRP (P = 0.001, <0.001, and 0.006, respectively). CONCLUSIONS -- Plasma resistin was associated with SNP -420 and was correlated with insulin resistance, low serum HDL cholesterol, and high hs-CRP in the Japanese general population. [ABSTRACT FROM AUTHOR]

Abstract: Resistin, secreted from adipocytes, causes insulin resistance and diabetes in rodents. To determine the relation between serum resistin and diabetic microangiopathies in humans, we analyzed 238 Japanese T2DM subjects. Mean serum resistin was higher in subjects with either advanced retinopathy (preproliferative or proliferative) (P =0.0130), advanced nephropathy (stage III or IV) (P =0.0151), or neuropathy (P =0.0013). Simple regression analysis showed that serum resistin was positively correlated with retinopathy stage (P =0.0212), nephropathy stage (P =0.0052), and neuropathy (P =0.0013). Multiple regression analysis adjusted for age, gender, and BMI, revealed that serum resistin was correlated with retinopathy stage (P =0.0144), nephropathy stage (P =0.0111), and neuropathy (P =0.0053). Serum resistin was positively correlated with the number of advanced microangiopathies, independent of age, gender, BMI, and either the duration of T2DM (P =0.0318) or serum creatinine (P =0.0092). Therefore, serum resistin was positively correlated with the severity of microangiopathies in T2DM. [Copyright &y& Elsevier]

Abstract: Phosphodiesterase 3B (PDE3B), a major PDE isoform in adipocytes, plays a pivotal role in the anti-lipolytic action of insulin. Insulin phosphorylates and activates PDE3B in a phosphatidylinositol 3-kinase-dependent manner. We identified a new 50kDa protein that is phosphorylated by insulin and is co-immunoprecipitated with PDE3B by anti-PDE3B antibodies in rat adipocytes. The insulin-induced phosphorylation of the 50kDa protein was also detected in a cell free system against the N-terminal and the catalytic regions, which are more than 700 amino acids apart recognize the 50kDa protein, suggesting that it is not a proteolytic product, but an associated protein with PDE3B. Phosphoamino acid analysis indicated that both serine and threonine residues in the 50kDa protein were phosphorylated, but only serine residues in PDE3B were phosphorylated. Therefore, it appears likely that this is a new protein which is associated with PDE3B. [Copyright &y& Elsevier]

Abstract: Resistin, secreted from adipocytes, causes insulin resistance in rodents. Its roles and main source in humans remain unknown. The G/G genotype of resistin single nucleotide polymorphism, SNP-420, induces type 2 diabetes mellitus (T2DM) by increasing promoter activity. We elucidated factors correlated with serum resistin and effects of SNP-420 on monocyte resistin mRNA. In 198 T2DM and 157 controls, fasting serum resistin was higher in T2DM. Multiple regression analysis revealed that SNP-420 genotype was the strongest determinant of serum resistin. In T2DM, 1-year duration of T2DM and 1% HbA1c was also correlated with 0.19 and 0.54ng/ml serum resistin, respectively. Logistic regression analysis revealed that serum resistin was an independent factor for T2DM. In 23 healthy volunteers, monocyte resistin mRNA was positively correlated with its simultaneous serum levels and was higher in G/G genotype. Thus, SNP-420 determines monocyte mRNA and serum levels of resistin, which could induce T2DM. [Copyright &y& Elsevier]

Insulin resistance is a major cause of type 2 diabetes mellitus (T2DM). Resistin, an adipocyte-secreted hormone, antagonizes insulin. Transgenic mice that overexpress the resistin gene (Rem) in adipose tissue are insulin-resistant, whereas Rem (-/-) mice show lower fasting blood glucose, suggesting that the altered Retn promoter function could cause diabetes. To determine the role of RETN in human T2DM, we analyzed polymorphisms in its 5' flanking region. We found that the - 420G/G genotype was associated with T2DM (397 cases and 406 controls) (P = .008; adjusted odds ratio = 1.97 [by logistic regression analysis]) and could accelerate the onset of disease by 4.9 years (P = .006 [by multiple regression analysis]). Meta-analysis of 1,888 cases and 1,648 controls confirmed this association (P = .013). Linkage disequilibrium analysis revealed that the - 420G/G genotype itself was a primary variant determining T2DM susceptibility. Functionally, Sp1 and Sp3 transcription factors bound specifically to the susceptible DNA element that included -420G. Overexpression of Sp1 or Sp3 enhanced RETN promoter activity with - 420G in Drosophila Schneider line 2 cells that lacked endogenous Sp family members. Consistent with these findings, fasting serum resistin levels were higher in subjects with T2DM who carried the - 420G/G genotype. Therefore, the specific recognition of - 420G by Sp⅓ increases RETN promoter activity, leading to enhanced serum resistin levels, thereby inducing human T2DM. [ABSTRACT FROM AUTHOR]

Resistin, specifically secreted from adipocytes, antagonizes insulin and represents a promising candidate gene for type 2 diabetes. We reported that a frequent single nucleotide polymorphism (SNP) +299G>A in this gene is not associated with type 2 diabetes. To determine whether this SNP affects insulin resistance syndrome associated with type 2 diabetes, we examined its effects on susceptibility to obesity, hyperlipidemia and hypertension in type 2 diabetic subjects and on susceptibility to type 2 diabetes by interaction with other frequent genes involved in lipid metabolism, namely, β3-adrenergic receptor (b3AR) Trp64Arg, phosphodiesterase 3B (PDE3B) c.1389G>A or lysosomal acid lipase (LAL) Thr-6Pro. The 99 type 2 diabetic and 99 control subjects were typed by PCR direct sequencing or PCR-RFLP. No differences in frequencies of obesity, hyperlipidemia and hypertension were found between the type 2 diabetic subjects with G/G and those with G/A or A/A genotypes of the resistin SNP. When the combination of the resistin SNP with each of b3AR, PDE3B and LAL SNPs was assessed, no association with type 2 diabetes was evident. Therefore, the frequent SNP +299G>A in the resistin gene is unlikely to have major effects on susceptibility to insulin resistance syndrome associated with type 2 diabetes in Japanese subjects. [Copyright &y& Elsevier]

Phosphodiesterase 3B (PDE3B) gene expression is generally reduced in large adipocytes of obese, insulin-resistant mice. This reduced gene expression is restored by peroxisome proliferator-activated receptor (PPAR) γ ligands accompanied by a reduced fat cell size. To determine whether PDE3B gene expression is regulated by PPARγ itself, we analyzed lean PPARγ (+/−) mice with adipocyte size comparable to control PPARγ (+/+) mice. In adipocytes of PPARγ (+/−) mice, PDE3B mRNA and protein were both reduced to 63% of wild-type levels. Basal PDE activity tended to be decreased to 70% of wild-type levels, and, similarly, insulin-induced PDE activity was significantly decreased to 70%. Thus, PPARγ is required for PDE3B gene expression independent of adipocyte size. [Copyright &y& Elsevier]

The activation of phosphodiesterase 3B (PDE3B) reduces free fatty acid output from adipocytes. A reduced PDE3B gene expression could lead to insulin resistance. To determine whether there are polymorphisms associated with type 2 diabetes in PDE3B gene promoter, this 5′ flanking region was isolated. The transcription initiation site was located 206 bp upstream from the translation start site. Sequences of 2 kb of the 5′ flanking region for 24 type 2 diabetic Japanese subjects were initially analyzed using PCR direct sequencing, and the regions including the identified polymorphisms were then examined. In 98 controls and 98 type 2 diabetic subjects, −1947T > C, −567G > A, −465G > T, −458T > C, and −1727_−1726insTCAATT were found. Only −465G > T and this insertion had more than 5% frequencies. Since a complete linkage disequilibrium existed between them, −465G > T was further analyzed, along with a previously identified +1389G > A in the coding region, in a total of 200 controls and 207 type 2 diabetic subjects. These allele frequencies were not significantly different between these two groups (controls vs. cases; −465G > T, 12.0% vs. 10.1%, P=0.435; +1389G > A, 30.3% vs. 33.3%, P=0.408). These genotype distributions were not significantly different between these two groups. The T/T genotype at −465 was rare although this frequency could be higher in type 2 diabetes (4/207 subjects) than controls (0/200 subjects). The linkage disequilibrium existed between −465G > T and +1389G > A, and the estimated haplotype frequencies defined by these SNPs were not significantly different between the cases and controls. Thus, the identified polymorphisms are unlikely to have major effects on susceptibility to Japanese type 2 diabetes. [Copyright &y& Elsevier]

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 approximately 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. [ABSTRACT FROM AUTHOR]

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 beta, 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 beta was then confirmed in vitro. The glutathione S-transferase (GST)-tagged 14-3-3 beta 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 beta in rat adipocytes, and this interaction is enhanced by insulin. Two different PI3-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 beta could function as a scaffolding protein in the activation of PDE3B by insulin. [ABSTRACT FROM AUTHOR]

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 whether there are single nucleotide polymorphisms (SNPs) in the resistin gene associated with type 2 diabetes, sequences for 24 Japanese type 2 diabetic patients were initially analyzed using PCR direct sequencing. Three SNPs were found in the introns, but none were present in the coding regions. The allele frequencies of genomic -167C>T, +157C>T, and +299G>A in 99 Japanese control subjects were determined to be 3.5, 6.6, and 39.4%, respectively. In each pair of these SNPs, linkage disequilibria were found between either -167C>T and +299G>A or +157C>T and +299G>A. A linkage disequilibrium was also detected among -167C>T, +157C>T, and +299G>A, and only four of the eight possible haplotypes defined by these SNPs were found. A comparison of the frequencies of these SNPs and haplotypes between 99 type 2 diabetes and 99 control subjects revealed no evidence for any association. These identified SNPs, which were in linkage disequilibrium, represent potentially useful tools for searching for their association with specific phenotypes of diabetes. [ABSTRACT FROM AUTHOR]

Aims/Introduction: This study aimed to identify risk factors that contribute to the progression of slowly‐progressive type 1 diabetes by evaluating the positive predictive value (PPV) of factors associated with the progression to an insulin‐dependent state. Materials and Methods: We selected 60 slowly‐progressive type 1 diabetes patients who tested positive for glutamic acid decarboxylase autoantibodies (GADA) at diagnosis from the Japanese Type 1 Diabetes Database Study. GADA levels in these patients were concurrently measured using both radioimmunoassay (RIA) and enzyme‐linked immunosorbent assay (ELISA) techniques. Results: Compared with the non‐progressor group (fasting C‐peptide [F‐CPR] levels maintained ≥0.6 ng/mL), the progressor group showed a younger age at diagnosis, lower body mass index (BMI), lower F‐CPR levels and a higher prevalence of insulinoma‐associated antigen‐2 autoantibodies (IA‐2A). The PPV of RIA‐GADA increased from 56.3 to 70.0% in the high titer group (≥10 U/mL), and further increased to 76.9, 84.2, 81.0 and 75.0% when combined with specific thresholds for age at diagnosis <47 years, BMI <22.6 kg/m2, F‐CPR <1.41 ng/mL and IA‐2A positivity, respectively. In contrast, the PPV of ELISA‐GADA (71.8%) remained the same at 73.1% in the high titer group (≥180 U/mL), but increased to 81.8, 82.4 and 79.0% when evaluated in conjunction with age at diagnosis, BMI and F‐CPR level, respectively. Conclusions: Our findings show that, unlike RIA‐GADA, ELISA‐GADA shows no association between GADA titers and the risk of progression to an insulin‐dependent state. The PPV improves when age at diagnosis, BMI and F‐CPR levels are considered in combination. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Gene–environment interactions are considered to critically influence type 2 diabetes mellitus development; however, the underlying mechanisms and specific interactions remain unclear. Given the increasing prevalence of low birthweight (LBW) influenced by the intrauterine environment, we sought to investigate genetic factors related to type 2 diabetes development in individuals with LBW. Materials and Methods: The interaction between 20 reported type 2 diabetes susceptibility genes and the development of type 2 diabetes in LBW (<2,500 g) individuals in a population‐based Japanese cohort (n = 1,021) was examined by logistic regression and stratified analyses. Results: Logistic regression analyses showed that only the G/G genotype at the rs1862513 locus of the resistin gene (RETN), an established initiator of insulin resistance, was closely related to the prevalence of type 2 diabetes in individuals with LBW. Age, sex and current body mass index‐adjusted stratified analyses showed a significant interaction effect of LBW and the RETN G/G genotype on fasting insulin, homeostatic model assessment 2‐insulin resistance, Matsuda index and the prevalence of type 2 diabetes (all P‐values for interaction <0.05). The adjusted odds ratio for type 2 diabetes in the LBW + G/G genotype group was 7.33 (95% confidence interval 2.43–22.11; P = 0.002) compared with the non‐LBW + non‐G/G genotype group. Similar results were obtained after excluding the influence of malnutrition due to World War II. Conclusions: Simultaneous assessment of LBW and the RETN G/G genotype can more accurately predict the risk of future type 2 diabetes than assessing each of these factors alone, and provide management strategies, including early lifestyle intervention in LBW population. [ABSTRACT FROM AUTHOR]

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 fatty acids (FFAs). An elevation of serum FFAs is known to cause insulin resistance in skeletal muscle and liver, which could be the primary cause of type 2 diabetes. To elucidate whether PDE3B is involved in this disease, we examined the PDE3B gene expression in epididymal fat tissues of obese insulin-resistant diabetic KKAy mice. We also examined the effect of an insulin-sensitizing drug, pioglitazone, on this gene expression. In adipose tissue of KKAy mice, PDE3B mRNA and its corresponding protein were reduced to 48 and 43% of those in C57BL/6J control mice. Basal and insulin-stimulated membrane-bound PDE activities were also decreased to 50 and 36% of those in the controls, respectively. Pioglitazone increased both PDE3B mRNA and protein levels by 1.8-fold of those in untreated KKAy mice. Basal and insulin-induced membrane-bound PDE activities were also increased by 1.6- and 2.0-fold, respectively. Pioglitazone reduced the elevated levels of serum insulin, glucose, FFAs, and triglyceride in KKAy mice. Thus, the reduced PDE3B gene expression in adipose tissues could be the primary event in the development of insulin resistance in KKAy mice, which was improved by pioglitazone possibly because of the restoration of the reduced PDE3B gene expression. [ABSTRACT FROM AUTHOR]

Coagulation factor XIII consists of two A- and two B-subunits, and either gene mutation can cause a complete deficiency. In a newborn patient with persistent bleeding from the umbilical cord stump, the plasma A-subunit protein was not detectable. Direct PCR sequencing revealed an nt 389 (ins G) frameshift mutation in exon 4 resulting in a new stop codon and a Ser 413 Leu missense mutation in exon 10 in either allele. His mother and father were heterozygous for the nt 389 (ins G) and the Ser 413 Leu, respectively, with about 50% reduction of the plasma A-subunit proteins. In all family members examined only those with either mutation showed the reduced subunit A protein levels. Thus, this complete deficiency of factor XIII was due to a novel compound heterozygous mutation in the A-subunit gene. [ABSTRACT FROM AUTHOR]

We aimed to investigate the association between pulse rate variability (PRV) and health-related quality of life (HRQOL) in the general population. A cross-sectional study was conducted with 5908 Japanese men and women aged 30–79 years. PRV was assessed at rest using 5-min recordings of pulse waves with a photoplethysmographic signal from a fingertip sensor, and the time and frequency domains of PRV were determined. HRQOL was assessed with the Short Form-8 (SF-8) Japanese version, and poor HRQOL was defined as an SF-8 sub-scale score < 50. A test for nonlinear trends was performed with the generalized additive model with a smoothing spline adjusted for confounders. The lowest multivariable-adjusted odds ratios for poor physical component score were found in those who had second or third quartile levels of standard deviation of normal-to-normal intervals (SDNN) and root mean square of successive difference (RMSSD), and high-frequency (HF) power and trended slightly upward in the higher levels. PRV-derived parameters were nonlinearly associated with poor physical component scores. In conclusion, reduced PRV-derived SDNN, RMSSD and HF power were associated with poor HRQOL in the domain of physical function. Higher levels of these parameters did not necessarily translate into better HRQOL. [ABSTRACT FROM AUTHOR]

The diagnostic criteria for slowly progressive type 1 diabetes (slowly progressive insulin‐dependent diabetes mellitus; SPIDDM) have been revised by the Committee on Type 1 Diabetes of the Japan Diabetes Society. All of the following three criteria must be met for 'a definitive diagnosis of SPIDDM': (1) presence of anti‐islet autoantibodies at some point in time during the disease course; (2) absence of ketosis or ketoacidosis at the diagnosis of diabetes with no requirement for insulin treatment to correct hyperglycemia immediately after diagnosis in principle; and (3) gradual decrease of insulin secretion over time, with insulin treatment required at more than 3 months after diagnosis, and the presence of severe endogenous insulin deficiency (fasting serum C‐peptide immunoreactivity <0.6 ng/mL) at the last observed point in time. When a patient fulfills only (1) and (2), but not (3), he/she is diagnosed with 'SPIDDM (probable)' because the diabetes is non‐insulin‐dependent type. [ABSTRACT FROM AUTHOR]

Tight junction disruption and dysfunction are involved in the progression of blood–brain barrier (BBB) breakdown. Recent investigations have revealed BBB disruption in patients with vascular cognitive decline. Our previous studies showed that miR‐501‐3p negatively regulates cerebral endothelial tight junction protein‐1, resulting in the disruption of the BBB, and playing an important role in the development of vascular cognitive impairment. BBB breakdown in white matter lesions is often seen in the patients with vascular mild cognitive impairment (MCI). We therefore hypothesize that most early‐phase MCI patients may demonstrate elevated expression of miR‐501‐3p and sought to investigate whether serum exosome miR‐501‐3p levels could be a clinical indicator for detecting mild cognitive impairment. One hundred and seventy‐eight subjects (aged 73 [68–75] years, 53% male) were recruited for this study. The Japanese version of the Montreal Cognitive Assessment (MoCA‐J) was used for detecting MCI. Serum exosome miR‐501‐3p expression levels were measured by qPCR methods. Patients were divided into two groups depending on whether their miR‐501‐3p ∆Ct values were above ("High"; n = 74) or below ("Low"; n = 104) cutoff levels determined by ROC curve. MCI was detected significantly more often in the miR‐501‐3p‐High group (vs. ‐Low group, 63.5% vs. 47.1%, respectively; p < 0.05). Multivariate logistic regression analysis showed a significant association between MCI status and High miR‐501‐3p (odds ratio 2.662; p < 0.01), improved vs. known risk factors. In non‐diabetic patients, High miR‐501‐3p was positively associated with MCI status (odds ratio 3.633; p < 0.01) and also positively associated with MCI status in those with atherosclerosis (odds ratio 3.219; p < 0.01). The present study demonstrates that elevated expression of blood exosomal miR‐501‐3p can indicate the presence of MCI in human patients. Early detection of vascular injuries may allow a reduction in progressive dementia through the management of vascular risk factors. [ABSTRACT FROM AUTHOR]

Presents a response to a letter to the editor of "Diabetes Care" regarding the results of a study on the clinical heterogeneity of patients with adult-onset diabetes and GAD autoantibodies.

Aim/Introduction: Resistin, which induces insulin resistance, is mainly expressed in monocytes/macrophages in humans. We reported previously that serum resistin was highest in the G–A haplotype defined by resistin single nucleotide polymorphisms (SNPs) at −420 (rs1862513) and − 358 (rs3219175). As sarcopenic obesity is associated with insulin resistance, we aimed to examine whether serum resistin and its haplotypes were associated with sarcopenic obesity at a latent stage. Materials and Methods: We cross‐sectionally analyzed 567 community‐dwelling Japanese participants attending annual medical check‐ups in which the sarcopenic obesity index was evaluated. The age‐ and gender‐matched normal glucose tolerance subjects with G–A homozygotes and those with C–G homozygotes were examined via RNA‐sequencing and pathway analysis (each n = 3), and RT‐PCR (each n = 8). Results: In multivariate logistic regression analyses, the fourth quartile (Q4) of serum resistin and G–A homozygotes were both associated with the latent sarcopenic obesity index defined by a visceral fat area of ≥ 100 cm2 and grip strength Q1 after adjustment for age and gender, with or without other confounding factors. RNA sequencing and pathway analysis showed that tumor necrosis factor (TNF) was involved in the top five pathways in the whole blood cells of G–A homozygotes compared with C–G homozygotes. RT‐PCR revealed that TNF mRNA was higher in G–A homozygotes than in C–G homozygotes. Conclusions: The G–A haplotype was associated with the latent sarcopenic obesity index defined by grip strength in the Japanese cohort, could be mediated by TNF‐α. [ABSTRACT FROM AUTHOR]

Aim/Introduction: To investigate the differences in the clinical significance and glutamic acid decarboxylase autoantibody (GADA) affinity between RIA (RIA‐GADA) and ELISA (ELISA‐GADA) in patients with type 1 diabetes. Methods: A total of 415 patients with type 1 diabetes were enrolled, including 199 acute‐onset type 1 diabetes, 168 slowly progressive type 1 diabetes (SPIDDM), and 48 fulminant type 1 diabetes. GADA affinity was measured by a competitive binding experiment using unlabeled recombinant human GAD65 protein, and the diagnostic performance of both assays and the relationship between GADA affinity and the decline of fasting C‐peptide (F‐CPR) were examined. Results: While the ELISA‐GADA displayed a higher sensitivity than the RIA method in diagnosing type 1 diabetes in acute‐onset patients, about 40% of SPIDDM patients with low‐titer RIA‐GADA were determined as negative by the ELISA method. Patients with type 1 diabetes with RIA‐GADA alone had an older age of onset, less diabetic ketoacidosis, a higher BMI, and a higher F‐CPR compared with patients positive for both RIA‐GADA and ELISA‐GADA. Additionally, 36% of RIA‐GADA‐positive patients had low‐affinity GADA (<1010 L/mol), which was significantly higher than in the ELISA‐GADA‐positive patients (4%, P < 0.0001). Furthermore, over a 3 year monitoring period, F‐CPR levels decreased in ELISA‐GADA‐positive SPIDDM, whereas it was maintained in patients with RIA‐GADA alone, regardless of GADA affinity. Conclusions: These results suggest that bivalent ELISA for GADA is superior to the RIA method in diagnosing type 1 diabetes. Moreover, the diagnostic superiority of the ELISA‐GADA made possible the concurrent identification of SPIDDM patients at high‐risk of early progression, and allowed for more accurate clinical diagnosis and management. [ABSTRACT FROM AUTHOR]

Aims/Introduction: This study aimed to investigate the clinical significance and antigen specificity of autoantibodies to insulinoma‐associated antigen‐2 (IA‐2A) by radioimmunoassay (RIA; IA‐2A‐RIA) and enzyme‐linked immunosorbent assay (ELISA; IA‐2A‐ELISA) in Japanese patients with type 1 diabetes. Materials and Methods: A total of 338 type 1 diabetic patients were enrolled, including 38 fulminant type 1 diabetes, 168 acute‐onset type 1 diabetes and 137 slowly‐progressive type 1 diabetes (SPIDDM). The concordance, correlation of autoantibody titer, and the relationship between IA‐2A and progression to the insulin‐deficient state were examined. Also, competitive assay was used to examine the antigen specificity. Results: The prevalence of IA‐2A‐ELISA was 4–5% lower than that of IA‐2A‐RIA in both the acute‐onset type 1 diabetes and SPIDDM, but the diagnostic sensitivities of both subtypes, when measured in combination with glutamic acid decarboxylase autoantibody, were comparable. The diagnosis of type 1 diabetes using either the RIA or ELISA methods showed substantial agreement with the exponential correlation of autoantibody titers detected by RIA and ELISA. Among the SPIDDM patients, the fasting C‐peptide for IA‐2A‐positive cases by ELISA, but not the RIA method, was significantly lower than in the negative cases (P < 0.05). Furthermore, IA‐2A‐ELISA proved superior to the RIA method in predicting the progression to insulin deficiency in SPIDDM. Competitive analysis showed that even sera with discrepant results by RIA and ELISA have IA‐2‐specific autoantibodies. Conclusion: These results suggest that IA‐2A‐ELISA is a reliable marker not only for the diagnosis of type 1 diabetes, but also for the prediction of future insulin dependency; that is, detection of IA‐2A‐ELISA helps identify a subtype of SPIDDM patients who would likely progress onto insulin‐deficient state. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Though poor glycemic control and insulin treatment are reported to be associated with sarcopenia in type 2 diabetes, type 1 diabetes may be a stronger risk for sarcopenia. We therefore studied the effect of the type of diabetes, glycemic control, and insulin therapy on the prevalence and characteristics of sarcopenia. Materials and Methods: A total of 812 Japanese patients with diabetes (type 1: n = 57; type 2: n = 755) were enrolled in this study. Sarcopenia was defined as low handgrip strength or slow gait speed and low appendicular skeletal muscle mass. Results: Among participants aged ≥65 years, the sarcopenia prevalence rate was higher among patients with type 1 diabetes (20.0%) than among those with type 2 diabetes (8.1%). The prevalence rate of low handgrip strength was higher in type 1 diabetes (50.0%) than in type 2 diabetes (28.7%). In logistic regression analysis, type 1 diabetes was significantly associated with the prevalence of low handgrip strength. In logistic regression analysis, medication with insulin was significantly associated with the prevalence of sarcopenia; this association was not retained after adjusting for HbA1c. Conclusions: The prevalence of sarcopenia in older adult patients was higher in those with type 1 diabetes than in those with type 2 diabetes. Among the components of sarcopenia, the difference was most prominent in the frequency of low handgrip strength. Poor glycemic control rather than type of diabetes or insulin treatment was revealed to be a primary risk factor for sarcopenia in diabetes mellitus. [ABSTRACT FROM AUTHOR]

Resistin, secreted from adipocytes, causes insulin resistance in rodents. We reported that the G/G genotype of a resistin gene promoter single nucleotide polymorphism (SNP) at -420 increases type 2 diabetes (T2DM) susceptibility by enhancing its promoter activity. We also showed that serum resistin was positively correlated with G at SNP-420, the duration of T2DM, and HbA1c in T2DM. To determine the relation between serum resistin and factors related to metabolic syndrome (MetS) in T2DM, we analyzed 238 Japanese T2DM patients. Fasting serum resistin was measured using ELISA. Serum resistin was higher in subjects with either obesity (P=0.041), past history of obesity (P-M).019), low HDL (P=0.004), high triglycerides (TG) (P=0.019), hypertension (HT) (P=0.001), or atherosclerosis (P=0.012). Simple regression analysis involving serum resistin (ng/ml) as a dependent variable revealed that serum resistin was correlated with max BMI (unstandardized coefficient (β)=0.383, P=0.025), HDL (mg/dl) (β=-0.142,P=0.003), TG (mg/dl) (β=0.013,P=0.042), HT (with= 1 or without=0) (β=5.044, P=0.001), high-sensitivity C-reactive protein (hsCRP) (mg/dl) (β=2.813, P=0.006), and atherosclerosis (with=1 or without=0) (β=4.157, P=0.012). Multiple regression analysis (or logistic regression analysis for HT) involving serum resistin as an independent variable, adjusted for age, gender, BMI (except analysis for max BMI), and the duration of T2DM, revealed that serum resistin was correlated with max BMI (P=0.026), HDL (P=0.008), TG (P=0.041), HT (P=0.031), and hsCRP (P=0.004). We then assessed the relation between serum resistin and the accumulation of each factor involved in MetS, namely, obesity, low HDL, high TG, and HT. Serum resistin was significantly different among the number of factors (ANOVA, P<0.001), and appears to be increased as the number was increased. Simple regression analysis involving the number of MetS factors as a dependent variable revealed that serum resistin was positively correlated with the number of MetS factors (β0.033, P<0.001). Multiple regression analysis showed that serum resistin was also positively correlated with the number of MetS factors, independent of age, gender, and the duration of T2DM (P<0.001). Therefore, serum resistin was associated with multiple factors related to MetS in T2DM. [ABSTRACT FROM AUTHOR]

Background. The purpose of this study is to investigate the relationship between serum resistin levels and chronic kidney disease (CKD).Methods. A total of 3192 community-dwelling subjects (1377 men, 1815 women), aged ≥40 years and without renal failure, were divided into four groups according to quartiles of serum resistin concentrations: ≤7.1, 7.2–9.9, 10.0–14.7 and ≥14.8 ng/mL. The associations of resistin levels with renal function status were examined cross-sectionally. The estimated glomerular filtration rate (eGFR) was calculated using the equation from the Modification of Diet in Renal Disease Study, and CKD was defined as an eGFR of <60 mL/min/1.73 m2.Results. The age- and sex-adjusted mean values of eGFR decreased significantly with elevating quartiles of resistin (P for trend <0.001). The age- and sex-adjusted odds ratios (ORs) for the presence of CKD increased progressively with higher quartiles of resistin. This trend remained robust even after controlling for age, sex, body mass index, diabetes, homeostasis model assessment of insulin resistance (HOMA-IR), high-sensitivity C-reactive protein (hs-CRP), triglycerides, high-density lipoprotein and total cholesterol, hypertension, current smoking, current drinking, and regular exercise [second quartile: OR 1.44, 95% confidence interval (CI) 1.05–1.99; third quartile: OR 2.15, 95% CI 1.58–2.92; fourth quartile: OR 2.32, 95% CI 1.71–3.16; P for trend <0.001]. In stratified analyses, high resistin level (≥7.2 ng/mL) was a significant relevant factor in CKD, independent of HOMA-IR or hs-CRP level.Conclusion. Our findings suggest that elevated resistin level is significantly associated with the likelihood of CKD in the general Japanese population. [ABSTRACT FROM AUTHOR]

Phosphodiesterase (PDE) 3B, a major isoform of PDE in adipocytes, mediates the antilipolytic action of insulin. PDE3B gene expression is generally reduced in adipocytes of either monogenic or polygenic rodent models of obese, insulin-resistance. An increased fat cell size, a common feature of obesity, could account for this reduction. Insulin receptor substrate-1 (IRS-1) (−/−) mice are lean with a reduced fat cell size and have insulin resistance due to a primary defect of insulin signaling. To determine whether the regulation of PDE3B gene expression is correlated with fat cell size, we examined this gene expression in adipose tissues of IRS-1 (−/−) mice. In IRS-1 (−/−) mice, PDE3B mRNA and protein levels were increased 1.24- and 1.35-fold those in C57BL/6J control mice, respectively. Independently, the fold induction of PDE activity by insulin (insulin-induced/basal) was 1.7-fold in control mice, but was reduced to 1.35-fold in IRS-1 (−/−) mice. Thus, PDE3B gene expression may be inversely correlated with a fat cell size, whereas insulin-induced PDE3B activation is mediated through IRS-1. [Copyright &y& Elsevier]

Aims/Introduction: Low birthweight is reportedly associated with type 2 diabetes mellitus; however, this association has not been confirmed in the Japanese population, and whether high birthweight is associated with type 2 diabetes mellitus is controversial. We aimed to investigate the association between birthweight and type 2 diabetes mellitus among a general Japanese population. Materials and Methods: Overall 1,135 middle‐ to old‐aged Japanese men and women were enrolled in the Toon Health Study. A 75‐g oral glucose tolerance test was used to diagnose type 2 diabetes mellitus, and a questionnaire survey about birthweight was administered. The association between birthweight and the prevalence of type 2 diabetes mellitus in later life of the participants was examined using multivariable logistic regression analysis. Stratified analysis by current body mass index was also carried out. Results: The mean age was 56.5 ± 12.2 years. Type 2 diabetes mellitus was observed in 9.3% of the participants in this study. Compared with the reference group (2,500–3,999 g), the adjusted odds ratio of the low‐birthweight group (<2,500 g) for type 2 diabetes mellitus was 2.46 (95% confidence interval 1.48–4.10). The association between the high‐birthweight group (≥4000 g) and type 2 diabetes mellitus was not significant after including family history of diabetes in the multivariable model. The odds ratio of the low‐birthweight group for type 2 diabetes mellitus was higher in the overweight/obese group than in the non‐overweight group. Conclusions: Low birthweight was associated with an increased risk of type 2 diabetes mellitus in a Japanese population, especially in overweight/obese individuals. [ABSTRACT FROM AUTHOR]

Keywords: Diabetes; Diagnosis; Guideline; Treatment EN Diabetes Diagnosis Guideline Treatment 1020 1076 57 07/27/20 20200701 NES 200701 PREFACE Objectives of the current guideline for the management of diabetes The current guideline represents the 6th edition of the "Japanese Clinical Practice Guideline for Diabetes" which has been revised every three years since its first appearance in 2004 to promote evidence-based, rational, efficient and consistent clinical practice in diabetes. b Intensive insulin therapy has been shown to be effective in preventing the onset of macroangiopathy in type 2 diabetes 9,31,32. 7 DIABETES SELF-MANAGEMENT EDUCATION AND SUPPORT FOR THE SELF-MANAGEMENT OF DIABETES B [CQ7-1] Are organized support and education for the self-management of diabetes useful for the management of diabetes? MNT for elderly patients with diabetes B [VIII-CQ-1] Is MNT as effective for elderly patients with diabetes as for non-elderly patients? Glycemic control and cancer risk in patients with diabetes The "Report of the Committee on Diabetes and Cancer II" addressed this issue and examined the impact of glycemic control on the subsequent risk of cancer in patients with diabetes[443], demonstrating that there is no high-quality evidence available, at present, to clarify the association between glycemic control and cancer risk in patients with diabetes. Management and prognosis of patients with cancer and diabetes It is reported that patients with cancer and diabetes are associated with poorer short-term and long-term life prognosis than patients with cancer without diabetes[[446]]. [Extracted from the article]

Aims/Introduction: Resistin is an adipocyte‐derived polypeptide that leads to the progression of insulin resistance and subsequent atherosclerosis. Some studies have reported an association between self‐reported intake of n−3 polyunsaturated fatty acids (PUFAs) and serum resistin levels. However, no studies have investigated the association between the ratio of serum levels of n−3 to serum n−6 PUFAs and the serum resistin concentration in the general population. Materials and Methods: We carried out a cross‐sectional study of 3,200 community‐dwelling Japanese individuals aged ≥40 years in 2002–2003. The ratios of serum eicosapentaenoic acid or docosahexaenoic acid to arachidonic acid (AA) were categorized into quartiles. The associations of serum eicosapentaenoic acid/AA and docosahexaenoic acid/AA with the serum resistin concentration were assessed using linear regression models with adjustment for potential confounding factors. Results: The geometric mean of serum resistin was 10.3 ng/mL. The age‐ and sex‐adjusted geometric mean of serum resistin decreased significantly with increased levels of serum eicosapentaenoic acid/AA (quartile 1: 11.3 ng/mL; quartile 2: 10.6 ng/mL; quartile 3: 10.3 ng/mL; quartile 4: 9.3 ng/mL; P for trend <0.001). A similar association was observed for serum docosahexaenoic acid/AA (quartile 1: 11.1 ng/mL; quartile 2: 10.6 ng/mL; quartile 3: 10.1 ng/mL; quartile 4: 9.7 ng/mL; P for trend <0.001). An adjustment for potential confounding factors did not change these associations. Conclusions: Higher ratios of serum n−3 to n−6 PUFAs were associated with lower serum resistin levels. Consumption of a large amount of n−3 PUFAs might have desirable effects on resistin‐mediated diseases. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Hyperglycemia is a risk factor for sarcopenia when comparing individuals with and without diabetes. However, no studies have investigated whether the findings could be extrapolated to patients with diabetes with relatively higher glycemic levels. Here, we aimed to clarify whether glycemic control was associated with sarcopenia in patients with type 2 diabetes. Materials and Methods: Study participants consisted of patients with type 2 diabetes (n = 746, the average age was 69.9 years) and an older general population (n = 2,067, the average age was 68.2 years). Sarcopenia was defined as weak grip strength or slow usual gait speed and low skeletal mass index. Results: Among patients with type 2 diabetes, 52 were diagnosed as having sarcopenia. The frequency of sarcopenia increased linearly with glycated hemoglobin (HbA1c) level, particularly in lean individuals (HbA1c <6.5%, 7.0%, ≥6.5% and <7.0%: 18.5%; HbA1c ≥7.0% and <8.0%: 20.3%; HbA1c ≥8.0%: 26.7%). The linear association was independent of major covariates, including anthropometric factors and duration of diabetes (HbA1c <6.5%: reference; ≥6.5% and <7.0%: odds ratio [OR] 4.38, P = 0.030; HbA1c ≥7.0% and <8.0%: 4.29, P = 0.024; HbA1c ≥8.0%: 7.82, P = 0.003). HbA1c level was specifically associated with low skeletal mass index (HbA1c ≥8.0%: OR 5.42, P < 0.001) rather than weak grip strength (OR 1.89, P = 0.058) or slow gait speed (OR 1.13, P = 0.672). No significant association was observed in the general population with a better glycemic profile. Conclusions: Poor glycemic control in patients with diabetes was associated with low muscle mass. [ABSTRACT FROM AUTHOR]

Aim/Introduction: Insulin administration was found to trigger type 1 diabetes in six Japanese type 2 diabetes patients with type 1 diabetes high‐risk human leukocyte antigen class II and the class I allele of the insulin gene variable number tandem repeat genotype. The objective of the present study was to assess the contribution of non‐human leukocyte antigen single‐nucleotide polymorphisms (SNPs) to the risk of developing insulin‐triggered type 1 diabetes. Materials and Methods: We genotyped 13 type 1 diabetes susceptible SNPs in six patients and compared them with those in Japanese controls (Hap Map3‐JPT). The SNPs that showed statistically significant results were further analyzed using non‐diabetic control participants and participants with type 2 diabetes at the Ehime University Hospital. Results: The risk allele frequency of BACH2 rs3757247 in the six patients was significantly more frequent than that in 86 Japanese controls (P = 0.038). No significant difference in the allele frequency was observed in the other SNPs. This result was confirmed by the findings that the risk allele frequency of BACH2 in the six patients was significantly higher than that in the non‐diabetic control participants (n = 179) and type 2 diabetes with or without insulin treatment (n = 154 or n = 152; P = 0.035, 0.034 or 0.037, respectively). Despite being statistically not significant, the six patients were all homozygous for the CLEC16A rs12708716 risk allele and five were homozygous for the CLEC16A rs2903692 risk allele. Conclusions: In addition to type 1 diabetes high‐risk human leukocyte antigen class II and the class I allele of the insulin gene variable number tandem repeat genotype, the possibility that the risk variants of BACH2 and CLEC16A could contribute to the development of insulin‐triggered type 1 diabetes cannot be excluded. [ABSTRACT FROM AUTHOR]

Aims: It is known that autonomic nerve activity (ANA) affects glucose metabolism by regulating the secretion of insulin and glucagon. Sympathetic nerve stimulation results in increased blood glucose levels. ANA also showed a circadian variation, and sympathetic nerve activity was minimal at night and began to rise at arousal. Therefore, a drastic alteration in ANA around wake-up would be associated with glycemic variability (GV) known risk factor for cardiovascular disease. We investigated the relation between ANA around wake-up and either morning or daily GV.Methods: We simultaneously performed Holter ECG and continuous glucose monitoring system in 41 patients with type 2 diabetes (T2D). ANA was assessed by heart rate variability (HRV) analysis. Delta (Δ) wake-up was defined as the difference between the maximum and minimum value during 1 h before and after wake-up time, before breakfast.Results: Δ of low frequency/high frequency (LF/HF) around wake-up time (Δ LF/HF wake-up) was positively associated with Δ glucose wake-up, standard deviation (SD) glucose wake-up, the mean amplitude of glucose excursions (MAGE24h), and SD glucose24h after adjustment for age, sex, BMI, the duration of diabetes, and the prevalence of diabetic polyneuropathy (β = 0.47, p = 0.011, β = 0.48, p = 0.009, β = 0.54, p = 0.002 and β = 0.41, p = 0.0025, respectively). No association was found between Δ LF/HFwake-up and either mean blood glucose for 24 h, or HbA1c as parameters of chronic hyperglycemia.Conclusions: In T2D, the fluctuation in fasting sympathetic nerve activity around wake-up was positively associated with not only morning but also daily GV. [ABSTRACT FROM AUTHOR]

Objective Resistin is secreted by monocytes/macrophages and is associated with insulin resistance, inflammation and cardiovascular diseases. In the Japanese cohort, serum resistin is tightly associated with a single-nucleotide polymorphism ( SNP) at -420 (rs1862513) in the promoter region of the human resistin gene. However, interactions between SNP-420 and environmental factors remain to be elucidated. The aim of this study was to investigate the association between serum resistin levels and nutrient intake, and the effect of SNP-420 on this association. Design, Participants and Measurements The Toon Genome Study is a cohort study of Japanese community-dwelling subjects. A total of 1981 participants were cross-sectionally analysed. Each nutrient intake was assessed using the semiquantitative food frequency questionnaire and categorized into the quartiles (Q1-Q4). Serum resistin was measured by ELISA. Results Serum resistin tended to be inversely associated with fish intake and positively associated with meat intake after adjustment for age, sex, BMI and energy intake. Serum resistin was inversely associated with n-3 polyunsaturated fatty acids ( PUFA) intake after adjustment for age, sex, BMI and energy intake (Q1 12.5, Q2 12.5, Q3 12.2, Q4 11.5 ng/mL; P for trend = .007). This inverse association was strongest in the G/G genotype of SNP-420, followed by C/G and C/C (G/G, Q1 18.9, Q2 19.5, Q3 18.4, Q4 14.5 ng/mL, P = .001; C/G, 14.4, 13.3, 13.1, 12.9, P = .015; C/C, 9.5, 9.5, 9.2, 8.8, P = .020; P for interaction = .004). Conclusions The inverse association between serum resistin and n-3 PUFA intake was strongest in SNP-420 G/G genotype in the Japanese cohort. [ABSTRACT FROM AUTHOR]

Background: Elevated resting heart rate (RHR) is a predictor of incident type 2 diabetes (T2D). Insulin resistance is thought to play a role in this association; however, the extent to which insulin resistance mediates this association is unclear.Methods: 1309 Japanese individuals without diabetes were recruited during 2009-2012 and followed for 5 years, of whom 78 developed T2D, as diagnosed by the 75 g oral glucose tolerance test. Supine RHR was measured by electrocardiography. Using logistic regression analysis, we examined the association between RHR and incident T2D, and interaction with the homeostasis model assessment of insulin resistance (HOMA-IR) index. Causal mediation analysis was applied to decompose the effect of RHR on the outcome and estimate the proportion mediated by the HOMA-IR index.Results: The sex- and age-adjusted cumulative incidence rate of T2D increased with increasing RHR. After adjustment for sex, age, waist circumference, current smoking status, alcohol use, habitual exercise, and cardiovascular disease medications, individuals with a RHR ≥80 bpm, compared with <60 bpm, showed an increased risk of incident T2D [odds ratio (OR), 2.89; 95 % confidence interval (CI), 1.07 to 7.80]. Multivariate adjusted OR for the total effect per 1 SD increase in RHR on incident T2D was 1.37 (95 % CI, 1.01 to 1.74) in the mediation analysis, and the proportion of the total indirect effect mediated by the HOMA-IR index was 27.5 % (95 % CI, 1.5 to 53.5).Conclusions: Approximately 30 % of the effect of RHR on incident T2D was explained by the indirect effect of insulin resistance. [ABSTRACT FROM AUTHOR]

Aims: Glutamic acid decarboxylase autoantibodies (GADAb) differentiate slowly progressive insulin-dependent (type 1) diabetes mellitus (SPIDDM) from phenotypic type 2 diabetes, but many GADAb-positive patients with diabetes do not progress to insulin-requiring diabetes. To characterize GADAb-positive patients with adult-onset diabetes who do not require insulin therapy for >5 years (NIR-SPIDDM), we conducted a nationwide cross-sectional survey in Japan. Methods: We collected 82 GADAb-positive patients who did not require insulin therapy for >5 years (NIR-SPIDDM) and compared them with 63 patients with insulin-requiring SPIDDM (IR-SPIDDM). Clinical and biochemical characteristics, HLA-DRB1-DQB1 haplotypes, and predictive markers for progression to insulin therapy were investigated. Results: Compared with the IR-SPIDDM group, the NIR-SPIDDM patients showed later diabetes onset, higher body mass index, longer duration before diagnosis, and less frequent hyperglycemic symptoms at onset. In addition, C-peptide, LDL-cholesterol, and TG were significantly higher in the NIR-SPIDDM compared to IR-SPIDDM patients. The NIR-SPIDDM group had lower frequency of susceptible HLA-DRB1*04:05-DQB1*04:01 and a higher frequency of resistant HLA-DRB1*15:01-DQB1*06:02 haplotype compared to IR-SPIDDM. A multivariable analysis showed that age at diabetes onset (OR = 0.82), duration before diagnosis of GADAb-positive diabetes (OR = 0.82), higher GADAb level (≥10.0 U/ml) (OR = 20.41), and fasting C-peptide at diagnosis (OR = 0.07) were independent predictive markers for progression to insulin-requiring diabetes. An ROC curve analysis showed that the optimal cut-off points for discriminating two groups was the GADAb level of 13.6 U/ml, age of diabetes onset of 47 years, duration before diagnosis of 5 years, and fasting C-peptide of 0.65 ng/ml. Conclusions: Clinical, biochemical and genetic characteristics of patients with NIR-SPIDDM are different from those of IR-SPIDDM patients. Age of diabetes onset, duration before GADAb-positivity, GADAb level, and fasting C-peptide at diagnosis must be carefully considered in planning prevention trials for SPIDDM. [ABSTRACT FROM AUTHOR]

Aims/Introduction Resistin, secreted from adipocytes, causes insulin resistance in mice. In humans, the resistin gene is mainly expressed in monocytes and macrophages. Tunicamycin is known to induce endoplasmic reticulum ( ER) stress, and reduce resistin gene expression in 3T3-L1 mouse adipocytes. The aim of the present study was to examine whether ER stress affects resistin gene expression in human monocytes. Materials and Methods The relationship between resistin messenger ribonucleic acid ( mRNA) and ER stress markers mRNA was analyzed by reverse transcription polymerase chain reaction in isolated monocytes of 30 healthy volunteers. The effect of endotoxin/lipopolysaccharides or tunicamycin on resistin gene expression was analyzed in THP-1 human monocytes. Signaling pathways leading to resistin mRNA were assessed by the knockdown using small interfering RNA or overexpression of key molecules involved in unfolded protein response. Results Resistin mRNA was positively associated with immunoglobulin heavy chain-binding protein (BiP) or CAAT/enhancer binding protein-α homologous protein ( CHOP) mRNA in human isolated monocytes. In THP-1 cells, lipopolysaccharides increased mRNA of BiP, pancreatic endoplasmic reticulum eukaryotic initiation factor 2α kinase (PERK) and CHOP, as well as resistin. Tunicamycin also increased resistin mRNA. This induction appeared to be dose- and time-dependent. Tunicamycin-induced resistin mRNA was inhibited by chemical chaperone, 4-phenylbutyric acid. The knockdown of either PERK, activating transcription factor 4 (ATF4) or CHOP reduced tunicamycin-induced resistin mRNA. Conversely, overexpression of ATF4 or CHOP increased resistin mRNA. Conclusions Endoplasmic reticulum stress induced by tunicamycin increased resistin mRNA through the PERK-ATF4-CHOP pathway in THP-1 human monocytes. ER stress could lead to insulin resistance through enhanced resistin gene expression in human monocytes. [ABSTRACT FROM AUTHOR]

Objective Lower heart rate variability (HRV) is associated with the inflammation that is linked with the progression of atherosclerosis. We examined this association, taking insulin sensitivity into consideration, as it is related to both HRV and inflammation. Methods Subjects were 1728 individuals ages 30–79 years who did not smoke between 2009 and 2012. C-reactive protein (CRP) concentrations and white blood cell (WBC) counts were assessed as markers of inflammation. The homeostasis model assessment index for insulin resistance (HOMA-IR) and Gutt's insulin sensitivity index (ISI) were calculated based on fasting and 2h-post-load glucose and insulin concentrations in a 75-g oral glucose tolerance test. Pulse was recorded for 5 min, and time-domain HRV indices of standard deviation of NN intervals (SDNN) and root mean square of successive differences (RMSSD) were calculated. Power spectral analysis provided frequency domain measures of HRV: high frequency (HF) power, low frequency (LF) power and LF/HF. Results Sex and age-adjusted logistic models presented quartiles of SDNN, RMSSD, LF, and HF significantly associated with the highest quartile of CRP or WBC. After adjustment for body mass index and ISI, the associations were attenuated for WBC; however, even after further adjustment for several variables, SDNN, RMSSD, LF, and HF remained significantly associated with elevated CRP concentrations. When results were stratified by weight, the associations appeared more evident among non-overweight individuals. Conclusion Lowered HRV, primarily due to parasympathetic dysfunction, was associated with elevated inflammation, independent of weight, insulin sensitivity, and other related factors. [ABSTRACT FROM AUTHOR]

Background Intermittent hypoxemia is a fundamental pathophysiological consequence of sleep-disordered breathing and may alter glucose metabolism. To characterize the association between sleep-related intermittent hypoxemia and glucose metabolism, overnight pulse-oximetry and an oral glucose tolerance test were completed in a cohort of middle-aged and older Japanese adults. Methods The study sample consisted of 1836 community-dwelling Japanese (age, 30–79 years; women, 65.5%; mean body mass index, 23.1 kg/m 2 ). The oxygen desaturation index (ODI) was quantified during sleep using a ≥3% oxygen desaturation threshold and categorized as normal (<5.0 events/h), mild (5.0–15.0 events/h), and moderate to severe (≥15.0 events/h). The independent associations between the ODI and the prevalence of impaired fasting glucose, impaired glucose tolerance, diabetes, and two metrics of insulin resistance [homeostasis model assessment index for insulin resistance (HOMA-IR) and Matsuda index] were examined. Results Compared with subjects with an ODI < 5 events/h, the adjusted odds ratio for prevalent impaired fasting glucose, glucose intolerance, and diabetes for subjects with an ODI ≥15.0 events/h were 1.27 (95% confidence interval, 0.72–2.23), 1.69 (1.03–2.76), and 1.28 (0.59–2.79), respectively. Both HOMA-IR and Matsuda index were significantly associated with the severity of sleep-related intermittent hypoxemia as assessed by the ODI ( P for trend = 0.03 and 0.007, respectively). Conclusion Among middle-aged and older Japanese adults, sleep-related intermittent hypoxemia is associated with glucose intolerance and insulin resistance, and may contribute to the development of type 2 diabetes mellitus. [ABSTRACT FROM AUTHOR]

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 in the gene encoding T-cadherin (CDH13), we conducted a longitudinal study to investigate the possible link between the CDH13 genotype, plasma adiponectin levels, and all-cause mortality.Research Design and Methods: This longitudinal study evaluated 2,020 Japanese subjects. Baseline clinical parameters were obtained from subjects' personal health records as evaluated at annual medical check-ups. Plasma high-molecular weight adiponectin (HMWA) levels were measured by an ELISA assay, and genotyping was performed by a TaqMan probe assay.Results: Mean follow-up duration was 6.5 years. Kaplan-Meier analysis showed that HMWA levels were positively associated with mortality (P < 0.001). HMWA levels were associated with older age, lower body weight, lower plasma triglyceride and glucose levels, and higher plasma HDL cholesterol. However, the Cox regression analysis showed that the positive association between HMWA and all-cause mortality was independent of these covariates (hazard ratio [HR] 1.92, P = 0.006). The CDH13 rs4783244 genotype was strongly associated with baseline HMWA levels (per-allele effect size 1.65 μg/mL, P < 0.001). In a separate analysis by the CDH13 genotype, the HR for all-cause mortality was linearly increased with the number of G alleles (P value for HMWA-CDH13 genotype interaction = 0.023).Conclusions: Higher plasma HMWA level was an independent prognostic factor for all-cause mortality in a general population. The CDH13 genotype may be a factor that affects not only the plasma level of HMWA but also the prognostic significance of HMWA. [ABSTRACT FROM AUTHOR]

Type 1 diabetes is a disease characterized by destruction of pancreatic β-cells, which leads to absolute deficiency of insulin secretion. Depending on the manner of onset and progression, it is classified as fulminant, acute-onset or slowly progressive type 1 diabetes. Here, we propose the diagnostic criteria for acute-onset type 1 diabetes mellitus. Among the patients who develop ketosis or diabetic ketoacidosis within 3 months after the onset of hyperglycemic symptoms and require insulin treatment continuously after the diagnosis of diabetes, those with anti-islet autoantibodies are diagnosed with 'acute-onset type 1 diabetes mellitus (autoimmune)'. In contrast, those whose endogenous insulin secretion is exhausted (fasting serum C-peptide immunoreactivity <0.6 ng/mL) without verifiable anti-islet autoantibodies are diagnosed simply with 'acute-onset type 1 diabetes mellitus'. Patients should be reevaluated after certain periods in case their statuses of anti-islet autoantibodies and/or endogenous insulin secretory capacity are unknown. [ABSTRACT FROM AUTHOR]

BACKGROUND: Elevated hematocrit levels have been suggested to be an independent determinant of insulin resistance and type 2 diabetes. To clarify the diagnostic significance of hematocrit level, we investigated the association with hemodynamic profiles, insulin resistance and insulin sensitivity, arterial properties, and asymptomatic cerebrovascular damage in a general Japanese population. METHODS: This study included 1,978 participants from two independent cohorts. Insulin sensitivity was assessed by the oral 75 g glucose tolerance test. Carotid ultrasonography was performed to evaluate atherosclerosis and wall shear stress. Periventricular hyperintensity and lacunar infarction were assessed by brain magnetic resonance imaging. RESULTS: Hematocrit quartile showed a stepwise association with insulin sensitivity (Q1: 2.2 ± 0.7, Q2: 2.0 ± 0.7, Q3: 1.9 ± 0.7, Q4: 1.8 ± 0.6, p < 0.001) and insulin resistance (1.0 ± 0.6, 1.2 ± 0.7, 1.3 ± 0.8, 1.5 ± 1.0, p < 0.001). Multiple linear regression analysis adjusted for possible covariates identified hematocrit as an independent determinant of insulin sensitivity (β = -0.074, p = 0.019) and insulin resistance (β = 0.115, p < 0.001). However, this association was lost after further adjustment for visceral fat area and plasma alanine aminotransferase level. Further, no significant association was observed between hematocrit and carotid intima-media thickness (p = 0.306) where as wall shear stress was inversely associated with the carotid atherosclerosis (r = -0.250, p < 0.001). In contrast, a low hematocrit level was independently associated with periventricular hyperintensity (odds ratio 0.87 (95% CI 0.80-0.95), p = 0.001). CONCLUSION: Hematocrit was positively associated with insulin resistance and insulin sensitivity. This association was epiphenomenon of visceral and hepatic adiposity. Conversely, low hematocrit was a significant risk factor for periventricular hyperintensity independent of insulin resistance. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

We have revised a part of the diagnostic criteria for fulminant type 1 diabetes. The new criteria were set both to express the essence of this disease of rapid increase of patients' blood glucose and to be highly sensitive to reduce the misdiagnosis. After analyzing the data of 382 patients with newly-diagnosed fulminant type 1 diabetes, we adopted the glycated hemoglobin (HbA1c) level of 8.7% (National Glycohemoglobin Standardization Program [ NGSP] value). The new criterion indicates 100% of sensitivity and the best value by receiver operating characteristic curve analysis. In addition, we added a comment that 'This value (HbA1c <8.7% in NGSP) is not applicable for patients with previously diagnosed glucose intolerance' in the new criteria and also a comment that 'Association with human leukocyte antigen DRB1*04:05- DQB1*04:01 is reported' as a related finding. We did not revise the screening criteria and the other part of the diagnostic criteria, because they are still reliable. [ABSTRACT FROM AUTHOR]

It was recently reported that GCKR rs780094 was associated with fasting plasma glucose (FPG) and triglyceride (TG) levels in various ethnic populations (A allele for low FPG and high TG). An association between GCKR rs780094 and type 2 diabetes mellitus (T2DM) (A allele for low risk) has also been reported. We examined the association between GCKR rs780094 and T2DM in Japanese subjects by analyzing 488 cases and 398 controls. A meta-analysis was performed involving two previous association studies. We also analyzed the association between the single-nucleotide polymorphism and clinical parameters in the general Japanese population (n=1854). In the case-control study, the A allele of GCKR rs780094 was associated with a reduced risk of T2DM (odds ratio=0.711 (95% confidence interval=0.589-0.859), P=4.2 × 10−4). A meta-analysis confirmed the association of GCKR rs780094 with T2DM susceptibility. In the general Japanese population, subjects with the A/A genotype had lower levels of FPG, fasting plasma insulin and homeostasis model assessment of insulin resistance than those with the G/G genotype. Conversely, subjects with the A/A genotype had higher levels of TG than those with the G/G genotype. We replicated GCKR rs780094 as a marker of T2DM susceptibility in Japanese subjects. This suggests that GCKR rs780094 is a common variant for T2DM susceptibility in various ethnic groups. [ABSTRACT FROM AUTHOR]