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.

Angiotensin II type 1 receptor antagonists prevent glucose-induced increases in islet blood flow in rats.

OBJECTIVE: Renin-angiotensin system inhibitors are reported to be beneficial in delaying the onset of diabetes mellitus. Since islet blood hyperperfusion during hyperglycaemia may be detrimental to endothelium in pancreatic islets and eventually lead to beta-cell dysfunction, we studied acute and chronic effects of angiotensin II type 1 receptor blockers (ARB) on islet blood flow before and after glucose load. MATERIAL AND METHODS: Islet blood flow was measured using the colour microsphere method in anaesthetized Sprague-Dawley rats before and 3 min after glucose injection. RESULTS: Olmesartan significantly reduced blood pressure, but did not affect islet blood flow 10 min after its injection. However, pretreatment with olmesartan blunted the glucose-induced increase in islet blood flow (62% of control). In rats treated with olmesartan or candesartan for 4 weeks, islet blood flow was not different from untreated control, whereas the glucose-induced increase in islet blood flow was significantly suppressed in chronically ARB-treated rats (olmesartan 59% of control, candesartan 64% of control, respectively). Acute or chronic treatment with ARB did not change insulin secretion before and in response to glucose load. Pancreatic or duodenal blood flow was not affected by ARB treatment, although acute olmesartan administration reduced pancreatic blood flow after glucose load. CONCLUSION: ARB appears to suppress the hyperglycaemia-induced islet hyperperfusion, which may ameliorate haemodynamic stress in pancreatic islets.

Overt diabetes mellitus in a patient with combined primary aldosteronism and Cushing's syndrome.

Although there are some case reports of combined aldosterone and cortisol producing adrenal tumor, overt diabetes mellitus has been rarely described. A 55-year-old hypertensive woman had hypokalemia and overt hyperglycemia without Cushingoid clinical features. The body mass index was 18.2 kg/m2, fasting blood glucose was 302 mg/dl and hemoglobin A1c was 11.6%. Endogenous insulin secretion was well preserved, whereas insulin sensitivity measured by short insulin tolerance test was markedly impaired. A solitary left aldosterone- and cortisol-producing adrenal tumor was diagnosed. We described a rare case of overt diabetes mellitus in a patient with combined primary aldosteronism and Cushing's syndrome.

Gastric emptying in patients with Type 2 diabetes mellitus and diabetes associated with mitochondrial DNA 3243 mutation using 13C-octanoic acid breath test.

Although the (13)C-octanoic acid breath test (OBT) has been applied to diabetic patients for assessing gastric emptying, such studies are still limited. Gastric emptying was measured using solid meal containing (13)C-octanoic acid in 52 patients with Type 2 diabetes mellitus and 4 diabetic patients with mitochondrial DNA (mitDNA) 3243 mutation. Delayed gastric emptying was detected in 29% of patients with Type 2 diabetes mellitus, and multiple regression analysis showed that gastric emptying was independently associated with gastrointestinal symptoms and cardiac autonomic neuropathy. Gastric emptying was not related to gastric dysrhythmia in cutaneous electrogastrography (EGG). Diabetic patients with mitDNA 3243 mutation showed delayed gastric emptying. Because the pathogenesis of delayed gastric emptying is multifactorial in diabetic patients, the recently developed OBT is useful for studying gastric emptying in various clinical settings of diabetic patients.

Nateglinide, a non-sulfonylurea rapid insulin secretagogue, increases pancreatic islet blood flow in rats.

We studied whether the rapid hypoglycemic action of nateglinide is associated with an increase in islet blood flow. Islet blood flow was measured using the two-colour microsphere method. Orally administered nateglinide with glucose acutely increased islet blood flow to levels greater than those after glucose alone or tolbutamide with glucose in conscious Sprague-Dawley rats (percent increase at 10 min after oral administration; nateglinide+glucose, 125+/-25%; glucose, 33+/-11%, p<0.001; tolbutamide+glucose, 42+/-23%, p<0.01). Nateglinide administered with non-metabolisable 3-O-methylglucose also increased islet blood flow (61+/-17%). The stimulated islet blood flow significantly correlated with serum insulin levels. N(G)-monomethyl-L-arginine, a nitric oxide synthase inhibitor, completely inhibited the increase in islet blood flow induced by nateglinide with glucose. Intravenously administered nateglinide did not significantly affect the already increased islet blood flow in diabetic Otsuka Long-Evans Tokushima Fatty rats. Our results indicated that nateglinide acutely increased islet blood flow at least in part through a nitric oxide-dependent mechanism.

Effect of exogenous cholecystokinin on islet blood flow in anesthetized rats.

Although a number of studies have investigated the effect of cholecystokinin (CCK) on pancreatic blood flow and exocrine function, few have addressed the effect of CCK on islet blood flow. Here, we studied the effect of exogenous CCK on islet blood flow in anesthetized rats. Islet blood flow was measured by the color microsphere method. Bolus intravenous administration of CCK (10 microg/kg) significantly increased pancreatic and islet blood flow in control Long-Evans Tokushima Otsuka (LETO) rats, but not in Otsuka Long-Evans Tokushima Fatty (OLETF) rats lacking CCK-A receptors. Since fractional islet blood flow expressed as a percentage of whole pancreatic blood flow was decreased after CCK administration in LETO rats, the vasodilating effect of CCK appeared to be stronger in exocrine than endocrine tissue. Although vagotomy failed to alter the CCK-induced increase in pancreatic and islet blood flow, pretreatment with nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine completely prevented the increase in pancreatic and islet blood flow. Our results demonstrated that exogenous CCK is a potent vasodilator of exocrine as well as islet vasculature via CCK-A receptors, and that such action is mediated by a NO-dependent mechanism rather than by vagal mechanisms.

Usefulness of brachial-ankle pulse wave velocity measurement: correlation with abdominal aortic calcification.

At present, brachial-ankle pulse wave velocity (baPWV) can be measured easily and noninvasively. We studied the correlation between aortic damage estimated by baPWV and that determined by measuring the length of abdominal aortic calcification (AAC) on X-ray films, which parameter has been significantly associated with cardiovascular morbidity and mortality. baPWV was measured using the form PWV/ankle brachial index (ABI) device in 97 patients free of end-stage renal failure or peripheral arterial disease. baPWV correlated significantly with age (r2=0.625, p<0.0001), was significantly higher in hypertensives than in normotensives (2,109+/-67 vs. 1,623+/-93 cm/s, p<0.0001), and correlated significantly with systolic blood pressure (r2=0.64, p<0.0001) and diastolic blood pressure (r2=0.397, p<0.0001). baPWV was significantly higher in diabetic patients than in nondiabetics (2,068+/-73 vs. 1,813+/-97 cm/s, p<0.05), but was similar in normolipidemic and hyperlipidemic patients. baPWV did not correlate with body mass index, fasting plasma glucose, total cholesterol, high density lipoprotein (HDL)-cholesterol, low density lipoprotein (LDL)-cholesterol or triglyceride levels, but correlated significantly with AAC length (r2=0.599, p<0.0001). Multiple regression analysis indicated that age, systolic blood pressure and AAC length were independent determinants of baPWV. Our results indicate that baPWV is useful for estimating aortic damage and could be a potentially useful predictor of vascular morbidity and mortality.