Kenta Okada

Distinct association of serum FGF21 or adiponectin levels with clinical parameters in patients with type 2 diabetes

Fibroblast growth factor 21 (FGF21) has been identified as a novel metabolic regulator. This cross-sectional study was performed to clarify how serum FGF21 levels were associated with clinical parameters in Japanese subjects with type 2 diabetes (n=139). Anthropometric and blood biochemical parameters, uses of drugs for diabetes, hypertension and dyslipidemia were examined regarding associations with fasting serum FGF21 concentrations. FGF21 levels were 6-times higher in those subjects taking fibrates. However, a use of thiazolidinediones did not affect serum FGF21 levels while it induced higher serum adiponectin levels. In univariate analyses, FGF21 levels showed associations with a use of fibrates, triglyceride levels, creatinine levels, waist circumference, and BMI. Multiple regression analyses adjusted for age, gender and BMI showed that a use of fibrates, triglyceride levels and creatinine levels were strong contributors to serum FGF21 levels. In contrast, a use of thiazolidinediones, HDL-cholesterol levels and fasting insulin levels were strong contributors to serum adiponectin levels. This study revealed that serum FGF21 levels were biochemical indicators correlating to a set of essential metabolic parameters, which was distinct from that correlating to serum adiponectin levels in subjects with type 2 diabetes.

Macrophage lipoprotein lipase modulates the development of atherosclerosis but not adiposity

The role of macrophage lipoprotein lipase (LpL) in the development of atherosclerosis and adiposity was examined in macrophage LpL knockout (MLpLKO) mice. MLpLKO mice were generated using cre-loxP gene targeting. Loss of LpL in macrophages did not alter plasma LpL activity or lipoprotein levels. Incubation of apolipoprotein E (ApoE)-deficient β-VLDL with peritoneal macrophages from ApoE knockout mice lacking macrophage LpL (MLpLKO/ApoEKO) led to less cholesteryl ester formation than that found with ApoEKO macrophages. MLpLKO/ApoEKO macrophages had reduced intracellular triglyceride levels, with decreased CD36 and carnitine palmitoyltransferase-1 mRNA levels compared with ApoEKO macrophages, when incubated with VLDL. Although both MLpLKO/ApoEKO and ApoEKO mice developed comparable hypercholesterolemia in response to feeding with a Western-type diet for 12 weeks, atherosclerosis was less in MLpLKO/ApoEKO mice. Epididymal fat mass and gene expression levels associated with inflammation did not differ between the two groups. In conclusion, macrophage LpL plays an important role in the development of atherosclerosis but not adiposity.

Liver-Specific Deletion of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Causes Hepatic Steatosis and Death

Objective—3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) catalyzes the rate-limiting step in cholesterol biosynthesis and has proven to be an effective target of lipid-lowering drugs, statins. The aim of this study was to understand the role of hepatic HMGCR in vivo. Methods and Results—To disrupt the HMGCR gene in liver, we generated mice homozygous for a floxed HMGCR allele and heterozygous for a transgene encoding Cre recombinase under the control of the albumin promoter (liver-specific HMGCR knockout mice). Ninety-six percent of male and 71% of female mice died by 6 weeks of age, probably as a result of liver failure or hypoglycemia. At 5 weeks of age, liver-specific HMGCR knockout mice showed severe hepatic steatosis with apoptotic cells, hypercholesterolemia, and hypoglycemia. The hepatic steatosis and death were completely reversed by providing the animals with mevalonate, indicating its essential role in normal liver function. There was a modest decrease in hepatic cholesterol synthesis in liver-specific HMGCR knockout mice. Instead, they showed a robust increase in the fatty acid synthesis, independent of sterol regulatory element binding protein-1c. Conclusion—Hepatocyte HMGCR is essential for the survival of mice, and its abrogation elicits hepatic steatosis with jaundice and hypoglycemia.

Pegylated interferon-α2b and ribavirin combination therapy induces Hashitoxicosis followed by type 1 diabetes mellitus

The combination of pegylated interferon-α2b (PEG-IFNα) and ribavirin (RBV) is a standard treatment for chronic hepatitis C. The case of a patient with chronic hepatitis C who developed Hashitoxicosis followed by type 1 diabetes mellitus (T1DM) with PEG-IFNα plus RBV combination therapy, but not IFNα alone, is presented.

Current smoking status may be associated with overt albuminuria in female patients with type 1 diabetes mellitus: a cross-sectional study

BackgroundThere are very few clinical reports that have compared the association between cigarette smoking and microangiopathy in Asian patients with type 1 diabetes mellitus (T1DM). The objective of this study was to assess the relationships between urinary protein concentrations and smoking and gender-based risk factors among patients with T1DM.MethodsA cross-sectional study of 259 patients with T1DM (men/women = 90/169; mean age, 50.7 years) who visited our hospital for more than 1 year between October 2010 and April 2011 was conducted. Participants completed a questionnaire about their smoking habits. Patient characteristics included gender, age, body mass index, blood pressure, hemoglobin A1c, lipid parameters, and microangiopathy. Diabetic nephropathy (DN) was categorized as normoalbuminuria (NA), microalbuminuria (MA), or overt albuminuria (OA) on the basis of the following urinary albumin/creatinine ratio (ACR) levels: NA, ACR levels less than 30 mg/g creatinine (Cr); MA, ACR levels between 30 and 299 mg/g Cr; and OA, ACR levels over 300 mg/g Cr.ResultsThe percentages of current nonsmokers and current smokers with T1DM were 73.0% (n = 189) and 27.0% (n = 70), respectively. In addition, the percentage of males was higher than that of females (52.2% versus 13.6%) in the current smoking population. The percentage of DN was 61.8% (n = 160) in patients with NA, 21.6% (n = 56) in patients with MA, and 16.6% (n = 43) in patients with OA. The percentage of males among OA patients was also higher than that of females (24.4% versus 12.4%). However, current smoking status was associated with OA in females with T1DM only [unadjusted odds ratio (OR), 4.13; 95% confidence interval (CI), 1.45–11.73, P < 0.01; multivariate-adjusted OR, 5.41; 95% CI, 1.69–17.30, P < 0.01].ConclusionsBased on our results in this cross-sectional study of Asian patients with T1DM, smoking might be a risk factor for OA among female patients. Further research is needed of these gender-specific results.

Cardio-Ankle Vascular Index and Indices of Diabetic Polyneuropathy in Patients with Type 2 Diabetes

The cardio-ankle vascular index (CAVI) is used to test vascular function and is an arterial stiffness marker and potential predictor of cardiovascular events. This study aimed to analyze the relation between objective indices of diabetic polyneuropathy (DPN) and the CAVI. One hundred sixty-six patients with type 2 diabetes mellitus were included in this study. We used nerve conduction studies (NCSs) and the coefficient of variation of the R-R interval to evaluate DPN. We estimated arteriosclerosis by the CAVI. Simple and multiple linear regression analyses were performed between neuropathy indices and the CAVI. In univariate analysis, the CAVI showed significant associations with sural sensory nerve conduction velocity and median F-wave conduction velocity. Multiple linear regression analysis for the CAVI showed that sural nerve conduction velocity and median F-wave conduction velocity were significant explanatory variables second only to age. In multiple linear regression analysis for sural nerve conduction velocity among neuropathy indices, the CAVI remained the most significant explanatory variable. In multiple linear regression analysis for median nerve F-wave conduction velocity among neuropathy indices, the CAVI remained the second most significant explanatory variable following HbA1c. These results suggest a close relationship between macroangiopathy and DPN.

Predictors of response to ipragliflozin treatment in patients with type 2 diabetes mellitus

OBJECTIVE The aim of the present study was to investigate the efficacy and safety of ipragliflozin treatment on glycemic control in patients with type 2 diabetes mellitus (T2DM). METHODS We recruited 44 patients with T2DM, treated them with 50 mg/day of ipragliflozin for 12 weeks, and assessed several diabetic variables before and after treatment. We used stepwise multiple regression analysis to evaluate response to ipragliflozin in terms of changes in hemoglobin A1c (HbA1c) levels after therapy. RESULTS Treatment with ipragliflozin for 12 weeks significantly decreased fasting glucose, HbA1c, and blood pressure levels without severe adverse events. The baseline HbA1c (β = -0.52, p < 0.01) and alanine aminotransferase (ALT) levels (β = -0.29, p = 0.03) were independently and significantly related to a decrease in HbA1c levels. CONCLUSIONS In patients with T2DM, ipragliflozin treatment improved glycemic control, and baseline HbA1c and ALT levels appeared to predict treatment response.

Urinary protein as a marker for systolic blood pressure reduction in patients with type 2 diabetes mellitus participating in an in-hospital diabetes education program.

Abstract Increased blood pressure (BP) and urinary protein (UP)/microalbuminuria are risk factors for cardiovascular disease in patients with diabetes. Although the management of BP in patients with diabetes should involve a multidisciplinary therapy, there are no reports in which modulators have been identified in an in-hospital diabetes education program. The aim of the present study was to investigate the change in BP levels in patients with type 2 diabetes mellitus (T2DM) during a short-term (2-week) in-hospital education program on lifestyle modifications. A total of 167 patients with T2DM (101 men, 66 women; mean age, 61.1 years; glycated hemoglobin, 9.2%) were divided into 2 groups on the basis of their urinary albumin levels: 1 group without UP (urinary albumin level < 30 mg/day) and 1 group with UP (urinary albumin level ≥ 30 mg/day). We defined efficacy in reducing BP as a 20-mm Hg reduction in systolic BP (SBP) and a 10-mm Hg reduction in diastolic BP, and compared the changes between the 2 groups. Although the group with UP had higher SBP levels than the group without UP at baseline, this difference disappeared at the end of the program. Adjusted multivariate logistic regression analysis showed that UP at baseline was associated with a reduction in SBP (odds ratio, 3.361; 95% confidence interval, 1.29–8.79; P = 0.013). The data suggest that UP may be a marker related to the management of SBP through lifestyle modifications in patients with T2DM.