Nobutaka Tsutsu

Lack of association between blood pressure and insulin in patients with insulinoma

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.

Glucose tolerance and insulin secretion in conscious and unrestrained normotensive and spontaneously hypertensive rats.

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.

Relationship between glycemic control and orthostatic hypotension in type 2 diabetes mellitus — a survey by the Fukuoka Diabetes Clinic Group

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.

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.

Glucose tolerance in middle-aged Japanese males with uncomplicated hypertension

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.

EFFECT OF AGING ON GLUCOSE TOLERANCE IN SPONTANEOUSLY HYPERTENSIVE RATS

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.

One-day survey of albuminuria in diabetic outpatients in Fukuoka prefecture, Japan

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 greater than or equal to 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 HbA1c, as determined by logistic regression analysis, although the explanation rate was low.

Blood pressure changes associated with hyperinsulinemia or long-standing diabetes mellitus in spontaneously hypertensive rats

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.

Diuretics and Other Antihypertensive Drugs and Glycemic Control in Non-Insulin-Dependent Diabetics with Hypertension A Survey By the Fukuoka Diabetes Clinic Group

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.

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, 56.7 U/ml; p < 0.0001) compared with T2D patients (22.5 U/ml) and controls (43.3 U/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.