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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, 56.7 U/ml; p, Highlights • T1D can be subtyped into 4 groups based on anti-GAD Ab, IgE levels and TYK2 promoter variant. • Only one subtype, without anti-GAD Ab or elevated IgE, was associated with TYK2 promoter variant and flu-like syndrome. • Profiling of T1D by anti-GAD Ab and IgE levels is useful to realize the variable immuno-pathogenesis of T1D. Since TYK2 gene is associated with T1D and HIES, we assessed the association between anti-GAD Ab, IgE levels, and TYK2 promoter variant in patients with T1D. Consequently, T1D can be subtyped into 4 distinct groups based on these clinical laboratory and genetic markers. Only those patients without anti-GAD Ab or elevated IgE were associated with TYK2 promoter variant and with flu-like syndrome at the diabetes onset, suggestive of association with virus-induced diabetes. This study describes the usefulness of subtyping of T1D with variable immunological bases and provides a clue to delineate the pathogenesis of T1D.

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., Highlights • TYK2 promoter variant with multiple polymorphisms was identified in the Japanese. • TYK2 promoter variant is associated with an increased risk of both type 1 and type 2 diabetes. • TYK2 promoter variant serves a good candidate as a virus-induced diabetes susceptibility gene in humans.

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%; 5of 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. Cancer 2002;94:2344–9. © 2002 American Cancer Society. DOI 10.1002/cncr.10493

A 45-year-old woman with chronic hepatitis B underwent partial hepatectomy for hepatocellular carcinoma (HCC). However, the HCC recurred 2 months after surgery and rapid progression of the disease resulted in her death. Immunohistochemistry showed that transforming growth factor-alpha (TGFalpha) was barely expressed in the liver specimens obtained at hepatic resection, whereas autopsy specimens were strongly stained with anti-TGFalpha antibody in the cytoplasm of both non-tumourous and tumourous liver cells. A higher level of Ki67 expression, a proliferating marker, was observed in the recurrent HCC, similar to that of TGFalpha. Thus, we speculate that the partial hepatectomy increased the level of TGFalpha leading to recurrence and progression of HCC through an autocrine/paracrine mechanism.

We studied the long-term change in blood pressures of spontaneously hypertensive rats (SHR) treated neonatally with streptozotocin (STZ). Two-day-old male SHR were injected intraperitoneally with 37.5-75.0 mg/kg STZ or with vehicle as control. STZ-treated SHR were divided into mildly or severely diabetic groups according to the nonfasting plasma glucose level at age 12 weeks (the former less than 300 mg/dl, the latter greater than or equal to 300 mg/dl). In the mildly diabetic group (MD) (n = 5), body weight increased and nonfasting plasma glucose was normalized. At 52 weeks of age, fasting plasma glucose levels were lower than controls owing to hyperinsulinemia, and insulinomas were found in 60% of rats. The systolic blood pressure (SBP) as measured by a tail-cuff method, decreased after 40 weeks, and the mean BP from 44 to 52 weeks (188 +/- 4 mmHg) was significantly lower than that in the control group (209 +/- 3 mmHg, p less than 0.01). In the severely diabetic group (SD) (n = 6), hyperglycemia persisted until 52 weeks, although its severity became less marked. BP in the SD group increased after 36 weeks, and the mean BP from 44 weeks to 52 weeks (224 +/- 5 mmHg) was significantly higher than control (p less than 0.05). The present study demonstrated that hypertension was ameliorated in SHR associated with hyperinsulinemia, and deteriorated with long-standing diabetes mellitus.

The protective effect of phosphate binder (PB) on nephropathy was examined in spontaneously hypertensive rats with non-insulin-dependent diabetes mellitus (NIDDM) fed a high-protein diet. The rats were treated with vehicle or streptozocin neonatally. After 14 weeks, all rats were fed a high-protein diet (50% protein content), and in half of the diabetic rats the diets were supplemented with PB. At 24 weeks, the urinary excretion rate of albumin and kidney weight increased in diabetic rats, but decreased or tended to decrease in diabetic rats treated with PB. The elevation of urinary excretion rate of N -acetyl-β-d-glucosaminidase, probably due to protein load, was also abolished with PB.

We studied the age-related changes of glucose tolerance in female spontaneously hypertensive rats (SHR) that did not become obese with aging. Oral glucose tolerance test was performed in young (3 months), middle-aged (6 to 11 months), and aged (26 months) SHR. Fasting plasma glucose was significantly lower in aged SHR than in young SHR. The increase in plasma glucose after glucose administration over fasting level was significantly higher in aged SHR than in middle-aged SHR, but did not differ between young and aged rats. Pancreatic islet size and pancreatic immunoreactive insulin content were similar between young and aged SHR. The present study demonstrated that glucose tolerance did not deteriorate in SHR with aging, while genetic hypertension persisted. This suggests that the persistence of hypertension per se may not affect glucose tolerance in SHR.

To investigate the hypothesis that insulin affects the regulation of blood pressure, blood pressure and fasting insulin and glucose levels were measured in seven patients with insulinoma both before and after resection of the insulinoma. The diagnosis of all insulinoma cases was confirmed during surgery. Before surgery, systolic and diastolic blood pressures were 127 +/- 15 and 74 +/- 9 mmHg, respectively, and did not correlate with the fasting insulin levels. At least 3 weeks after the surgery, significant decreases in fasting insulin levels (from 568 +/- 571 to 74 +/- 43 pmol/l, P less than 0.005) and body weight (-9.8 +/- 7.1%, P less than 0.05) were observed along with a significant increase in fasting glucose levels (98.2 +/- 43.2%, P less than 0.001). However, both systolic (-4.7 +/- 9.9%) and diastolic (-0.2 +/- 6.3%) blood pressures remained unchanged. The changes in fasting insulin levels were not linearly correlated with those in systolic and diastolic blood pressures. Even after the changes in both body weight and fasting glucose levels were taken into consideration using partial correlations, the changes in fasting insulin levels did not correlate with those in systolic and diastolic blood pressures. It was concluded that blood pressure, both systolic and diastolic, was not at hypertensive levels in the patients with insulinoma and showed no decrease after resection of the insulinoma. Therefore, insulin may not affect the regulation of blood pressure in patients with insulinoma.

We examined the prevalence of orthostatic hypotension and its association with glycemic control, as assessed by hemoglobin A1 (HbA1) concentration, in type 2 diabetic patients. The prevalence of orthostatic hypotension in 886 diabetics who were referred to our study and in 587 diabetics who were not given any antihypertensive drugs was 7% and 6%, respectively. The relationship between orthostatic hypotension and HbA1 levels was evaluated only in subjects not receiving antihypertensive drugs, since antihypertensive agents might induce orthostatic hypotension. HbA1 levels were 11.0 +/- 2.1% in the diabetic patients with orthostatic hypotension, which was significantly higher than the HbA1 levels of 9.9 +/- 2.2% in the diabetic patients without orthostatic hypotension. Multivariate analysis also revealed that the association remained significant after adjustment for the treatment and duration of diabetes, age, sex and body mass index. These findings suggest that glycemic control contributes to the development of orthostatic hypotension in type 2 diabetic patients.

The prevalences and risk factors of micro- and macroalbuminuria were surveyed in all 927 patients with diabetes mellitus who visited outpatient clinics in 27 hospitals in the Fukuoka prefecture on a designated day. The urinary albumin-creatinine ratio (UAI; mg/g Cr) of spot urine was determined in all patients except those with persistent macroproteinuria. The results were as follows: (1) The prevalences of microalbuminuria (UAI 30–299) and macroalbuminuria (UAI ≥ 300) were 26% and 15%, respectively. (2) Hyperglycemia and high blood pressure synergistically increased the prevalences. (3) The independent risk factors of microalbuminuria were severities of retinopathy and neuropathy, duration of diabetes, blood pressure, and HbA 1c , as determined by logistic regression analysis, although the explanation rate was low.

Plasma glucose levels in 50 g oral glucose tolerance test (OGTT) were compared between uncomplicated hypertensives ( n = 507, mean age = 48 ± 0.3 years) and normotensives ( n = 378, mean age = 46 ± 0.3 years). The subjects were selected in a systematic way from 10,120 male employees in a work-site population in Japan. None of hypertensives took any antihypertensive drugs. Plasma glucose levels at each time point of OGTT were significantly higher in the hypertensives than in the normotensives when the differences in age, obesity, and other factors that might influence glucose metabolism were adjusted, using multiple linear regression analysis. Similarly, multiple regression analysis for subjects including both normotensives and hypertensives revealed a significant relationship between plasma glucose levels and blood pressure, which was independent of age and body mass index. These findings indicate a more direct association between hypertension and hyperglycemia, which is not mediated via aging or obesity.

Hypertensives screened among a work-site male population were treated either with or without antihypertensive drugs according to WHO stage of hypertension, and followed up by medical teams at the work site. The outcome during 8 years of follow-up was compared between two hypertension cohorts; one (cohort 1) instituted in 1970 included 1,092 hypertensives from 11,860 employees, while the other (cohort 2) made in 1975 contained 1,190 from 10,789 persons. Age-adjusted mortality or morbidity rate from cardiovascular diseases (CVD) was lower in cohort 2 than in cohort 1. Multiple regression analysis was used to adjust inter-cohort differences in factors to influence the prognosis, showed that CVD occurred less frequently in cohort 2 than in cohort 1. The results suggest that this system of controlling blood pressure is useful in preventing CVD in a large population.

最近2年間に経験した脳卒中合併の原発性アルドステロン症(PA) 3例と特発性アルドステロン症(IHA) 1例を報告した.全例男で年令は26才から64才,高血圧歴は7年から20年,脳梗塞と脳出血がそれぞれ2例であった. PAの1例は多発性脳梗塞のため未だ外科的治療を行なわず,スピロノラクトンで治療した.副腎腺腫を摘出した2例では低K血症は是正されたが,血圧は正常域までは低下せず,少量の降圧薬を必要とした. IHAの1例は19才と25才時に脳出血を発症,既に副腎の3/4が摘出されていたが,なお低K血症を伴う著しい高血圧がある.摘出副腎は球状層のびまん性過形成を示した. PAおよびIHAにおいても高血圧が長期間持続すれば,脳血管障害が発症する.

We compared the levels of fasting plasma glucose (FPG) and glycosylated hemoglobin (HbA1) in non-insulin-dependent diabetics with hypertension who were treated with monotherapy of diuretics or other antihypertensive drugs (AHD) and in those who were not given any AHD. Total 162 patients were divided into the four groups; the control group without AHD (n = 45), the diuretics group (n = 42), the beta-blocker group (n = 30) and the Ca-antagonist group (n = 45). FPG and HbA1 levels were 153 +/- 44 mg/dl and 10.0 +/- 2.3% for the control group, 145 +/- 55 mg/dl and 9.8 +/- 2.2% for the diuretics, 165 +/- 63 mg/dl and 10.2 +/- 2.1% for the beta-blocker and 158 +/- 42 mg/dl and 10.4 +/- 2.0% for the Ca-antagonist, respectively. There were no significant differences in the levels of FPG and HbA1 among the four groups. Multivariate analysis also revealed no difference in glycemic control even when anti-diabetic treatment (diet alone, oral hypoglycemic agents or insulin), body mass index, serum potassium, systolic and diastolic blood pressures and age were taken into account. Blood pressure levels did not differ among the groups except control and they were well controlled at the low doses of AHD. Our results suggest that the choice of low dose diuretics for the treatment of hypertension in non-insulin-dependent diabetics might not be necessarily excluded by the only reason of the possible deleterious influence on glycemic control.

We compared the glucose tolerance and insulin responses to intravenous (IV) glucose administration of a dose of 1 g/kg body weight in a conscious and unrestrained state of spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) with catheters chronically indwelled into artery and vein. Both plasma glucose levels at two minutes and ten minutes following IV glucose load as well as the incremental and total areas of plasma glucose were slightly but significantly lower in SHR than in WKY. Glucose disappearance rate (K value) was 7.7 ± 0.3%/min in SHR, being slightly but significantly higher than that of 6.8 ± 0.3%/min in WKY. On the other hand, insulin responses to the glucose load at ten minutes and 30 minutes as well as incremental and total insulin areas were significantly lower in SHR than in WKY. There was no significant difference in insulinogenic index between SHR and WKY. Our observations suggest that in a conscious and unrestrained state, SHR have the greater glucose tolerance associated with reduced insulin secretion than do WKY.