Subtyping of Type 1 Diabetes as Classified by Anti-GAD Antibody, IgE Levels, and Tyrosine kinase 2 (TYK2) Promoter Variant in the Japanese.

OBJECTIVE: Type 1 diabetes (T1D) is known to be caused by Th1 cell-dependent autoimmunity. Recently, we reported that TYK2 promoter variant serves as a putative virus-induced diabetes susceptibility gene associated with deteriorated interferon-dependent antiviral response. TYK2 is also related to HIES, that is, Th2 cell-dependent. Therefore, TYK2 promoter variant may be also associated with the pathogenesis of T1D, modulating Th1/Th2 balance. RESEARCH DESIGN AND METHODS: We assessed the association between anti- GAD Ab, IgE levels, and TYK2 promoter variant among 313 T1D patients, 184 T2D patients, and 264 YH controls in the Japanese. RESULTS: T1D patients had elevated IgE (median, 56.7U/ml; p<0.0001) compared with T2D patients (22.5U/ml) and controls (43.3U/ml). Contrary to our expectations, there was no correlation between TYK2 promoter variant and IgE levels. We found that T1D could be subtyped as four groups based on anti-GAD Ab and IgE profile: Subtype 1, anti-GAD Ab positive and non-elevated IgE (47.0%); Subtype 2, anti-GAD Ab negative and non-elevated IgE (35.1%); Subtype 3, anti-GAD Ab positive and elevated IgE (10.9%); and Subtype 4, anti-GAD Ab negative and elevated IgE (7.0%). In Subtype 2, a significantly higher incidence was observed in T1D cases carrying the TYK2 promoter variant (OR, 2.60; 95%CI, 1.03-6.97; p=0.032), and also showing a flu-like syndrome at diabetes onset (OR, 2.34; 95%CI, 1.27-4.35; p=0.003). INTERPRETATION: Anti-GAD Ab and IgE profiling helps classifying T1D into four groups that recognize variable pathogenic bases of T1D.

TYK2 Promoter Variant and Diabetes Mellitus in the Japanese.

BACKGROUND: Recently, natural mutation of Tyrosine kinase 2 (Tyk2) gene has been shown to determine susceptibility to murine virus-induced diabetes. In addition, a previous human genome-wide study suggested the type 1 diabetes (T1D) susceptibility region to be 19p13, where the human TYK2 gene is located (19p13.2). METHODS: Polymorphisms of TYK2 gene at the promoter region and exons were studied among 331 healthy controls, and 302 patients with T1D and 314 with type 2 diabetes (T2D) in the Japanese. FINDINGS: A TYK2 promoter haplotype with multiple genetic polymorphisms, which are in complete linkage disequilibrium, named TYK2 promoter variant, presenting decreased promoter activity, is associated with an increased risk of not only T1D (odds ratio (OR), 2.4; 95% confidence interval (CI), 1.2 to 4.6; P = 0.01), but also T2D (OR, 2.1; 95% CI, 1.1 to 4.1; P = 0.03). The risk is high in patients with T1D associated with flu-like syndrome at diabetes onset and also those without anti-glutamic acid decarboxylase autoantibody. INTERPRETATION: The TYK2 promoter variant is associated with an overall risk for diabetes, serving a good candidate as a virus-induced diabetes susceptibility gene in humans. FUNDING: Ministry of Education, Culture, Sports, Science and Technology and of Health, Labor and Welfare of Japan.

A prospective pancreatographic study of the prevalence of pancreatic carcinoma in patients with diabetes mellitus.

BACKGROUND: The correlation between diabetes mellitus and pancreatic carcinoma is well documented, but no criteria have been established for the efficient selection of a high-risk group among patients with diabetes mellitus. METHODS: Eighty-seven patients were selected prospectively from outpatients with diabetes and underwent endoscopic retrograde pancreatography (ERP) according to the authors' original criteria, including the onset of diabetes after age 55 years, deterioration of diabetes or loss of body weight despite strict medical control, elevation of serum amylase and/or CA19-9 levels, and pancreatobiliary abnormalities on routine ultrasonography. The patients were divided into two groups according to the time from the onset of diabetes to ERP: Patients in Group A had recent-onset diabetes (within 3 years), and Group B patients had diabetes for > 3 years. RESULTS: A total of 86 patients (excluding 1 patient with unsuccessful ERP who had undergone previous Billroth-2 gastrectomy) were enrolled. There were 33 males and 53 females, age 40-90 years, with a mean age of 65.1 years. ERP demonstrated pancreatic carcinoma, although it was advanced disease in all patients, at an extremely high rate of 7.0% (6 of 86 patients) with no serious complications. The prevalence of pancreatic carcinoma in Group A (13.9%; 5 of 36 patients) was significantly greater compared with Group B (2.0%; 1 of 50 patients; P = 0.0442). ERP with an indwelling balloon catheter and subsequent pancreatic juice sampling was performed in 49 patients, yielding positive cytology in 1 patient with pancreatic tail carcinoma, whereas measurements of carcinoembryonic antigen and CA19-9 levels in pancreatic juice were of no use in the diagnosis of pancreatic carcinoma. CONCLUSIONS: Selective ERP in patients with diabetes who were at high risk did not lead to the early diagnosis of pancreatic carcinoma, although this study showed that the 3-year period after the onset of diabetes was critical. A more aggressive diagnostic approach within this period in diabetic patients with the authors' criteria may contribute to the earlier diagnosis of pancreatic carcinoma.