Hideo Kanehara

Pitavastatin-Induced Thrombomodulin Expression by Endothelial Cells Acts Via Inhibition of Small G Proteins of the Rho Family

Objective—3-Hydroxyl-3-methyl coenzyme A reductase inhibitors (statins) can function to protect the vasculature in a manner that is independent of their lipid-lowering activity. The main feature of the antithrombotic properties of endothelial cells is an increase in the expression of thrombomodulin (TM) without induction of tissue factor (TF) expression. We investigated the effect of statins on the expression of TM and TF by endothelial cells. Methods and Results—The incubation of endothelial cells with pitavastatin led to a concentration- and time-dependent increase in cellular TM antigen and mRNA levels. In contrast, the expression of TF mRNA was not induced under the same conditions. A nuclear run-on study revealed that pitavastatin accelerates TM transcription rate. The stimulation of TM expression by pitavastatin was prevented by either mevalonate or geranylgeranylpyrophosphate. Specific inhibition of geranylgeranyltransferase-I and Rac/Cdc42 by GGTI-286 and Clostridium sordellii lethal toxin, respectively, enhanced TM expression, whereas inactivation of Rho by Clostridium botulinum C3 exoenzyme was ineffective. Conclusions—Statins regulate TM expression via inhibition of small G proteins of the Rho family; Rac/Cdc42. A statin-mediated increase in TM expression by endothelial cells may contribute to the beneficial effects of statins on endothelial function.

CLD (chronic liver diseases)-HbA1C as a suitable indicator for estimation of mean plasma glucose in patients with chronic liver diseases.

In patients with chronic liver diseases (CLD), turnover of erythrocytes is increased whereas that of serum albumin is decreased. Thus, glycated hemoglobin (HbA(1C)) and glycated albumin (GA) cannot be used as adequate indicators for chronic plasma glucose control in diabetic patients with CLD. In this investigation, we have proposed CLD-HbA(1C), a novel long-term glycemic control marker by using measured HbA(1C) and GA. We studied 82 patients with CLD in whom glycemic control was regarded as to be stable. Daily plasma glucose profiles were monitored and estimated levels of HbA(1C) were calculated on the conversion formula established by Rohlfing et al. [C.L. Rohlfing, J.D. England, H.M. Wiedmeyer, A. Tennill, R.R. Little, D.E. Goldstein, Defining the relationship between plasma glucose and HbA1c, Diabetes Care 25 (2002) 275-278]. Cholinesterase (ChE) as an indicator for hepatic function was determined at the same time when HbA(1C) and GA levels were measured. CLD-HbA(1C) was defined as the average of measured HbA(1C) and GA/3, based upon the results that among healthy individuals, GA levels were roughly estimated at approximately threefold higher than HbA(1C) levels. While measured HbA(1C) levels in patients with CLD were generally lower than estimated HbA(1C) levels, GA/3 values were generally higher than estimated HbA(1C) levels. Such discrepancies lineally increased in accordance with a decrease in ChE levels. On the other hand, CLD-HbA(1C) levels were highly correlated with estimated HbA(1C) levels (R=0.883), while no significant correlation between CLD-HbA(1C) and ChE was noted. In conclusion, CLD-HbA(1C) has been found a superior chronic glycemic control marker than HbA(1C) or GA in diabetic patients with chronic liver diseases.

Association of serum glycated albumin to haemoglobin A1C ratio with hepatic function tests in patients with chronic liver disease

Background In patients with chronic liver disease (CLD), glycated haemoglobin (HbA1C) levels have been shown to be apparently lower than real values, whereas serum glycated albumin (GA) levels are apparently higher. The present study was aimed to examine whether both glycaemic indices are influenced by hepatic function. Methods Subjects consisted of 82 patients with CLD. Various indicators for hepatic function as well as HbA1C and GA were also measured. Estimated HbA1C values were calculated from the mean plasma glucose levels. Two hundred and two type 2 diabetic patients without CLD were studied as controls. Results Although GA was strongly correlated with HbA1C in patients with CLD as well as diabetic patients, GA levels in patients with CLD were relatively higher than those in diabetic patients. In patients with estimated HbA1C ≤5.8%, GA levels significantly increased but HbA1C levels decreased as a function of decreasing hepaplastin test (HPT). The ratio of GA/HbA1C (G/H ratio) increased as a function of decreasing HPT. In patients with estimated HbA1C >5.8%, in contrast, GA levels were independent of HPT levels. In the patients with CLD, GA and HbA1C were associated with mean plasma glucose levels and some indicators for hepatic function. The multivariate analysis revealed a significant association of G/H ratio with HPT, cholinesterase and direct bilirubin. The G/H ratio was not associated with the mean plasma glucose but with HPT and cholinesterase levels. Conclusions The G/H ratio correlates with hepatic function but not with plasma glucose levels. Therefore, CLD should be suspected for diabetic patients with an elevated G/H ratio.

Obesity may attenuate the HbA1c-lowering effect of sitagliptin in Japanese type 2 diabetic patients

Aims/Introduction:  The aim of the present study was to assess the independent predictors of the HbA1c‐lowering effect of sitagliptin in Japanese type 2 diabetic patients.

Characteristics of undiagnosed diabetes mellitus in a population undergoing health screening in Japan: Target populations for efficient screening

AIMS To estimate the prevalence of undiagnosed diabetes mellitus and its relationship with various risk factors in a population undergoing health screening in Japan. METHODS Oral glucose tolerance tests were carried out in a total sample of 14,674 Japanese subjects undergoing health screening, aged 20-83 years and without known diabetes. The prevalence of glucose tolerance categories (1999 WHO criteria) was adjusted for sample probabilities. The optimal FPG cut-off point for screening diabetes was estimated using ROC curve analysis for the continuous value of FPG corresponding to a 2-h PG of 200 mg/dl. The number needed to screen (NNTS) to identify one person with undiagnosed diabetes with various risk factors was estimated using the following equation: the number of undiagnosed diabetic plus nondiabetic subjects/the number of undiagnosed diabetic subjects. RESULTS The prevalence of undiagnosed diabetes among men and women was 6.4% (NNTS 15.7) and 3.2% (NNTS 31.7), respectively. The optimal FPG cut-off point for screening diabetes among men and women was 105 and 106 mg/dl, respectively. NNTS was lower in individuals with more risk factors, e.g. aging (> or =50), BMI (> or =25), hypertension (SBP> or =140 mmHg and/or DBP> or =90 mmHg) and dyslipidemia (TC> or =220 and/or HDL-C<40 and/or TG> or =150 mg/dl), resulting in the lowest NNTS in individuals having all four risk factors among men (6.1) and women (6.7), respectively. CONCLUSIONS In Japan, screening for diabetes may be more efficient among individuals having an FPG of more than 105-106 mg/dl and with more risk factors, especially in men.

Thrombomodulin expression by THP-1 but not by vascular endothelial cells is upregulated by pioglitazone

Thrombomodulin-protein C pathway is a major anti-thrombotic mechanism present in endothelial cells (EC), and an important modulator of inflammation. Peroxisomal proliferator activated receptor-gamma (PPARgamma) expressed in monocytes/macrophages may have a role in cell differentiation. Since the expression of thrombomodulin (TM) by monocytes is upregulated during differentiation into macrophages, we investigated the effect of pioglitazone, a thiazolidinedione (TZD) that is a synthetic ligand of PPARgamma, on the expression of TM by a human monocyte/macrophage cell line; human acute monocytic leukemia (THP-1) cells. Pioglitazone dose-dependently upregulated TM antigen expression by THP-1 cells accompanied by an upregulation of TM cofactor activity for thrombin-dependent protein C activation. Thrombomodulin mRNA expression in THP-1 cells was also upregulated by pioglitazone, whereas tissue factor (TF) mRNA expression was not induced at all. Treatment cells with a natural PPARgamma ligand, 15-deoxy-delta12,14-prostaglandin J(2) (PGJ2), also enhanced TM protein expression. PGF(2alpha) an agent known to inactivate PPARgamma, diminished the stimulatory effect of pioglitazone and PGJ2 on TM protein expression. In contrast, pioglitazone had no effect on TM antigen expression by human umbilical vein ECs. These results suggest that PPARgamma activation in macrophages may counteract potentially prothrombotic and putative inflammatory properties in activated macrophages.

Glycated albumin levels are higher relative to HbA1c levels in people with autoimmune acute-onset type 1 diabetes mellitus than in people with type 2 diabetes mellitus at the time of diagnosis.

Glycated albumin (GA) is a new glycemic control indicator. GA/HbA1c ratio in autoimmune acute-onset type 1 diabetes mellitus patients was significantly higher than in type 2 diabetes mellitus patients at the time of diagnosis. This difference might reflect speed of increase in plasma glucose after the onset of diabetes.

1,5-Anhydroglucitol levels are low irrespective of plasma glucose levels in patients with chronic liver disease

Backgound Serum 1,5-anhydroglucitol (1,5-AG) is a known marker reflecting recent glycaemic control. In this study, we examined serum 1,5-AG levels in chronic liver disease (CLD) patients with and without diabetes mellitus. Methods Eighty patients with CLD were compared with 667 subjects without CLD. Glycaemic control of the CLD patients was evaluated by estimated glycated haemoglobin (HbA1C) calculated using the equation by Rohlfing et al. from mean plasma glucose because CLD patients have apparently low HbA1C. Results When the study participants were divided into subgroups stratified by HbA1C levels, the CLD patients whose estimated HbA1C levels were less than 7.0% showed significantly lower 1,5-AG than their counterparts of the control subjects. Stepwise multivariable analysis revealed that estimated HbA1C was the significant explanatory variable for 1,5-AG in the CLD patients. However, in the CLD patients with estimated HbA1C less than 5.8%, only hepaplastin test was the significant explanatory variable for 1,5-AG. Conclusions Serum 1,5-AG levels are low irrespective of plasma glucose levels in the CLD patients with and without diabetes. The CLD patients who had low serum 1,5-AG levels were associated with deteriorated liver function.

The glycated albumin to glycated haemoglobin ratio increases along with the fibrosis stage in non-alcoholic steatohepatitis

Background We previously reported that the indicator of glycaemic control, glycated albumin (GA) levels, are low in relation to glycaemia in patients with high alanine aminotransferase (ALT) levels in non-alcoholic fatty liver disease because of chronic inflammation, and that the GA/glycated haemoglobin ratio (G/H ratio) is inversely correlated with hepatic function in patients with chronic liver disease. The severity of liver fibrosis is known to be a good indicator for surveillance, and for determining the prognosis and optimal treatment of non-alcoholic steatohepatitis (NASH). In this study, we aimed to investigate the clinical usefulness of measuring the G/H ratio for predicting the severity of liver fibrosis in patients with NASH. Methods The study subjects were 36 patients with histologically diagnosed NASH (19 men, 17 women; mean age54.8 ± 12.2 years, body mass index 28.3 ± 5.0 kg/m2). The relationships of the G/H ratio to hepatic function tests and fibrosis stage in the liver were investigated. Results The G/H ratio in patients with NASH was inversely correlated with ALT (P < 0.001) and platelet count (P < 0.0001). Furthermore, the G/H ratio was positively correlated with the fibrosis stage in liver (P = 0.003). Conclusions These results suggest that the G/H ratio increases along with the fibrosis stage in patients with NASH.

Ipragliflozin lowers small, dense low-density lipoprotein cholesterol levels in Japanese patients with type 2 diabetes mellitus

Highlights • Small dense LDL-C (sd LDL-C) convey cardiovascular risk in type 2 diabetes (T2D).• Ipragliflozin reduced sd LDL-C levels in Japanese patients with T2D.• Changes in body weight, TG and LDL-C levels contributed to sd LDL-C reduction.