Mutsuhiro Kobayashi

Nicotinamide Adenine Dinucleotide Phosphate-Dependent Cytosolic T3 Binding Protein as a Regulator for T3-Mediated Transactivation

Nicotinamide adenine dinucleotide phosphate (NADPH)dependent cytosolic T3 binding protein (CTBP) plays a role in the regulation of nuclear transport of T3 in vitro. However, it is not known whether CTBP regulates the T3 action. In this study, we examined the effects of CTBP on cellular translocation of T3 and on transcriptional activation using established CTBP-expressing CHO or GH3 cells. The expression of CTBP increased cellular and nuclear uptake of T3 in the CTBP-expressing cells. The efflux rate was decreased by induction of CTBP. Efflux from nuclei also inhibited by induction of CTBP. Expression of CTBP suppressed the T3-regulated luciferase activity in GH3 cells. Suppression was observed to be related to the expression level of CTBP. T3 induction of rat GH mRNA was lower in the cells expressing CTBP than that in CTBP-null cells. These results suggest that CTBP regulates the T3-induced gene expression, with which an increase in the nuclear content of the T3 is associated. Because we observed that a part of CTBP could be transported into nuclei and that acceptor protein for CTBP is present in nuclei as previously reported, interaction of CTBP with certain proteins, including transcription factors or nuclear T3 receptor, may contribute to the regulation. (Endocrinology 143: 1538 –1544, 2002)

Correlation between mean platelet volume and fasting plasma glucose levels in prediabetic and normoglycemic individuals

BackgroundPrediabetes is an independent risk factor for cardiovascular diseases. Mean platelet volume (MPV) can reflect platelet activity, and high MPV is associated with thrombogenic activation and an increased risk of cardiovascular disease. In diabetic patients, MPV is higher when compared with normal subjects. However, the relationship between MPV and prediabetes is poorly understood. The purpose of the present study was to compare MPV in prediabetic and normoglycemic subjects, and to evaluate the relationship between MPV and fasting plasma glucose (FPG) levels in these two groups.MethodsWe retrospectively studied 1876 Japanese subjects who had undergone health checks at Iida Municipal Hospital. Age, sex, body mass index (BMI), blood pressure, medical history, smoking habits, alcohol intake, lipid profiles, FPG levels, and MPV were evaluated. Subjects were categorized into four groups according to FPG: Q1 (70 mg/dL ≤ FPG < 90 mg/dL, n = 467), Q2 (90 mg/dL ≤ FPG < 95 mg/dl, n = 457), Q3 (95 mg/dL ≤ FPG < 100 mg/dL, n = 442), and Q4 (100 mg/dL ≤ FPG < 126 mg/dL, n = 512). Q1, Q2, and Q3 were defined as normal FPG groups and Q4 was defined as prediabetic group.ResultsThe MPV increased with the increasing FPG levels, in the following order: Q1 (9.89 ± 0.68 fl), Q2 (9.97 ± 0.69 fl), Q3 (10.02 ± 0.72 fl), and Q4 (10.12 ± 0.69 fl). After adjusting for the confounding parameters, MPV of the prediabetic group was higher than that in other groups (P < 0.001 for Q4 vs. Q1 and Q2, and P < 0.05 for Q4 vs. Q3). MPV in the high-normal glucose group (Q3) was significantly higher than in the low-normal glucose group (Q1). MPV was independently and positively associated with FPG, not only in prediabetic subjects but also in normal FPG subjects (β = 0.020 and β = 0.006, respectively).ConclusionsMPV in patients with prediabetes was higher than that in normal subjects, and was positively associated with FPG levels in prediabetic and normal subjects.

Evidence for the existence of protein inhibitors for S-adenosyl-L-methionine-mediated methylation of phosphatidylethanolamine in rat liver cytosol

The effect of rat liver cytosol on phosphatidylcholine biosynthesis via the N-methylation of phosphatidylethanolamine has been studied. The purified rat liver plasma membrane was used as an enzyme source. The rat liver 105,000 x g supernatant(cytosol) contained two different inhibitors for S-adenosyl-L-methionine-mediated methylation of phosphatidylethanolamine to phosphatidyl-N-mono-methylethanolamine. The inhibitors were inactivated by pretreatment with trypsin or heating at 96 degrees C, but were not inactivated by RNase. The inhibitors did not inhibit the synthesis of phosphatidylcholine from phosphatidyl-N-mono-methylethanolamine. The results indicate that two different protein inhibitors for methylation are present in rat liver cytosol fraction and that the inhibition by these proteins may have a role for the regulation of phosphatidylcholine synthesis in the plasma membrane.

Gender differences in the relationship between serum uric acid and mean platelet volume in a Japanese general population

Abstract Mean platelet volume (MPV) can reflect platelet activity. Furthermore, high MPV is associated with thrombogenic activation and increased risk of cardiovascular disease. MPV of subjects with hypertension, hyperglycemia, or hyperlipidemia is higher compared with that of normal subjects. In contrast, the relationship between MPV and uric acid (UA) is poorly understood. The present study aims to evaluate the relationship between MPV and serum UA levels in both genders. We retrospectively studied 2104 Japanese subjects (1221 males, 883 females) undergoing general health examinations. Age, gender, body mass index (BMI), blood pressure (BP), smoking habits, alcohol intake, lipid profiles, fasting plasma glucose (FPG), high-sensitivity C-reactive protein, serum UA levels and MPV were evaluated. On the basis of the serum UA levels, the subjects were categorized into the following tertiles: 1st (Q1), 2nd (Q2), and 3rd (Q3). In males, a univariate analysis revealed that age, FPG and systolic and diastolic BP were significantly associated with MPV; in addition to these parameters, in females, UA and LDL-cholesterol correlate with MPV. Furthermore, in females, a stepwise linear regression analysis showed a significant positive correlation between UA and MPV (β = 0.059, p = 0.008). MPV in females increased gradually based on the serum UA tertile, despite adjusting for confounding variables (Q1, Q2, and Q3 values were 9.88 ± 0.70, 9.95 ± 0.73, and 10.00 ± 0.77 fL, respectively; p < 0.039). The serum UA levels were found to be a key determinant of MPV in females.

Impact of serum triglyceride and high density lipoprotein cholesterol levels on early-phase insulin secretion in normoglycemic and prediabetic subjects.

Background Increased triglycerides (TGs) and decreased high density lipoprotein cholesterol (HDL-C) levels are established as diabetic risks for nondiabetic subjects. The aim of this study was to investigate the relationship among TG, HDL-C, TG/HDL-C ratio, and early-phase insulin secretion in normoglycemic and prediabetic subjects. Methods We evaluated 663 Japanese subjects who underwent the 75-g oral glucose tolerance test. On the basis of these results, the subjects were divided into four groups: those with normal glucose tolerance (NGT; n=341), isolated impaired fasting glucose (i-IFG; n=211), isolated impaired glucose tolerance (i-IGT; n=71), and combined IFG and IGT (IFG+IGT; n=40). Insulin secretion was estimated by the insulinogenic index (IGI) (Δinsulin/Δglucose [30 to 0 minutes]) and disposition index (DI) (IGI/homeostasis model assessment of insulin resistance). Results In prediabetic subjects (i-IFG, i-IGT, and IFG+IGT), linear regression analyses revealed that IGI and DI were positively correlated with HDL-C levels. Moreover, in subjects with i-IGT and (IFG+IGT), but not with i-IFG, the indices of insulin secretion were negatively correlated with the log-transformed TG and TG/HDL-C ratio. In both the subjects with i-IGT, multivariate linear regression analyses revealed that DI was positively correlated with HDL-C and negatively with log-transformed TG and TG/HDL-C ratio. On the other hand, in subjects with NGT, there was no association between insulin secretion and lipid profiles. Conclusion These results revealed that serum TG and HDL-C levels have different impacts on early-phase insulin secretion on the basis of their glucose tolerance status.

Possible Link Between a Low Prevalence of Cardiovascular Disease and Mild Dyslipidaemia: a Study in Japanese Patients with Type 2 Diabetes

In 98 Japanese patients with Type 2 diabetes mellitus, serum total cholesterol, triglyceride, high density lipoprotein cholesterol (HDL‐C), free fatty acid (FFA), and apolipoproteins (apo) A‐I, A‐II, B, C‐II, C‐III, and E were determined. The data were compared with those in 47 normolipidaemic normal controls. The total cholesterol value of the diabetic patients was also compared to that of a general population (n = 2227). The diabetic patients were separated into those with cardiovascular disease (n = 20) and without it (n = 78) and a comparison of clinical characteristics and dyslipidaemia was also performed. The diabetic patients had slightly but significantly higher FFA, LDL‐C, apo B, C‐II, C‐III, E, and B/A‐I, and lower apo A‐I and A‐II compared to the normal controls. The total cholesterol level of the diabetic patients (5.17 ± 0.96 mmol−1) was not significantly higher than that of the general population (5.12 ± 0.91 mmol−1). By multivariate stepwise discriminant analyses, only total cholesterol significantly discriminated the patients with and without cardiovascular disease. In Japanese patients with Type 2 diabetes, a diabetic population with a very low prevalence of cardiovascular disease, high total cholesterol ís a risk factor for developing cardiovascular disease. Nevertheless, a markedly low prevalence of cardiovascular disease in Japanese with Type 2 diabetes compared to Caucasian counterparts may partly be due to the mildness of dyslipidaemia.

Calorie restriction increases serum parathyroid hormone and decreases serum calcitonin levels in patients with maturity onset diabetes mellitus

Calorie restriction is important in managing patients with maturity onset diabetes mellitus (NIDDM). The effect of such restriction on calcium metabolism is not known. The objective of this study was to determine whether patients on calorie restricted diets would show any modification of parathyroid hormone (PTH) and calcitonin (CTN).The serum levels of PTH and CTN were measured by radioimmunoassays in 269 patients with NIDDM. The patients were divided into two groups depending on the intake of calorie, and PTH and CTN were monitored for 2 years. Plasma levels of vitamin D were measured by competitive protein binding assays before and after each program.The level of PTH (520.8±266.0 pg/ml) (mean±S.D.) was significantly (P<0.01) higher in 109 diabetic patients whose calorie intake was restricted for 2 years (diet (D) group) as compared with that (256.6±103.8 pg/ml) of 160 diabetic patients whose calorie intake was not restricted (non-diet (ND) group). The daily oral calcium intake of the two groups did not differ significantly. We found no significant difference in the serum PTH level in the ND groupVS. normal control subjects (248.8±98.4, N=78). The serum calcium concentration and the amount of calcium excreted in urine were slightly but significantly (P<0.01) lower in the D than in the ND group. The rate of tubular reabsorption of phosphate (% TRP) was significantly lower in the D group than that in the ND group (P<0.01). The serum CTN level was significantly (P<0.01) lower in the D group (33.9±11.3 pg/ml) than in the ND group (64.9±21.2 pg/ml) 2 years after each treatment. The plasma 1,25-(OH)2-vitamin D level was significantly (P<0.01) lower in the D group (22.2±6.6 pg/ml) than in the ND group (50.6±4.2 pg/ml). When the restriction of calorie intake in the D group was canceled, their PTH levels decreased, which was accompanied by increase in the 1,25-(OH)2-vitamin D levels, whereas their CTN levels were unchanged.These observations suggested that a restricted calorie intake is a risk factor for secondary hyperparathyroidism as well as for a low serum level of CTN in patients with NIDDM.

Correlation between mean platelet volume and blood glucose levels after oral glucose loading in normoglycemic and prediabetic Japanese subjects

Mean platelet volume (MPV) reflects platelet activity, and high MPV is associated with thrombogenic activation and increased cardiovascular disease risk. Although a positive correlation between MPV and fasting plasma glucose (FPG) levels has been reported, the correlation between MPV and postprandial glucose levels remains unclear. The purpose of the present study was to evaluate the correlation between MPV and postprandial glucose levels in prediabetic and normoglycemic participants.

The relationship between serum uric acid levels and β-cell functions in nondiabetic subjects.

High serum uric acid (UA) levels are believed to be an independent risk factor for the development of diabetes. We aimed to investigate the relationship between serum UA concentrations and early-phase insulin secretion following a 75 g oral glucose tolerance test (OGTT) in nondiabetic subjects. We enrolled 570 Japanese subjects (354 males and 216 females, aged 50.5 ± 8.9 years and 52.6 ± 7.3 years, respectively), who underwent the 75 g OGTT during their annual health examination. The OGTT confirmed their nondiabetic status. Insulin secretion was estimated by the disposition index (DI) [(Δ insulin/Δ glucose (0-30 min) × (1/HOMA-IR)], which is an adjusted measure of β-cell function relative to variations in insulin sensitivity. Simple linear regression analysis showed negative correlations between serum UA levels and DI, when examined in the whole study population and female subjects only (r = -0.209, p < 0.001 and r = -0.232, p < 0.001, respectively). However, in male subjects, UA levels did not correlate with DI. In females, multivariate linear regression analysis revealed that serum UA levels were the major predictors of DI, explaining 16.4% of its variation (p < 0.001). Serum UA levels significantly correlate with early-phase insulin secretion in nondiabetic Japanese women. It may be an independent risk factor for predicting β-cell function in women.

Serum Triglyceride Levels Correlated with the Rate of Change in Insulin Secretion Over Two Years in Prediabetic Subjects

Background/Aims: Increased triglyceride (TG) and decreased high-density lipoprotein cholesterol (HDL-C) levels are considered risk factors for diabetes among prediabetic subjects. In this study, we retrospectively investigated the relationship between lipid profiles and the rate of change in early-phase insulin secretion in prediabetic subjects. Methods: To evaluate insulin secretion, 50 prediabetic subjects underwent a 75-gram oral glucose tolerance test at the beginning of the study (baseline), and they were reexamined after a 2-year interval. The results were expressed as insulinogenic index (IGI) and disposition index (DI). Results: The lipid profiles and indices of insulin secretion had not significantly changed over 2 years. However, Pearsons correlation analyses indicated that the rate of change in IGI and DI was negatively correlated with log-transformed baseline TG level, but not with baseline HDL-C level. Multiple linear regression analysis confirmed that the rate of change in IGI and DI was negatively correlated with the log-transformed baseline TG level (β = -0.38, p = 0.006, and β = -0.39, p = 0.006, respectively). Conclusions: Baseline TG level of prediabetic subjects appeared to be associated with rate of change in IGI and DI over a 2-year period, indicating that TG levels among prediabetic subjects should be carefully monitored.