Molecular Mechanism and its Clinical Significance of Abnormalities in Voltage-Sensitive Calcium Channel in the Diabetic Heart.

科学研究費補助金研究成果報告書研究種目: 一般研究(C)研究期間: 1989～1990課題番号: 01570357研究代表者: 柏木 厚典（滋賀医科大学・医学部・講師

Molecular Mechanisms of Vascular Oxidative Stress in the Insulin Resistant State

科学研究費補助金研究成果報告書研究種目: 基盤研究(C)研究期間: 2000～2001課題番号: 12671108研究代表者: 柏木 厚典（滋賀医科大学・医学部・教授

Vascular biological analysis of risk factors for atherogenesis in diabetes - oxidative stress and hyperinsulinemia -

科学研究費補助金研究成果報告書研究種目: 基盤研究(C)研究期間: 1995～1996課題番号: 07671127研究代表者: 柏木 厚典（滋賀医科大学・医学部・助教授

Abnormality in molecular mechanism of cardiac -adrenergic signalling system and its usefulness in diabetes mellitus.

科学研究費補助金研究成果報告書研究種目: 一般研究(C)研究期間: 1987～1988課題番号: 62570284研究代表者: 柏木 厚典（滋賀医科大学・医学部・講師

Serum Concentrations of Trace Elements in Patients with Crohn’s Disease Receiving Enteral Nutrition

We investigated the trace element status in Crohn’s disease (CD) patients receiving enteral nutrition, and evaluated the effects of trace element-rich supplementation. Thirty-one patients with CD were enrolled in this study. All patients were placed on an enteral nutrition regimen with Elental® (Ajinomoto pharmaceutical. Ltd., Tokyo, Japan). Serum selenium, zinc and copper concentrations were determined by atomic absorption spectroscopy. Serum selenoprotein P levels were determined by an ELISA system. Average serum levels of albumin, selenium, zinc and copper were 4.1 ± 0.4 g/dl, 11.2 ± 2.8 µg/dl, 71.0 ± 14.8 µg/dl, and 112.0 ± 25.6 µg/dl, respectively. In 9 patients of 31 CD patients, serum albumin levels were lower than the lower limit of the normal range. Serum selenium, zinc and copper levels were lower than lower limits in 12 patients, 9 patients and 1 patient, respectively. Serum selenium levels significantly correlated with both serum selenoprotein P levels and glutathione peroxidase activity. Supplementation of selenium (100 µg/day) and zinc (10 mg/day) for 2 months significantly improved the trace element status in CD patients. In conclusion, serum selenium and zinc levels are lower in many CD patients on long-term enteral nutrition. In these patients, supplementation of selenium and zinc was effective in improving the trace element status

Hyperglycemia and atherosclerosis : Radical scavenger dysfunction and abnormal gene expression in endothelial cells

科学研究費補助金研究成果報告書研究種目: 一般研究(C)研究期間: 1993～1994課題番号: 05670854研究代表者: 柏木 厚典（滋賀医科大学・医学部・講師）研究分担者: 前川 聡（滋賀医科大学・医学部・助手

MafA differentiates rat intestinal cells into insulin-producing cells.

科学研究費補助金研究成果報告書研究種目: 基盤研究(C)研究期間: 2004～2005課題番号: 16590143研究代表者: 中村 高秋（滋賀医科大学・医学部・助手）研究分担者: 柏木 厚典（滋賀医科大学・医学部・教授）研究分担者: 工藤 基（滋賀医科大学・医学部・教授

Elucidation of the mechanism for the activation of transcription factors and gene response in the aorta of the postprandial state ofrata

科学研究費補助金研究成果報告書研究種目: 基盤研究(B)研究期間: 2005～2007課題番号: 17390262研究代表者: 柏木 厚典（滋賀医科大学・医学部・教授）研究分担者: 前川 聡（滋賀医科大学・医学部・准教授）研究分担者: 西尾 善彦（滋賀医科大学・医学部・講師

Sodium-glucose cotransporter 2 inhibitors represent a paradigm shift in the prevention of heart failure in type 2 diabetes patients.

Recent major clinical trials of the use of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with type 2 diabetes have shown that they reduce three-point major adverse cardiovascular events, cardiovascular death, hospitalization for heart failure (HF) and a composite renal outcome. These beneficial effects of SGLT2 inhibitors are also evident in type 2 diabetes patients with a previous history of atherosclerotic cardiovascular disease or advanced renal disease. HF is a major determinant of the prognosis of diabetes patients. Although HF with low ejection fraction can be effectively treated with antihypertensive drugs, these treatments do not reduce mortality in HF patients with preserved ejection fraction (HFpEF). HFpEF is clinically characterized by left ventricular diastolic dysfunction, perivascular fibrosis and stiffness of cardiomyocytes, defined as "cardiomyopathy". Therefore, HFpEF is considered to be an entirely separate entity to HF with low ejection fraction. Recent studies have suggested that HFpEF might be treatable using SGLT2 inhibitors, which ameliorate visceral adiposity, insulin resistance, hyperglycemia, hyperlipidemia, volume overload, hypertension and cardiac inflammation. In the final part of the present review, we discuss the biochemical and molecular mechanisms of the effects of SGLT2 inhibitors in type 2 diabetes patients with HFpEF. These involve amelioration of the low nitric oxide production and oxidative stress, a reduction in cardiac inflammatory cytokine signaling, inhibition of Ca2+ overload, and an improvement in cardiac energy metabolism as a result of ketone body production. Investigations of the beneficial effects of SGLT2 inhibitors on cardiorenal outcomes, including hospitalization for HF, are now being carried out in preclinical and clinical studies

Cardiovascular events in Japanese asymptomatic patients with type 2 diabetes: a 1-year interim report of a J-ACCESS 2 investigation using myocardial perfusion imaging

金沢大学医薬保健研究域医学系Purpose Diabetic patients have a high risk for cardiovascular events. The role of myocardial perfusion imaging was investigated in asymptomatic diabetic patients to evaluate short-term prognosis in a Japanese population. Methods A total of 506 asymptomatic patients ≥50 years of age who had carotid artery maximum intima-media thickness ≥1.1 mm, urinary albumin excretion of ≥30 mg/g creatinine, with additional criteria of abdominal obesity, low HDL cholesterol, high triglyceride level, and hypertension were enrolled and followed up over a 3-year period. Gated SPECT with stress-rest protocol was performed and analyzed by summed defect scores and QGS software. One-year cardiovascular events were analyzed. Results Myocardial ischemia was observed in 17% of patients, and abnormal perfusion findings of ischemia and/or scar were observed in 32% of patients. By the end of the 1-year follow-up, 33 (6.5%) cardiovascular events occurred including 6 all-cause deaths. Patients with summed stress score (SSS) >8 had a higher incidence of either death or cardiovascular events. Event-free survival rates for SSS 0–3, 4–8, 9–13, and ≥14 were 0.96, 0.95, 0.82, and 0.76, respectively. Multivariate Cox regression analysis showed that significant variables were SSS, history of cerebrovascular accident, and electrocardiographic abnormality at rest. Conclusion The 1-year interim summary showed that cardiovascular events were significantly higher in patients with SPECT abnormality, although hard cardiac event rate was relatively low. Targeted treatment strategy is required for asymptomatic but potentially high-risk diabetic patients