Hitomi Nakayama

Reduction of skeletal muscle, especially in lower limbs, in Japanese type 2 diabetic patients with insulin resistance and cardiovascular risk factors.

BACKGROUND The aim of the present study was to evaluate characteristics of body composition in Japanese patients with type 2 diabetes. METHODS Measurement of regional body composition was performed using bioelectrical impedance analysis (INBODY720) in 198 patients with type 2 diabetes (group D) and 198 apparently healthy subjects matched for age, gender, and body mass index (BMI) (group C), together with measurements of metabolic parameters. RESULTS The percentage of skeletal muscle of whole body (M%) and in lower extremities (leg M%) was significantly lower in group D than that in group C. These sarcopenic features were manifest in patients with longer durations of diabetes or lack of exercise. M% and leg M% in diabetic patients were negatively correlated with the log-transformed triglyceride/high-density lipoprotein cholesterol (HDL-C) ratio, a marker of insulin resistance and atherosclerosis risk. Furthermore, reduced leg M% was significantly correlated with increasing numbers of risk factors for cardiovascular disease (CVD). CONCLUSIONS Because this distinctive feature of body composition becomes more evident as duration of diabetes is longer and less marked in patients with habitual exercise, early intervention, such as the instruction of exercise including resistance training, seems to be worthwhile for the prevention of future burdens in these patients.

Beneficial effects of metformin on energy metabolism and visceral fat volume through a possible mechanism of fatty acid oxidation in human subjects and rats

Objective Metformin is known to have a beneficial effect on body weight and body composition, although the precise mechanism has not been elucidated yet. The aim of this study is to investigate the effects of metformin on energy metabolism and anthropometric factors in both human subjects and rats. Methods In human studies, metformin (1500mg/day) was administered to 23 healthy subjects and 18 patients with type 2 diabetes for 2 weeks. Metabolic parameters and energy metabolism were measured during a meal tolerance test in the morning before and after the treatment of metformin. In animal studies, 13 weeks old SD rats were fed 25–26 g of standard chow only during 12-hours dark phase with either treated by metformin (2.5mg/ml in drinking water) or not for 2 weeks, and metabolic parameters, anthropometric factors and energy metabolism together with expressions related to fat oxidation and adaptive thermogenesis were measured either in fasting or post-prandial state at 15 weeks old. Results Post-prandial plasma lactate concentration was significantly increased after the metformin treatment in both healthy subjects and diabetic patients. Although energy expenditure (EE) did not change, baseline respiratory quotient (RQ) was significantly decreased and post-prandial RQ was significantly increased vice versa following the metformin treatment in both groups. By the administration of metformin to SD rats for 2 weeks, plasma levels of lactate and pyruvate were significantly increased in both fasting and post-prandial states. RQ during a fasting state was significantly decreased in metformin-treated rats compared to controls with no effect on EE. Metformin treatment brought about a significant reduction of visceral fat mass compared to controls accompanied by an up-regulation of fat oxidation-related enzyme in the liver, UCP-1 in the brown adipose tissue and UCP-3 in the skeletal muscle. Conclusion From the results obtained, beneficial effects of metformin on visceral fat reduction has been demonstrated probably through a mechanism for a potential shift of fuel resource into fat oxidation and an upregulation of adaptive thermogenesis independent of an anorexigenic effect of this drug.

Selective Modulation of Wnt Ligands and Their Receptors in Adipose Tissue by Chronic Hyperadiponectinemia

Background Adiponectin-transgenic mice had many small adipocytes in both subcutaneous and visceral adipose tissues, and showed higher sensitivity to insulin, longer life span, and reduced chronic inflammation. We hypothesized that adiponectin regulates Wnt signaling in adipocytes and thereby modulates adipocyte proliferation and chronic inflammation in adipose tissue. Materials and Methods We examined the expression of all Wnt ligands and their receptors and the activity of Wnt signaling pathways in visceral adipose tissue from wild-type mice and two lines of adiponectin-transgenic mice. The effects of adiponectin were also investigated in cultured 3T3-L1 cells. Results The Wnt5b, Wnt6, Frizzled 6 (Fzd6), and Fzd9 genes were up-regulated in both lines of transgenic mice, whereas Wnt1, Wnt2, Wnt5a, Wnt9b, Wnt10b, Wnt11, Fzd1, Fzd2, Fzd4, Fzd7, and the Fzd coreceptor low-density-lipoprotein receptor-related protein 6 (Lrp6) were reduced. There was no difference in total β-catenin levels in whole-cell extracts, non-phospho-β-catenin levels in nuclear extracts, or mRNA levels of β-catenin target genes, indicating that hyperadiponectinemia did not affect canonical Wnt signaling. In contrast, phosphorylated calcium/calmodulin-dependent kinase II (p-CaMKII) and phosphorylated Jun N-terminal kinase (p-JNK) were markedly reduced in adipose tissue from the transgenic mice. The adipose tissue of the transgenic mice consisted of many small cells and had increased expression of adiponectin, whereas cyclooxygenase-2 expression was reduced. Wnt5b expression was elevated in preadipocytes of the transgenic mice and decreased in diet-induced obese mice, suggesting a role in adipocyte differentiation. Some Wnt genes, Fzd genes, and p-CaMKII protein were down-regulated in 3T3-L1 cells cultured with a high concentration of adiponectin. Conclusion Chronic hyperadiponectinemia selectively modulated the expression of Wnt ligands, Fzd receptors and LRP coreceptors accompanied by the inhibition of the Wnt/Ca2+ and JNK signaling pathways, which may be involved in the altered adipocyte cellularity, endogenous adiponectin production, and anti-inflammatory action induced by hyperadiponectinemia.

Effects of a sodium glucose co-transporter 2 selective inhibitor, ipragliflozin, on the diurnal profile of plasma glucose in patients with type 2 diabetes: A study using continuous glucose monitoring

To assess the effects of sodium glucose co‐transporter 2 inhibitor therapy on the pathophysiology of type 2 diabetes.

IL‐18 gene polymorphism confers susceptibility to the development of anti‐GAD65 antibody in Graves’ disease

Aims  This study aimed to investigate whether interleukin‐18 (IL‐18) gene polymorphisms are associated with the development of antibody against the 65‐kDa isoform of recombinant human glutamic acid decarboxylase (GAD65Ab) in patients with Graves’ disease.

Serum albumin-adjusted glycated albumin reflects glycemic excursion in diabetic patients with severe chronic kidney disease not treated with dialysis

OBJECTIVE Diabetic patients with severe chronic kidney disease (CKD) not treated with dialysis falsely show low levels of HbA1c and GA due to renal anemia and proteinuria, respectively. Recently, we reported that serum albumin-adjusted GA (adjGA) accurately reflects mean plasma glucose (PG) in these patients. It is considered that GA reflects not only mean PG but also glycemic excursion; therefore, in the present study we investigated whether adjGA reflects glycemic excursion in these patients. METHODS Thirty type 2 diabetic patients with severe CKD not treated with dialysis were enrolled in the present study. PG was monitored by seven times a day, and indicators of glycemic excursion [SD, max PG, ΔPG, M value, J index, and mean amplitude of glucose excursion (MAGE)] were calculated. The correlations between HbA1c, GA or adjGA and indicators of glycemic excursion were investigated. RESULTS HbA1c showed no significant correlation with indicators of glycemic excursion. GA was significantly correlated with them except for ΔPG. adjGA was significantly and strongly associated with them except for MAGE. GA, but not adjGA, showed a significant positive correlation with serum albumin. CONCLUSION adjGA was not influenced by serum albumin and showed a significant correlation with indicators of glycemic excursion in diabetic patients with severe CKD not treated with dialysis. These results suggest that adjGA could be useful for indicating glycemic control in diabetic patients with severe CKD not treated with dialysis.

Serum albumin-adjusted glycated albumin is a better indicator of glycaemic control in diabetic patients with end-stage renal disease not on haemodialysis

Backgrounds Diabetic patients with end-stage renal disease who are not on haemodialysis show low concentrations of HbA1c and glycated albumin due to renal anaemia and proteinuria, respectively. In the present study, we examined whether serum albumin-adjusted glycated albumin could accurately reflect glycaemic control in these patients. Methods To examine the correlation between glycated albumin and serum albumin (Study 1), 49 diabetic patients with end-stage renal disease not on haemodialysis were used. To evaluate the association between the glycaemic control indicators and the glycaemic control state (Study 2), 30 diabetic patients with end-stage renal disease were enrolled. The estimated HbA1c and the estimated glycated albumin concentrations were calculated based on the mean blood glucose concentrations obtained from the diurnal variation. The adjusted glycated albumin concentrations were calculated from the regression formula between the serum albumin and glycated albumin obtained from Study 1. Results No significant correlation was found between the measured HbA1c and estimated HbA1c concentrations. The estimated HbA1c (inversely) and measured HbA1c/estimated HbA1c ratio (positively), but not measured HbA1c, showed a significant correlation with Hb concentrations. The estimated glycated albumin was positively associated with the measured glycated albumin and adjusted glycated albumin concentrations. Although measured glycated albumin/estimated glycated albumin ratio was positively correlated with serum albumin, there was no significant association between the adjusted glycated albumin/estimated glycated albumin ratio and serum albumin, Hb and estimated glomerular filtration rate. Conclusions We found for the first time that the adjustment of glycated albumin by serum albumin could be useful to determine glycaemic control in diabetic patients with end-stage renal disease not on haemodialysis. These findings suggest that adjusted glycated albumin might be a better indicator of glycaemic control than measured HbA1c and measured glycated albumin in these patients.

Pivotal Role of TNF-α in the Development and Progression of Nonalcoholic Fatty Liver Disease in a Murine Model

Previously, we have shown that the adipocyte-specific nuclear form of sterol regulatory element-binding protein-1c (nSREBP-1c) transgenic mice spontaneously developed hepatic lesions that are similar to those of human nonalcoholic steatohepatitis (NASH) with a concomitant elevation of plasma TNF-α. In this study, we analyzed the role of TNF-α in the progression of nonalcoholic fatty liver disease (NAFLD). We established a Tnf knockout nSREBP-1c transgenic mouse line. Glucose tolerance and liver histology were examined at the age of 20 weeks. The gene expression and protein levels were assessed by quantitative RT-PCR and Western blot, respectively. The Tnf knockout improved glucose tolerance and significantly reduced the prevalence of hepatic steatosis (20% vs. 100%, p<0.0001) and fibrosis (15% vs. 65%, p=0.0057). The expressions of Acaca, Scd1, Mcp1, Tgfb1, Col1a1, and Timp1 were increased in the liver from the original nSREBP-1c transgenic mice. However, gene upregulation was reduced in the livers from the Tnf(-/-) nSREBP-1c transgenic mice. Furthermore, the hepatic levels of TIMP1 protein were increased in the original nSREBP-1c transgenic mice but not in Tnf(-/-) nSREBP-1c transgenic mice. To assess the direct effect of TNF-α on the expression of the genes, we cultured primary hepatocytes in the presence of TNF-α and found that TNF-α increased the expression of Mcp1, Tgfb1, and Timp1 in hepatocytes. These observations indicate that TNF-α plays a pivotal role in the development of NAFLD and progression to NASH through upregulating key molecules associated with lipid metabolism, inflammatory cytokines, and fibrosis in the liver.

Development of a novel, short, self-completed questionnaire on empowerment for patients with type 2 diabetes mellitus and an analysis of factors affecting patient empowerment.

BackgroundPatient empowerment has recently been proposed as an important concept in self-management for effective glycemic control. A concise self-completed questionnaire for patients with type 2 diabetes mellitus was created to comprehensively evaluate their empowerment on the basis of self-managed dietary/exercise behaviors, psychological impact, and family support. The reliability and validity of this short questionnaire were tested and factors relating to patient empowerment were analyzed.MethodsThe self-completed empowerment questionnaire was based on questionnaires for self-managed dietary and exercise behaviors, the Appraisal of Diabetes Scale, and the Diabetes Family Behavior Checklist. The questionnaire was trialed on 338 male and female patients with type 2 diabetes mellitus who lived with family. The validity and reliability of the questionnaire were investigated and stepwise multiple linear regression analysis was used to identify factors that affect patient empowerment.ResultsThe self-completed patient empowerment questionnaire included 13 questions on background data (e.g., age, gender, and HbA1c) and 18 questions within five scales to assess self-managed dietary behaviors, self-managed exercise behaviors, and psychological impact of diabetes, as well as positive and negative feedback in patient-family communication. The questionnaire showed sufficient internal consistency, construct validity, reproducibility, factorial construct validity, and concurrent validity. The results were generally satisfactory, and the questionnaire reflected the particular characteristics of treatment methods. Multiple linear regression analysis showed that patient empowerment was strongly affected by the number of disease-related symptoms, age, and gender.ConclusionsThe results suggest that the concise self-completed empowerment questionnaire developed here is useful for measuring the empowerment of individual patients and evaluating the impact of symptoms and therapies on empowerment.

Surrogate index for insulin sensitivity composed of factors not using glucose and insulin in Japanese patients with diabetes.

Introduction:  The aim of the present study is to propose a novel index of insulin sensitivity instead of homeostasis model assessment of insulin resistance (HOMA‐IR), which has a fundamental limitation of validity when applied to subjects with lower insulin secretions or high fasting plasma glucose (FPG) levels.