Takumi Hirata

Effect of Telmisartan or Losartan for Treatment of Nonalcoholic Fatty Liver Disease: Fatty Liver Protection Trial by Telmisartan or Losartan Study (FANTASY)

Aim. This study compared the effects of telmisartan and losartan on nonalcoholic fatty liver disease (NAFLD) and biochemical markers of insulin resistance in hypertensive NAFLD patients with type 2 diabetes mellitus. Methods. This was a randomized, open-label, parallel-group comparison of therapy with telmisartan or losartan. Nineteen hypertensive NAFLD patients with type 2 diabetes were randomly assigned to receive telmisartan at a dose of 20 mg once a day (n = 12) or losartan at a dose of 50 mg once a day (n = 7) for 12 months. Body fat area as determined by CT scanning and hepatic fat content based on the liver-to-spleen (L/S) ratio, as well as several parameters of glycemic and lipid metabolism, were compared before and after 12 months. Results. The telmisartan group showed a significant decline in serum free fatty acid (FFA) level (from 0.87 ± 0.26 to 0.59 ± 0.22 mEq/L (mean ± SD), P = 0.005) and a significant increase in L/S ratio (P = 0.049) evaluated by CT scan, while these parameters were not changed in the losartan group. Conclusion. Although there was no significant difference in improvement in liver enzymes with telmisartan and losartan treatment in hypertensive NAFLD patients with type 2 diabetes after 12 months, it is suggested that telmisartan may exert beneficial effects by improving fatty liver.

Effects of epalrestat, an aldose reductase inhibitor, on diabetic peripheral neuropathy in patients with type 2 diabetes, in relation to suppression of Nɛ-carboxymethyl lysine

OBJECTIVE We investigated the efficacy of epalrestat, an aldose reductase inhibitor, for diabetic peripheral neuropathy in Japanese patients with type 2 diabetes. METHODS A total of 38 type 2 diabetic patients (22 men and 16 women; mean ± S.E.M. age 63.3 ± 1.0 years; duration of diabetes 9.6 ± 0.8 years) with diabetic neuropathy were newly administered 150 mg/day epalrestat (EP group). Motor nerve conduction velocity (MCV), sensory nerve conduction velocity (SCV), and minimum F-wave latency were evaluated before administration of epalrestat and after 1 and 2 years. Serum N(ɛ)-carboxymethyl lysine (CML) as a parameter of advanced glycation end products (AGEs), lipid peroxide, and soluble vascular cell adhesion molecule (sVCAM)-1 as a parameter of angiopathy were measured before administration and after 1 year. We compared the results with those of 36 duration of diabetes-matched type 2 diabetic patients (mean ± S.E.M. duration of diabetes 8.2 ± 0.7 years) as control (C group). RESULTS The EP group showed significant suppression of deterioration of MCV (P<.01) and minimum F-wave latency (P<.01) in the tibial nerve and SCV (P<.05) in the sural nerve compared to those in the C group after 2 years. There was a significant difference in change in CML level between groups (-0.18 ± 0.13 mU/ml in the EP group vs. +0.22 ± 0.09 mU/ml in the C group, P<.05) after 1 year. CONCLUSIONS Epalrestat suppressed the deterioration of diabetic peripheral neuropathy, especially in the lower extremity. Its effects might be mediated by improvement of the polyol pathway and suppression of production of AGEs.

Body mass index negatively regulates glycated albumin through insulin secretion in patients with type 2 diabetes mellitus

BACKGROUND Glycated albumin (GA) is known to be negatively regulated by body mass index (BMI) in non-diabetic subjects and patients with type 2 diabetes mellitus (T2DM). In non-diabetic subjects, a mechanism has been proposed in which chronic inflammation associated with obesity increases albumin metabolism and negatively regulates GA levels. However, whether this same mechanism exists in T2DM is unclear. We investigated the factor(s) which influence GA levels in T2DM patients. METHODS This study included 179 T2DM patients from among people undergoing complete medical examinations. Correlations between GA and the following variables were examined among fasting samples for T2DM patients: BMI, C-reactive protein (CRP), homeostasis model assessment for β-cell function (HOMA-β) and homeostasis model assessment for insulin resistance (HOMA-R). RESULTS BMI was significantly positively correlated with CRP, but CRP was not significantly correlated with GA. HOMA-β was significantly positively correlated with BMI and significantly negatively correlated with GA. Multivariate analysis showed that HOMA-β was a significant explanatory variable for GA, but not CRP and HOMA-R. CONCLUSIONS Our findings suggest that insulin secretion plays a greater role than chronic inflammation in the mechanism by which BMI negatively regulates GA in T2DM patients.

Palmitic acid-rich diet suppresses glucose-stimulated insulin secretion (GSIS) and induces endoplasmic reticulum (ER) stress in pancreatic islets in mice

Abstract The objective was to clarify whether dietary palmitic acid supplementation affects glucose-stimulated insulin secretion (GSIS) and the endoplasmic reticulum (ER) stress pathway in pancreatic islets in mice. Eight-week-old male C57BL/6J mice were randomly divided into three treatment diet groups: control diet, palmitic acid-supplemented diet (PAL) and oleic acid-supplemented diet (OLE). After 2 weeks of treatment, intraperitoneal glucose tolerance test and intraperitoneal insulin tolerance test were performed. GSIS was assessed by pancreatic perfusion in situ with basal (100 mg/dL) glucose followed by a high (300 mg/dL) glucose concentration. We measured mRNA levels of ER stress markers such as C/EBP homologous protein (CHOP), immunoglobulin heavy-chain binding protein (BIP) and X-box binding protein (XBP)-1 using real-time polymerase chain reaction (PCR) analyses in isolated islets. Immunohistochemical staining was also performed. Mice fed PAL showed significantly decreased glucose tolerance (p < 0.05). In the perfusion study, GSIS was significantly suppressed in the PAL group (p < 0.05). Semi-quantitative RT-PCR revealed that islet CHOP, BIP, and XBP-1 mRNA expression were significantly increased in the PAL group (p < 0.05). TUNEL-positive β-cells were not detected in all groups. Dietary palmitic acid-supplementation for 2 weeks might suppress GSIS and induce ER stress in pancreatic islets in mice, in the early stage of lipotoxicity.

Relationship between non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol in the general population: The KOBE study and Tsuruoka Metabolomic cohort study

AIM The Japan Atherosclerosis Society (JAS) Guidelines for Diagnosis and Prevention of Atherosclerotic Cardiovascular Diseases for Japanese 2012 version have set a non-high-density lipoprotein cholesterol (non-HDL-C)-management target of low-density lipoprotein cholesterol (LDL-C) ＋30 mg/dL. However, the actual difference between non-HDL-C and LDL-C is not clear. Therefore, we evaluated its joint distribution and assessed the validity of this criterion in the general Japanese population. METHODS We used baseline cross-sectional data of 4,110 participants from two studies; the KOBE Study (n=1,108) and the Tsuruoka Metabolomic Cohort Study (n=3,002). To evaluate whether the difference between LDL-C and non-HDL-C in the general population match that of the current guidelines, we classified LDL-C levels into four groups according to the JAS Guideline and evaluated its agreement with the corresponding non-HDL-C group. Analysis was also done using six groups (the previous four groups plus the upper and lower cut-off values). RESULTS The mean difference (mg/dL) between the non-HDL-C and LDL-C (for the KOBE Study and Tsuruoka Metabolomic Cohort Study, respectively) was 19.6 and 24.1 (p<0.001) for men and 15.9 and 18.3 (p<0.001) for women. In both the cohort studies, the difference was lower than 30 mg/dL. It was especially small among individuals with normal triglyceride levels. CONCLUSIONS In the general Japanese population, the difference between non-HDL-C and LDL-C was lower than the expected difference of 30 mg/dL. Changes to the criteria for non-HDL-C target levels may be considered in the future.

Effects of olmesartan medoxomil, an angiotensin II type 1 receptor antagonist, on plasma concentration of B-type natriuretic peptide, in hypertensive patients with type 2 diabetes mellitus: A preliminary, observational, open-label study

AbstractBackground and Objective: Angiotensin II type 1 (AT1) receptor antagonists (angiotensin receptor blockers [ARBs]) are widely used for the treatment of not only hypertension but also cardiac dysfunction. B-type natriuretic peptide (BNP) is secreted mainly by the cardiac ventricle and plays an important role in the regulation of blood pressure (BP) and body fluid. It has been established that the plasma level of BNP is increased in patients with chronic heart failure in proportion to the severity of cardiac dysfunction. Because cardiac dysfunction is closely associated with a high risk of mortality in patients with diabetes mellitus, early identification and prevention of cardiac dysfunction are important. The objective of this study was to determine the effects of olmesartan medoxomil, a novel ARB, on the plasma level of BNP in hypertensive patients with type 2 diabetes. Methods: This was a preliminary, prospective, observational, open-label study. Sixty-eight type 2 diabetic patients with hypertension (systolic BP [SBP] ≥140 mmHg or diastolic BP [DBP] ≥90 mmHg) received olmesartan medoxomil 10–20 mg/day for 24 weeks. Plasma levels of BNP, as well as several clinical parameters of glycaemic control and lipid metabolism, were compared before and after 24 weeks of treatment. Another group consisting of 22 age-and body mass index-matched subjects not treated with olmesartan medoxomil was observed for reference purposes. Results: In the olmesartan medoxomil group, mean ± SD SBP decreased from 152.8 ± 16.4 at baseline to 146.8 ± 14.4mmHg after 24 weeks’ treatment (p < 0.05); similarly, mean ± SD DBP decreased from 85.6 ± 10.5 to 81.3 ± 11.6 mmHg (p < 0.05). In 53 subjects in whom plasma levels of BNP could be measured both before and after treatment, mean ± SD BNP decreased from 41.3 ± 49.9 to 32.5 ± 36.3 pg/mL (p < 0.05). Change in plasma BNP level over the 24-week treatment period in the olmesartan medoxomil group was not correlated with change in SBP or DBP. Multiple regression analysis revealed that change in plasma BNP level was not correlated with baseline value of or change in any other parameters. No other parameters in the olmesartan medoxomil group, and no parameters in the non-olmesartan medoxomil reference group, showed significant changes. Conclusion: The current preliminary study showed that olmesartan medoxomil treatment might decrease plasma BNP levels, independent of its BP-lowering effect, in hypertensive patients with type 2 diabetes.

Surveillance rates for hepatocellular carcinoma among patients with cirrhosis, chronic hepatitis B, and chronic hepatitis C based on Japanese claims database.

Surveillance is recommended for patients with risk of hepatocellular carcinoma (HCC) such as viral hepatitis and liver cirrhosis (LC). Although populations are at higher risk in Asia, surveillance rates have not been evaluated in those countries. Therefore, we aimed to examine surveillance rates for HCC and to compare predictors for surveillance among each type of liver disease in Japan.

HOMA-IR Values are Associated With Glycemic Control in Japanese Subjects Without Diabetes or Obesity: The KOBE Study

BACKGROUND Several studies have reported that insulin resistance was a major risk factor for the onset of type 2 diabetes mellitus in individuals without diabetes or obesity. We aimed to clarify the association between insulin resistance and glycemic control in Japanese subjects without diabetes or obesity. METHODS We conducted a community-based cross-sectional study including 1083 healthy subjects (323 men and 760 women) in an urban area. We performed multivariate regression analyses to estimate the association between the homeostasis model assessment of insulin resistance (HOMA-IR) values and markers of glycemic control, including glycated haemoglobin (HbA1c), 1,5-anhydroglucitol (1,5-AG), and fasting plasma glucose (FPG) levels, after adjustment for potential confounders. RESULTS Compared with the lowest tertile of HOMA-IR values, the highest tertile was significantly associated with HbA1c and FPG levels after adjustment for potential confounders, both in men (HbA1c: β = 1.83, P = 0.001; FPG: β = 0.49, P < 0.001) and women (HbA1c: β = 0.82, P = 0.008; FPG: β = 0.39, P < 0.001). The highest tertile of HOMA-IR values was inversely associated with 1,5-AG levels compared with the lowest tertile (β = -18.42, P = 0.009) only in men. CONCLUSIONS HOMA-IR values were associated with markers of glycemic control in Japanese subjects without diabetes or obesity. Insulin resistance may influence glycemic control even in a lean, non-diabetic Asian population.Background Several studies have reported that insulin resistance was a major risk factor for the onset of type 2 diabetes mellitus in individuals without diabetes or obesity. We aimed to clarify the association between insulin resistance and glycemic control in Japanese subjects without diabetes or obesity. Methods We conducted a community-based cross-sectional study including 1083 healthy subjects (323 men and 760 women) in an urban area. We performed multivariate regression analyses to estimate the association between the homeostasis model assessment of insulin resistance (HOMA-IR) values and markers of glycemic control, including glycated haemoglobin (HbA1c), 1,5-anhydroglucitol (1,5-AG), and fasting plasma glucose (FPG) levels, after adjustment for potential confounders. Results Compared with the lowest tertile of HOMA-IR values, the highest tertile was significantly associated with HbA1c and FPG levels after adjustment for potential confounders, both in men (HbA1c: β = 1.83, P = 0.001; FPG: β = 0.49, P < 0.001) and women (HbA1c: β = 0.82, P = 0.008; FPG: β = 0.39, P < 0.001). The highest tertile of HOMA-IR values was inversely associated with 1,5-AG levels compared with the lowest tertile (β = −18.42, P = 0.009) only in men. Conclusions HOMA-IR values were associated with markers of glycemic control in Japanese subjects without diabetes or obesity. Insulin resistance may influence glycemic control even in a lean, non-diabetic Asian population.

Relationships of Muscle Echo Intensity with Walking Ability and Physical Activity in the Very Old Population

This study investigated the relationships between muscle echo intensity (EI), physical activity (PA), and functional mobility in 108 Japanese (88-92 years). We measured EI and muscle thickness (MT) at the midpoint of the anterior superior iliac spine and patella using B-mode ultrasound. Light and moderate-to-vigorous PA (LPA and MVPA) were assessed with a triaxial accelerometer. The timed up and go (TUG) test was used to measure for functional mobility. EI, but not MT, was significantly associated with both TUG scores (β = 0.17, p = .047) and MVPA (β = -0.31, p = .01) when adjusted by potential confounders. However, association between EI and TUG disappeared after adjusted for MVPA. Meanwhile, MVPA was significantly associated with TUG scores independent of EI (β = -0.35, p < .001). Although EI of anterior thigh muscles might be a weaker predictor of functional morbidity than MVPA, it is a noninvasive and practical approach for assessing muscle quality in the very old.

Glycated albumin is not significantly correlated with body mass index in patients with acute-onset type 1 diabetes.

BACKGROUND No previous reports have clarified the relationship between glycated albumin (GA) and BMI in patients with acute-onset type 1 diabetes. METHODS We conducted a cross-sectional study evaluating the correlation between GA and BMI in 209 patients with acute-onset type 1 diabetes and in 159 patients with type 2 diabetes who were designated as the control group. The correlation between fasting serum C-peptide immunoreactivity (CPR) and GA or BMI was also evaluated to clarify the impact of insulin secretion capacity on the relationship between GA and BMI. RESULTS GA was significantly inversely correlated with BMI in patients with type 2 diabetes (r=-0.317, p<0.001) but not in patients with type 1 diabetes (r=0.031, p=NS). In patients with type 2 diabetes, GA was significantly inversely correlated with fasting CPR, and BMI was significantly correlated with fasting CPR. In patients with type 1 diabetes, GA was significantly inversely correlated with fasting CPR (r=-0.291, p<0.001), but BMI was not correlated with fasting CPR (r=-0.010, p=NS). CONCLUSIONS Unlike in patients with type 2 diabetes, GA was not significantly correlated with BMI in patients with acute-onset type 1 diabetes.