Masao Kanauchi

Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: A randomized controlled trial

CONTEXT Previous trials have investigated the effects of low-dose aspirin on primary prevention of cardiovascular events, but not in patients with type 2 diabetes. OBJECTIVE To examine the efficacy of low-dose aspirin for the primary prevention of atherosclerotic events in patients with type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS Multicenter, prospective, randomized, open-label, blinded, end-point trial conducted from December 2002 through April 2008 at 163 institutions throughout Japan, which enrolled 2539 patients with type 2 diabetes without a history of atherosclerotic disease and had a median follow-up of 4.37 years. INTERVENTIONS Patients were assigned to the low-dose aspirin group (81 or 100 mg per day) or the nonaspirin group. MAIN OUTCOME MEASURES Primary end points were atherosclerotic events, including fatal or nonfatal ischemic heart disease, fatal or nonfatal stroke, and peripheral arterial disease. Secondary end points included each primary end point and combinations of primary end points as well as death from any cause. RESULTS A total of 154 atherosclerotic events occurred: 68 in the aspirin group (13.6 per 1000 person-years) and 86 in the nonaspirin group (17.0 per 1000 person-years) (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.58-1.10; log-rank test, P = .16). The combined end point of fatal coronary events and fatal cerebrovascular events occurred in 1 patient (stroke) in the aspirin group and 10 patients (5 fatal myocardial infarctions and 5 fatal strokes) in the nonaspirin group (HR, 0.10; 95% CI, 0.01-0.79; P = .0037). A total of 34 patients in the aspirin group and 38 patients in the nonaspirin group died from any cause (HR, 0.90; 95% CI, 0.57-1.14; log-rank test, P = .67). The composite of hemorrhagic stroke and significant gastrointestinal bleeding was not significantly different between the aspirin and nonaspirin groups. CONCLUSION In this study of patients with type 2 diabetes, low-dose aspirin as primary prevention did not reduce the risk of cardiovascular events. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00110448.

Epithelial-Mesenchymal Transition as a Potential Explanation for Podocyte Depletion in Diabetic Nephropathy

BACKGROUND Depletion of glomerular podocytes is an important feature of progressive diabetic nephropathy. Although the most plausible explanation for this podocyte depletion is detachment from the glomerular basement membrane after cellular apoptosis, the mechanism is unclear. Fibroblast-specific protein 1 (FSP1; encoded by the S100A4 gene) is a member of the S100 family of calcium-binding proteins and is constitutively expressed in the cytoplasm of tissue fibroblasts or epithelial cells converted into fibroblasts by means of epithelial-mesenchymal transition. STUDY DESIGN Retrospective cross-sectional analysis. SETTINGS & PARTICIPANTS 109 patients with type 2 diabetes mellitus, of whom 43 (39%) underwent kidney biopsy. PREDICTOR Clinical stage (4 categories) and histological grade (5 categories) of diabetic nephropathy. OUTCOME FSP1 expression in podocytes in urine and glomeruli in kidney biopsy specimens. MEASUREMENTS Immunohistochemistry, real-time polymerase chain reaction, and in situ hybridization. RESULTS 38 of 109 patients (35%) were normoalbuminuric, 16 (15%) had microalbuminuria, 8 (7%) had macroalbuminuria, and 47 (43%) had decreased kidney function. Approximately 95% of podocytes in urine sediment were not apoptotic, and 86% expressed FSP1. The number of FSP1-positive podocytes in urine sediment was significantly larger in patients with macroalbuminuria than in those with normoalbuminuria (P = 0.03). Intraglomerular expression of FSP1 occurred almost exclusively in podocytes from patients with diabetes, and the number of FSP1-positive podocytes was larger in glomeruli showing diffuse mesangiopathy than in those showing focal mesangiopathy (P = 0.01). The number also was larger in glomeruli with nodular lesions than in those without nodular lesions (P < 0.001). FSP1-positive podocytes selectively expressed Snail1 and integrin-linked kinase, a known trigger for epithelial-mesenchymal transition. LIMITATIONS Nonrepresentative study population. CONCLUSIONS These results suggest that the appearance of FSP1 in podocytes of patients with diabetes is associated with more severe clinical and pathological findings of diabetic nephropathy, perhaps because of induction of podocyte detachment through epithelial-mesenchymal transition-like phenomena.

Oxidative DNA Damage and Tubulointerstitial Injury in Diabetic Nephropathy

Background: Oxidative stress is an important pathogenetic factor in underlying diabetic complications. Recently, 8-hydroxy-2′-deoxyguanosine (8-OHdG) has been reported to serve as a new sensitive biomarker of the oxidative DNA damage in vivo. We studied the relationship between oxidative DNA damage and tubulointerstitial injury in patients with diabetic nephropathy. Methods: Type 2 diabetic patients (n = 25) and healthy control subjects (n = 20) were studied. The urine concentrations of 8-OHdG were measured by a competitive ELISA. The severity of the glomerular changes was graded using Gellman’s criteria, and the severity of the tubulointerstitial lesions was determined by a semiquantitative estimate of the space occupied by the fibrous tissue and/or interstitial infiltrates. Results: The urinary 8-OHdG excretion were significantly higher in the diabetics than in the healthy controls, and tended to increase with severity of the glomerular diffuse lesion, but it was not significant. The urinary 8-OHdG excretion significantly increased with severity of the tubulointerstitial lesion. Conclusions: Oxidative stress may contribute to the progression of tubulointerstitial injury in patients with diabetic nephropathy.

Increased Excretion of Urinary Transforming Growth Factor Beta 1 in Patients with Diabetic Nephropathy

The accumulation of extracellular matrix in the glomeruli of human and experimental models of diabetic nephropathy is associated with disease progression. Transforming growth factor beta 1 (TGF-β1), which is a multifunctional peptide growth factor, plays a key role in the synthesis of extracellular matrix protein in vitro, and the expression of TGF-β1 is elevated in human and rat diabetic nephropathy. In this study, we measured the urinary TGF-β1 excretion in 57 patients with non-insulin-dependent diabetes mellitus and in 20 healthy volunteers to examine whether the determination of urinary TGF-β1 excretion would facilitate the evaluation of the degree of mesangial expansion in patients with diabetic nephropathy. Both active and total TGF-β1 levels in 24-hour urine samples collected from patients with diabetes mellitus and normal controls were measured using an enzyme-linked immunosorbent assay. We observed a higher excretion of urinary TGF-β1 in patients with diabetes mellitus than in normal controls. In addition, the urinary TGF-β1 excretion was elevated in patients with severe mesangial expansion. These results suggest that urinary TGF-β1 may represent one parameter that can be used to evaluate the progression of diabetic nephropathy.

Frailty, health-related quality of life and mental well-being in older adults with cardiometabolic risk factors

Objective:  Frailty is an emergent health‐related problem in older adults. The aim of this study was to examine the health‐related quality of life (HRQOL) and the effect of frailty in elderly patients with cardiometabolic risk factors.

Metabolic syndrome and new category 'pre-hypertension' in a Japanese population

SUMMARY Objective: To examine whether insulin resistance and metabolic syndrome are associated with pre-hypertension, a new stage developed by the Joint National Committee on Prevention, Detection, Education and Treatment of High Blood Pressure (JNC-7). Patients and methods: Subjects included 506 Japanese taking no anti-hypertensive medication. Subjects were divided into three groups according to blood pressure status using the JNC-7 criteria. Normotension (NTN) was defined as a Systolic Blood Pressure (SBP) < 120 mmHg and a Diastolic Blood Pressure (DBP) < 80 mmHg, pre-hypertension (PHT) as a SBP 120–139 mmHg or a DBP 80–89 mmHg and hypertension (HTN) as a SBP ≥ 140 mmHg or a DBP ≥ 90 mmHg. The metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III as modified for waist circumference criteria by the Regional Office for the Western Pacific Region of WHO. Insulin sensitivity was assessed by plasma glucose and insulin concentrations obtained at fasting or during a 75 g oral glucose tolerance test. Results: There were no differences with respect to age, gender or glucose intolerance status among the three groups. The mean values of body mass index were similar between NTN and PHT, but were significantly higher in HTN than in other groups. The prevalence of the metabolic syndrome was 9.9% in NTN, 19.2% in PHT and 35.5% in HTN, respectively. The prevalence increased linearly with worsening of blood pressure status ( p < 0.0001). An increase in the number of metabolic syndrome components (MS score) was also associated with a progress in blood pressure status. Even in the non-obese persons, the prevalence of the metabolic syndrome and the MS score increased linearly with worsening in blood pressure status. The homeostasis model assessment of insulin resistance (HOMA-R) was significantly higher in PHT and HTN than in NTN and increased significantly with worsening in blood pressure status. Furthermore, the quantitative insulin sensitivity check index (QUICKI) and the insulin sensitivity index proposed by Stumvoll et al. decreased significantly with worsening in blood pressure status. Conclusions: The metabolic syndrome is prevalent even in the pre-hypertensive stage in a Japanese population and insulin resistance contributes to the underlying mechanisms of these abnormalities.

Discordance between Retinopathy and Nephropathy in Type 2 Diabetes

The aim of this study was to investigate the relationship between the grade of retinopathy and the severity of glomerular lesions in patients with type 2 diabetes and to describe 5 patients without diabetic retinopathy for whom renal biopsy specimens demonstrated advanced diabetic nephropathy. A total of 221 patients with type 2 diabetes (139 males and 82 females) who consectively underwent renal biopsy between 1982 and 1996 were investigated. The severity of diffuse glomerular lesions was graded using the criteria of Gellman and coworkers, and diabetic retinopathy was classified as absent, nonproliferative, or proliferative. The incidence of advanced nephropathy without retinopathy for all 221 cases was 2.3%. Advanced nephropathy was present in 5 of the 122 (4.1%) patients without retinopathy. These 5 patients were all males and aged 50–70 (mean 61) years. Their clinical characteristics were not uniform, and no special clinical features distinguished the patients who were regarded as having possible advanced nephropathy without retinopathy. In our study, although concordance of retinopathy and nephropathy is relatively common, a little discordance was pronounced in Japanese type 2 diabetic patients. Our findings are consistent with the hypothesis that there are important differences in some aspects of the pathogenesis of retinopathy and nephropathy.

Beta-cell function and insulin sensitivity contribute to the shape of plasma glucose curve during an oral glucose tolerance test in non-diabetic individuals.

To clarify whether beta‐cell function and/or insulin resistance contributes to the shape of plasma glucose curve during an oral glucose tolerance test (OGTT), we investigated 583 Japanese subjects with normal glucose tolerance (NGT, n = 306) or impaired glucose tolerance (IGT, n = 277). Each subject was subdivided into three shapes of plasma glucose curve as follows: monophasic pattern (M type), biphasic pattern (B type) and two peaks (T type). Homeostasis model assessment of insulin resistance, quantitative insulin sensitivity check index and insulinogenic index were assessed by plasma glucose and insulin concentrations obtained at fasting or during an OGTT. There was a greater proportion of M type in the IGT group (M = 80.9%, B = 15.5% and T = 3.6%), whereas the prevalence of B and T types was much higher in the NGT group (M = 66.6%, B = 26.5% and T = 6.9%). There were significant differences in the proportions of shape types between the NGT and IGT groups (p = 0.0006). Among the NGT category, insulin sensitivity was significantly higher in the B type than in the M type, and beta‐cell function adjusted for insulin resistance was significantly higher in the B and T types than in the M type. Among the IGT category, no significant differences were seen among the three shape types with respect to insulin sensitivity, but the beta‐cell function adjusted for insulin resistance was significantly lower in the M type than in the B and T types. In conclusion, both impaired insulin secretion and insulin resistance may contribute to the underlying mechanisms of the shape of plasma glucose curve in Japanese subjects.

Transferrinuria in type 2 diabetic patients with early nephropathy and tubulointerstitial injury

BACKGROUND: Transferrinuria is thought to be a marker for early stages of diabetic nephropathy. Transferrin has also been proposed as a mediator of tubular toxicity because the reabsorption of transferrin results in the release of reactive iron in proximal tubular cells, promoting the formation of hydroxyl radicals. We evaluated the role of urinary transferrin excretion in diabetic patients with early nephropathy by comparing tubulointerstitial injury in renal biopsy specimens. PATIENTS AND METHODS: 45 type 2 diabetic patients with normoalbuminuria (urinary albumin excretion <30 mg/24 h) or microalbuminuria (30-300 mg/24 h) were studied. All patients with microalbuminuria underwent renal biopsy, and the severity of the tubulo-interstitial lesions was determined by a semiquantitative estimate of interstitial fibrosis, tubular atrophy, and interstitial inflammatory infiltrates. Subjects were classified into group A (normoalbuminuria, n=25), group B (microalbuminuria without tubulointerstitial changes, n=11) or group C (microalbuminuria with tubulointerstitial changes, n=9). RESULTS: Urinary transferrin excretion (UTf), as well as UTf/creatinine clearance (Ccr), and transferrin clearance (CTf/Ccr), was significantly higher in groups B and C than in group A, and it was significantly higher in group C than in group B. There were no significant differences in urinary albumin excretion or mesangial expansion rate (MR% estimated by quantitative morphometric studies) between groups B and C. Although urinary beta2-microglobulin excretion was significantly higher in group C than in groups A and B, urinary N-acetyl-beta-D-glucosaminidase activity was significantly higher in groups B and C than in group A. CONCLUSIONS: Increased transferrinuria in the microalbuminuric stage may lead to the development of tubulointerstitial injuries in type 2 diabetic patients.

Validation of simple indices to assess insulin sensitivity based on the oral glucose tolerance test in the Japanese population

The homeostasis model assessment (HOMA) represents a simple index for evaluating insulin sensitivity, but clinical use is limited. Insulin sensitivity indices calculated from plasma glucose and plasma insulin concentrations after an oral glucose tolerant test (OGTT) have been proposed, but have not been validated in the Japanese population. We compared these indices with the euglycemic hyperinsulinemic clamp technique to evaluate the predicting insulin sensitivities in 77 Japanese subjects with varying degrees of glucose tolerance (normal glucose tolerance, n=40; impaired glucose tolerance, n=22; and type 2 diabetes mellitus, n=15). Insulin sensitivity was measured by the euglycemic hyperinsulinemic glucose clamp technique using an artificial pancreas, and expressed as the M-value. Weak inverse correlations existed between the HOMA index and M-values (r=-0.227, P=0.0468). An alternative index calculated by Matsudas formula correlated with the M-value (r=0.450, P=0.0001). A second index calculated by Stumvolls formula also correlated with the M-value (r=0.641, P=0.0001). Finally, a third index calculated by Gutts formula also significantly correlated with the M-value (r=0.526, P=0.0001). All three indices are applicable for clinical use. The second index is the most sensitive measure of insulin sensitivity in the Japanese population.