We carried out a multistage genome-wide association study of type 2 diabetes mellitus in Japanese individuals, with a total of 1,612 cases and 1,424 controls and 100,000 SNPs. The most significant association was obtained with SNPs in KCNQ1, and dense mapping within the gene revealed that rs2237892 in intron 15 showed the lowest Pvalue (6.7 x 10(-13), odds ratio (OR) = 1.49). The association of KCNQ1 with type 2 diabetes was replicated in populations of Korean, Chinese and European ancestry as well as in two independent Japanese populations, and meta-analysis with a total of 19,930 individuals (9,569 cases and 10,361 controls) yielded a P value of 1.7 x 10(-42) (OR = 1.40; 95% CI = 1.34-1.47) for rs2237892. Among control subjects, the risk allele of this polymorphism was associated with impairment of insulin secretion according to the homeostasis model assessment of beta-cell function or the corrected insulin response. Our data thus implicate KCNQ1 as a diabetes susceptibility gene in groups of different ancestries.

OBJECTIVE -To describe the clinical and immunologic characteristics of fulminant type 1 diabetes, a novel subtype of type 1 diabetes, we conducted a nationwide survey.RESEARCH DESIGN AND METHODS -History and laboratory data, including isletrelated autoantibodies, were examined in 222 patients with fulminant and nonfulminant type 1 diabetes in our hospitals in addition to another 118 patients with fulminant type 1 diabetes located outside our hospitals in Japan.RESULTS -In our hospitals, of the 222 patients studied, 43 (19.4%) were diagnosed with fulminant type 1 diabetes, 137 (61.7%) were classified as having autoimmune type 1 diabetes, and 42 were type 1 diabetic subjects who were not fulminant and did not have anti-islet antibodies. An additional 118 fulminant patients outside our hospitals were enrolled, making a total of 161 fulminant type 1 diabetic subjects (83 male and 78 female subjects; 14 children/ adolescents and 147 adults) identified from all over Japan. (In 2000, the average incidence was three cases per month.) Flu-like symptoms and pregnancy were more frequently observed in the fulminant than in the autoimmune group (P Ͻ 0.001). In the fulminant patients, 4.8% were positive for anti-GAD antibodies and none were positive for anti-islet antigen 2 antibodies.CONCLUSIONS -Fulminant type 1 diabetes is a distinct subtype and accounts for ϳ20% of the ketosis-onset type 1 diabetes cases in Japan. Flu-like symptoms are characteristic of disease onset. Metabolic derangement is more severe in this subtype than in autoimmune type 1 diabetes. Diabetes Care 26:2345-2352, 2003T ype 1 (insulin-dependent) diabetes is characterized by insulin deficiency from the destruction of pancreatic ␤-cells. According to the recently proposed classification of diabetes by the American Diabetes Association (ADA) and the World Health Organization (WHO), type 1 diabetes is divided into two subtypes: autoimmune type 1 (immune-mediated; type 1A) diabetes and idiopathic (type 1B) diabetes (1,2).Since 1974, when Bottazzo et al. (3) reported the presence of islet cell antibodies (ICAs) in the sera of type 1 diabetic patients, several autoantibodies to pancreatic islet cells have been recognized as a marker of type 1 diabetes. These isletrelated autoantibodies are anti-GAD antibodies (GADAb), insulin autoantibodies (IAA), and anti-islet antigen 2 (IA-2)/ IA-2␤ antibodies (4,5).However, type 1 diabetic patients are not always positive for these autoantibodies, even at the onset of overt diabetes (6,7). Patients with type 1 diabetes who do not have islet autoantibodies at the time of diagnosis are classified as having idiopathic or type 1B diabetes. In Japan, several cases have been reported in which islet-related autoantibodies were negative and the onset of diabetes was acute (8 -12). Imagawa and colleagues (13,14) have proposed that these cases are "nonautoimmune fulminant" type 1 diabetes. The clinical characteristics of this subtype of type 1 diabetes are 1) remarkably abrupt onset of disease; 2) very short (Ͻ1 week) duration of di...

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 (Retn) in adipose tissue are insulin-resistant, whereas Retn (-/-) 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 Sp1/3 increases RETN promoter activity, leading to enhanced serum resistin levels, thereby inducing human T2DM.

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 (HbA 1c ) 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 (HbA 1c <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. (J Diabetes Invest

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 Ϫ420 increases type 2 diabetes susceptibility by enhancing promoter activity. We report here on the relation between plasma resistin and either SNP Ϫ420 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 Ϫ420 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 Ϫ420 genotype (P Ͻ 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 Ͻ 0.001, 0.003, Ͻ0.001, 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 Ͻ 0.001, 0.003, Ͻ0.001, 0.004, Ͻ0.001, 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 ϭ 0.001, Ͻ0.001, and 0.006, respectively).CONCLUSIONS -Plasma resistin was associated with SNP Ϫ420 and was correlated with insulin resistance, low serum HDL cholesterol, and high hs-CRP in the Japanese general population.

These data suggest that HLA associations with fulminant type 1 diabetes are qualitatively different from those with other subtypes of type 1 diabetes, whereas the HLA contribution to slowly progressive type 1 diabetes is qualitatively similar to, but quantitatively different from, that in acute-onset type 1 diabetes.

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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.