アディポネクチン様作用を有する分子の探索と抗糖尿病作用メカニズムの解析

学位の種別: 課程博士審査委員会委員 : (主査)東京大学教授 小室 一成, 東京大学教授 齋藤 延人, 東京大学准教授 小川 純人, 東京大学講師 眞鍋 一郎, 東京大学講師 竹本 さやかUniversity of Tokyo(東京大学

Left atrial volume predicts adverse cardiac and cerebrovascular events in patients with hypertrophic cardiomyopathy

<p>Abstract</p> <p>Aims</p> <p>To prospectively evaluate the relationship between left atrial volume (LAV) and the risk of clinical events in patients with hypertrophic cardiomyopathy (HCM).</p> <p>Methods</p> <p>We enrolled a total of 141 HCM patients with sinus rhythm and normal pump function, and 102 patients (73 men; mean age, 61 ± 13 years) who met inclusion criteria were followed for 30.8 ± 10.0 months. The patients were divided into two groups with or without major adverse cardiac and cerebrovascular events (MACCE), a composite of stroke, sudden death, and congestive heart failure. Detailed clinical and echocardiographic data were obtained.</p> <p>Results</p> <p>MACCE occurred in 24 patients (18 strokes, 4 congestive heart failure and 2 sudden deaths). Maximum LAV, minimum LAV, and LAV index (LAVI) corrected for body surface area (BSA) were significantly greater in patients with MACCE than those without MACCE (maximum LAV: 64.3 ± 25.0 vs. 51.9 ± 16.0 ml, p = 0.005; minimum LAV: 33.9 ± 15.1 vs. 26.2 ± 10.9 ml, p = 0.008; LAVI: 40.1 ± 15.4 vs. 31.5 ± 8.7 ml/mm², p = 0.0009), while there were no differences in the other echocardiographic parameters.</p> <p>LAV/BSA of ≥ 40.4 ml/m²to identify patients with cardiovascular complications with a sensitivity of 73% and a specificity of 88%.</p> <p>Conclusion</p> <p>LAVI may be an effective marker for detecting the risk of MACCE in patients with HCM and normal pump function.</p

Clinical features and sulfonylurea usage among outpatients with diabetes aged ≥90 years in an urban diabetes clinic in Tokyo

ABSTRACT Aims/Introduction Aging of society is accelerating in many countries. The purpose of this study was to describe the clinical features and sulfonylurea usage among diabetes outpatients aged ≥90 years (nonagenarians). Materials and Methods This study was a retrospective observational study. The study population consisted of 69 nonagenarian diabetes outpatients and 857 diabetes outpatients aged <90 years. Patients were classified into four groups: group 1, <65 years; group 2, 65–74 years; group 3, 75–89 years; and group 4, ≥90 years. The presence of hypoglycemic episodes was defined as having self‐reported symptoms, or self‐monitored or clinically measured blood glucose level <70 mg/dL. Results The median glycated hemoglobin (HbA1c) in group 1 and group 4 was 7.0% and 7.2%, respectively (P = 0.506). The proportion of sulfonylurea treatment in group 4 was 45.5%, which is significantly higher compared with the other three groups (20.0–27.8%, P < 0.001). In group 4, there was no difference between patients with or without sulfonylurea in age, sex, body mass index, HbA1c and number of antihyperglycemic agents. Five out of 25 nonagenarian sulfonylurea‐treated patients had hypoglycemic episodes within the last 2 years, their HbA1c were all 7.0 ≤ HbA1c < 8.0, and sulfonylurea or insulin was tapered in all cases after confirming hypoglycemia. Tapering dosage was attempted in all 25 sulfonylurea‐treated nonagenarian patients, but 15 needed to continue sulfonylurea for glycemic control, and 10 continued sulfonylurea with unknown reasons from their medical records. Conclusions Although tapering the dosage of sulfonylurea was attempted in nonagenarian patients, sulfonylurea was widely continued for glycemic control. Reverse clinical inertia may exist in some sulfonylurea‐treated nonagenarian patients

Decreased AdipoR1 signaling and its implications for obesity-induced male infertility

Abstract Obesity is among the risk factors for male infertility. Although several mechanisms underlying obesity-induced male subfertility have been reported, the entire mechanism of obesity-induced male infertility still remains unclear. Here, we show that sperm count, sperm motility and sperm fertilizing ability were decreased in male mice fed a high-fat diet and that the expression of the AdipoR1 gene and protein was decreased, and the expression of pro-apoptotic genes and protein increased, in the testis from mice fed a high-fat diet. Moreover, we demonstrate that testes weight, sperm count, sperm motility and sperm fertilizing ability were significantly decreased in AdipoR1 knockout mice compared to those in wild-type mice; furthermore, the phosphorylation of AMPK was decreased, and the expression of pro-apoptotic genes and proteins, caspase-6 activity and pathologically apoptotic seminiferous tubules were increased, in the testis from AdipoR1 knockout mice. Furthermore, study findings show that orally administrated AdipoRon decreased caspase-6 activity and apoptotic seminiferous tubules in the testis, thus ameliorating sperm motility in male mice fed a high-fat diet. This was the first study to demonstrate that decreased AdipoR1/AMPK signaling led to increased caspase-6 activity/increased apoptosis in the testis thus likely accounting for male infertility