Bilirubin reduces visceral obesity and insulin resistance by suppression of inflammatory cytokines.

OBJECTIVE: Although previous studies have reported a negative relationship between serum bilirubin concentration and the development of diabetes mellitus (DM), the relationship between bilirubin and insulin resistance has not been thoroughly assessed. This study was designed to determine the relationships between bilirubin, body fat distribution, and adipose tissue inflammation in patients with type 2 DM and the effect of bilirubin in an obese animal model. METHOD: Body fat distribution was measured using an abdominal dual bioelectrical impedance analyzer in patients with type 2 DM. We also measured glycemic control, lipid profile, serum bilirubin concentration and other clinical characteristics, and determined their relationships with body fat distribution. In the animal study, biliverdin (20 mg/kg daily) was orally administered to high-fat diet (HFD)-induced obese (DIO) mice for 2 weeks, after which intraperitoneal insulin tolerance testing was performed. Then, adipocyte area, adipocytokine expression, and macrophage polarization were evaluated in epididymal adipose tissues. RESULTS: In the clinical study, univariate analysis showed that a lower bilirubin concentration was significantly correlated with higher body mass index, waist circumference, triglyceride, uric acid, creatinine, visceral fat area and lower HDL-C. In multivariate analyses, bilirubin concentration significantly correlated with diastolic blood pressure, creatinine, and visceral fat area. However, there was no association between bilirubin concentration and subcutaneous fat area. In the animal study, DIO mice treated with biliverdin had smaller adipocytes than untreated DIO mice and biliverdin improved HFD-induced insulin resistance. Biliverdin treatment reversed the higher gene expression of Cd11c, encoding an M1 macrophage marker, and Tnfa, encoding the proinflammatory cytokine tumor necrosis factor-α, in the adipose tissues of DIO mice. These data suggest biliverdin administration alleviates insulin resistance by ameliorating inflammation and the dysregulation of adipocytokine expression in adipose tissues of DIO mice. CONCLUSIONS: Bilirubin may protect against insulin resistance by ameliorating visceral obesity and adipose tissue inflammation.

Clinical significance of barriers to blood glucose control in type 2 diabetes patients with insufficient glycemic control.

BACKGROUND: The purpose of this study was to assess actual barriers to blood glucose control in patients with type 2 diabetes mellitus and to investigate barrier-related factors in an exploratory manner. METHODS: This cross-sectional study assessed patients with type 2 diabetes mellitus treated as outpatients at medical institutions within Fukuoka Prefecture, Japan. Barriers to blood glucose control were examined in patients with glycated hemoglobin ≥6.9% using a nine-item questionnaire. Answers were also obtained from physicians in charge of the patients for seven of nine questions. RESULTS: Seven hundred and thirteen patients answered the questionnaire. Many physicians and patients described barriers that involved difficulty in complying with diet therapy. For six of the seven barriers, patient awareness was lower than physician awareness. Patient-reported lack of concern for diabetes mellitus was more prevalent among patients with macrovascular complications. Patients who reported difficulty in compliance with exercise therapy and fear of hypoglycemia were more likely to suffer from microvascular complications. CONCLUSION: For many of the barriers to blood glucose control, patients were less aware than physicians, suggesting that we need to take action to raise patient awareness. Of interest are the observations that the relevant barriers differed for macrovascular and microvascular complications and that the relationship between presence of macrovascular complications and lack of concern about diabetes mellitus.

Maternal high-fat diet induces insulin resistance and deterioration of pancreatic ß-cell function in adult offspring with sex differences in mice.

Intrauterine environment may influence the health of postnatal offspring. There have been many studies on the effects of maternal high-fat diet (HFD) on diabetes and glucose metabolism in offspring. Here, we investigated the effects in male and female offspring. C57/BL6J mice were bred and fed either control diet (CD) or HFD from conception to weaning, and offspring were fed CD or HFD from 6 to 20 wk. At 20 wk, maternal HFD induced glucose intolerance and insulin resistance in offspring. Additionally, liver triacylglycerol content, adipose tissue mass, and inflammation increased in maternal HFD. In contrast, extending previous observations, insulin secretion at glucose tolerance test, islet area, insulin content, and PDX-1 mRNA levels in isolated islets were lower in maternal HFD in males, whereas they were higher in females. Oxidative stress in islets increased in maternal HFD in males, whereas there were no differences in females. Plasma estradiol levels were lower in males than in females and decreased in offspring fed HFD and also decreased by maternal HFD, suggesting that females may be protected from insulin deficiency by inhibiting oxidative stress. In conclusion, maternal HFD induced insulin resistance and deterioration of pancreatic ß-cell function, with marked sex differences in adult offspring accompanied by adipose tissue inflammation and liver steatosis. Additionally, our results demonstrate that potential mechanisms underlying sex differences in pancreatic ß-cell function may be related partially to increases in oxidative stress in male islets and decreased plasma estradiol levels in males.

GLP-1 analog liraglutide protects against oxidative stress and albuminuria in streptozotocin-induced diabetic rats via protein kinase A-mediated inhibition of renal NAD(P)H oxidases.

Accumulating evidence has implicated that GLP-1 may have a beneficial effect on cardiovascular and renal diseases but the mechanism is not fully understood. Here we show that GLP-1 analog, liraglutide, inhibits oxidative stress and albuminuria in streptozotocin (STZ)-induced type 1 diabetes mellitus rats, via a protein kinase A (PKA)-mediated inhibition of renal NAD(P)H oxidases. Diabetic rats were randomly treated with subcutaneous injections of liraglutide (0.3 mg/kg/12 h) for 4 weeks. Oxidative stress markers (urinary 8-hydroxy-2'-deoxyguanosine and renal dihydroethidium staining), expression of renal NAD(P)H oxidase components, transforming growth factor-ß (TGF-ß), fibronectin and urinary albumin excretion were measured. In vitro effect of liraglutide was evaluated using cultured renal mesangial cells. Administration of liraglutide did not affect plasma glucose levels or body weights in STZ diabetic rats, but normalized oxidative stress markers, expression of NAD(P)H oxidase components, TGF-ß, fibronectin in renal tissues and urinary albumin excretion, all of which were significantly increased in diabetic rats. In addition, in cultured renal mesangial cells, incubation with liraglutide for 48 h inhibited NAD(P)H-dependent superoxide production evaluated by lucigenin chemiluminescence in a dose-dependent manner. This effect was reversed by both PKA inhibitor H89 and adenylate cyclase inhibitor SQ22536, but not by Epac2 inhibition via its small interfering RNA. Liraglutide may have a direct beneficial effect on oxidative stress and diabetic nephropathy via a PKA-mediated inhibition of renal NAD(P)H oxidase, independently of a glucose-lowering effect.

Chymase inhibition prevents myocardial fibrosis through the attenuation of NOX4-associated oxidative stress in diabetic hamsters.

UNLABELLED: Aims/Introduction: Diabetic cardiomyopathy entails the cardiac injury induced by diabetes, independent of vascular disease or hypertension. Despite numerous experimental studies and clinical trials, the pathogenesis of diabetic cardiomyopathy remains elusive. Here, we report that chymase, an immediate angiotensin II (AngII)-forming enzyme in humans and hamsters, and NOX4-induced oxidative stress have pathogenic roles in myocardial fibrosis in diabetic hamsters. MATERIALS AND METHODS: Expression of chymase was evaluated in the hearts of streptozotocin (STZ)-induced diabetic hamsters. The impact of chymase-specific inhibitors, TEI-E00548 and TEI-F00806, on myocardial fibrosis, and increased levels of intracardiac AngII, accumulation of 8-hydroxy-2'-deoxyguanosine (an oxidative stress marker in urine and heart tissue) and expression of heart NOX4 in diabetic hamsters were investigated. RESULTS: Myocardial chymase expression was markedly upregulated in STZ hamsters in a glucose-dependent manner. A total of 8 weeks after STZ administration, the diabetic hamsters showed enhanced oxidative stress and NOX4 expression in the heart, in parallel with increased myocardial AngII production. Oral administration of chymase-specific inhibitors, TEI-F00806 and TEI-E00548, normalized heart AngII levels, and completely reversed NOX4-induced oxidative stress and myocardial fibrosis in STZ-induced diabetic hamsters, although they did not affect the activity of the systemic renin-angiotensin system or systolic blood pressure. CONCLUSIONS: Chymase inhibition might prevent oxidative stress and diabetic cardiomyopathy at an early stage by reducing local AngII production. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2012.00202.x, 2012).

Inhibition of chymase protects against diabetes-induced oxidative stress and renal dysfunction in hamsters.

Accumulating evidence suggests that the intrarenal renin-angiotensin system may be involved in the progression of diabetic nephropathy. Chymase is a potent local angiotensin II-forming enzyme in several species, including humans and hamsters. However, the pathophysiological role of chymase is not fully understood. Here, we report a causal role of chymase in diabetic nephropathy and the therapeutic effectiveness of chymase inhibition. In the present study, renal chymase expression was markedly upregulated in streptozotocin-induced diabetic hamsters. Oral administration of a specific chymase inhibitor, TEI-F00806, completely ameliorated proteinuria, the overexpression of transforming growth factor-ß and fibronectin in glomeruli, and renal mesangial expansion, by normalizing the increase in intrarenal angiotensin II levels in diabetic hamsters independently of blood pressure levels. In contrast, ramipril did not show such sufficient effects. These effects occurred in parallel with improvements in superoxide production and expression of NAD(P)H oxidase components [NAD(P)H oxidase 4 and p22(phox)] in glomeruli. This study showed for the first time that chymase inhibition may protect against elevated intrarenal angiotensin II levels, oxidative stress, and renal dysfunction in diabetes. These findings suggest that chymase offers a new therapeutic target for diabetic nephropathy.

Attenuated metabolic effect of waist measurement in Japanese female patients with type 2 diabetes mellitus.

Waist circumference (WC) was measured in 200 Japanese patients with type 2 diabetes mellitus (T2DM: male 106, female 94, mean age 61 years old) who had been admitted in our hospital, and relationship with various risk factors to predict future cardiovascular disease (CVD) was analyzed. There was a positive and statistically significant trend in WC levels with an increasing number of CVD risk factors in male patients, whereas no significant trend of WC was observed in female patients. The receiver operator characteristic (ROC) curve for WC to predict the presence of two or more risk factors of CVD depicted greater area under the curve in male patients (0.732) than that in female patients (0.571). Apart from positive correlation with fasting serum C-peptide (S-CPR) and log-transformed high-sensitivity C-reactive protein (log HS-CRP) in both genders, WC was positively correlated with log-transformed triglyceride (log TG), systolic and diastolic blood pressure (SBP and DBP) and negatively with HDL-cholesterol (HDL-C) in male patients, whereas it was negatively correlated with HbA1c and fasting plasma glucose (FPG) in female patients. The change of WC after administration (DeltaWC) was correlated with DeltaS-CPR, DeltaLDL-C, DeltaSBP and DeltaDBP in male patients, while no relationship was observed in female patients. In conclusion, WC is a reliable marker to predict future CVD events at least in Japanese male, but not female patients with T2DM.

Indicators for the efficacy of pioglitazone before and during treatment in Japanese patients with type 2 diabetes.

BACKGROUND: The aim of this study is to explore appropriate indicators for the efficacy of pioglitazone (Pio) before and during treatment of Japanese patients with type 2 diabetes mellitus (T2DM). METHODS: Forty-eight Japanese patients with T2DM (22 men, 26 women, 60 +/- 2 years old) were enrolled and treated with 15 mg/day of Pio for 12 weeks. Before and after the treatment, various parameters were evaluated regarding the efficacy of Pio. Patients who had a reduction in hemoglobin A1c (HbA1c) of >1% after 12 weeks of treatment were defined as responders. RESULTS: Twenty-two patients were classified as responders. In the responder group, age, fasting plasma glucose (FPG), and percentage female were significantly (P < 0.05) higher compared with the non-responder group. In logistic regression analysis, female sex and higher FPG were selected as explanatory variables for the efficacy of Pio. Furthermore, the change of HbA1c (DeltaHbA1c) was positively correlated with that of fasting C-peptide level (DeltaCPR) and log-transformed high-sensitivity C-reactive protein (Deltalog HS-CRP), and negatively correlated with that of high-density lipoprotein cholesterol (DeltaHDL-C) and log-transformed adiponectin (Deltalog AP). In multiple stepwise regression analysis, DeltaCPR, Deltalog HS-CRP, and Deltalog AP (or DeltaFPG) were selected as explanatory variables for DeltaHbA1c. CONCLUSIONS: We concluded that Pio is likely to show favorable effects on blood glucose control especially in female patients with higher FPG levels. Administration of Pio ameliorates blood glucose control accompanied by the increase of AP and the decrease of CPR or HS-CRP, suggesting that Pio exerts its beneficial effects through the enhancement of AP, which leads to suppression of inflammation and amelioration of insulin resistance.