[The status of glycemic control and hypoglycemia in elderly patients visiting the outpatient department specializing in diabetes].

AIM: The Japan Diabetes Society (JDS)/Japan Geriatrics Society (JGS) Joint Committee reported 'Glycemic Targets for Elderly Patients with Diabetes' in 2016. Based on this recommendation, we aimed to clarify 1) the achievement status of glycemic targets in the elderly and 2) the presence of hypoglycemia in real life among elderly individuals with an HbA1c below the lower limit. SUBJECTS AND METHODS: [Analysis I] In 326 elderly with diabetes ≥65 years of age visiting the outpatient department specializing in diabetes, the proportions of patients with HbA1c values below the lower limit and the use of drugs potentially associated with severe hypoglycemia (e.g. insulin formulations, sulfonylureas, glinides) were investigated. [Analysis II] Of the patients with HbA1c values below the lower limit, seven were tested for hypoglycemia in real life using a continuous glucose monitoring system (CGM). RESULTS: [Analysis I] Among the 326 subjects, 235 (72.1%) were using drugs potentially associated with severe hypoglycemia, and 63 (19.3%) had an HbA1c value below the lower limit. [Analysis II] In the seven patients examined using CGM, hypoglycemia was detected in five, all of whom were unaware. CONCLUSIONS: A considerable number of elderly patients were taking drugs associated with hypoglycemic risks and had an HbA1c value below the lower limit, some of whom actually had hypoglycemia as detected by CGM. Using tools such as CGM, preventive measures against hypoglycemia should be taken.

Telmisartan treatment decreases visceral fat accumulation and improves serum levels of adiponectin and vascular inflammation markers in Japanese hypertensive patients.

Hypertension contributes to the occurrence and progression of cardiovascular diseases. The angiotensin II type 1 receptor blocker telmisartan is reported to activate the peroxisome proliferator-activated receptor gamma and improve insulin sensitivity. We investigated the effects of telmisartan treatment on visceral fat, serum adiponectin and vascular inflammation markers in Japanese hypertensive patients. This was an open-label, non-controlled study. Twenty-eight essential hypertensive patients (22 men and 6 women; age 60.6+/-1.9 years; body mass index [BMI] 25.5+/-0.6 kg/m(2)) participated. Fat area was assessed with computerized tomography. All the subjects were started on telmisartan 40 mg/day, which was increased to 80 mg/day to achieve the blood pressure target of less than 130/80 mmHg. We assessed the visceral and subcutaneous fat areas, serum adiponectin levels, and vascular inflammation markers at baseline and 24 weeks of telmisartan treatment. There were significant reductions in visceral fat area (from 103.1+/-7.9 to 93.3+/-8.4 cm(2), p<0.01) and pulse wave velocity (from 1,706+/-52 to 1,587+/-51 cm/s, p<0.01) at 24 weeks. In contrast, significant increases in serum high-density lipoprotein cholesterol (from 5.06+/-0.15 to 5.32+/-0.13 mmol/L, p<0.05) and adiponectin levels (from 8.27+/-0.76 to 9.13+/-0.81 microg/mL, p<0.05) were observed. Also, there were reductions in the interleukin-6 level (from 2.26+/-0.27 to 1.60+/-0.14 pg/mL, p<0.01). We also conducted these investigations in male subjects alone and similar findings were obtained for all of these parameters. In conclusion, telmisartan treatment was associated with an improvement of vascular inflammation, reductions in visceral fat and increases in serum adiponectin.

Association of genetic variation of the adiponectin gene with body fat distribution and carotid atherosclerosis in Japanese obese subjects.

AIM: The aim of this study was to investigate the effect of SNP45 of the adiponectin gene on body fat distribution and carotid atherosclerosis in Japanese obese subjects. METHODS: A total of 64 obese subjects were investigated. Genotypes of SNP45 were assayed by polymerase chain reaction-restriction fragment length polymorphism. Visceral fat area (VFA) and subcutaneous fat area (SFA) were measured using computed tomography. The progression of atherosclerosis was evaluated by plaque score (PS) of carotid artery using B-mode ultrasonography. RESULTS: Men carrying the G allele of SNP45 showed higher VFA (172.8+/-50.8 vs. 147.1+/-58.7, p=0.005), lower SFA (209.9+/-101.8 vs. 273.4+/-142.2, p=0.007), higher VFA/SFA (V/S) ratio (1.00+/-0.46 vs. 0.60+/-0.26, p <0.001) and higher PS (9.5+/-3.7 vs. 6.8+/-4.2, p=0.012) than those with TT genotype. Multivariate analysis showed that SNP45 was an independent determinant of V/S ratio and PS in men. In subgroup analysis, PS tended to be associated with V/S ratio only in the carrier of 45G allele. CONCLUSION: These results suggest that the G allele could be a risk factor of metabolic syndrome and the development of atherosclerosis in Japanese obese subjects.

The relationship between post-prandial plasma glucose and post-challenge plasma glucose in Japanese population.

The relationship between post-prandial plasma glucose (PPG) and post-challenge plasma glucose (PCG) within individuals was investigated in Japanese population. The oral glucose tolerance test (OGTT) and measurements of PPG 2h after ingestion of a standardized rice-based meal (PPG2h), were performed in 4471 middle-aged Japanese subjects (2774 men and 1697 women, 50.7+/-8.5 years). There was a loose correlation between PPG2h and PCG2h (r=0.327, p<0.001). The diabetes group (n=170) showed the highest PPG2h, followed by the IGT group (n=786) and the NGT group (n=3414) (p<0.05). At the cutoff point of 140 mg/dl (7.8 mmol/l) for PPG2h, specificities were 94.9% for IGT plus diabetes and 92.9% for diabetes, but sensitivities were as low as 23.2% for IGT plus diabetes and 44.7% for diabetes. The correlation of PPG2h with PCG2h was stronger in the obese group (BMI>or=25 kg/m2) than in the lean group (BMI<20 kg/m2). We conclude that the correlation between PPG2h and PCG2h was significant but not very tight. In evaluating PPG2h, if the cutoff point of 140 mg/dl (7.8 mmol/l) for PCG2h is extrapolated, the majority of subjects with dysglycemia could be overlooked.

Effect of walking with a pedometer on serum lipid and adiponectin levels in Japanese middle-aged men.

OBJECTIVE: To clarify the effects of walking with a pedometer on metabolic parameters, including adiponectin (APN). METHODS: We recruited 44 male Japanese volunteers (age, 37 +/- 9 yrs; body mass index (BMI), 24.2 +/- 2.9 kg/m2; fasting plasma glucose (FPG), 96 +/- 11 mg/dL; total cholesterol (TC) 190 +/- 26 mg/dL; triglycerides (TG) 119 +/- 80 mg/dL; HDL-C56 +/- 14 mg/dL). Subjects were instructed to walk with a pedometer and record the number of steps they walked every day for 50 days. Serum adiponectin (APN) levels were measured by enzyme immunoassay. Treatment effects were examined by Wilcoxon's rank test. RESULTS: The average number of steps was 8211 +/- 2084 per day. There were significant reductions in BMI, sBP, TG and TNF-alpha levels after 50 days, but no changes in adiponectin levels. We then divided the subjects into 2 groups according to the steps walked per day, namely, more than 8000 steps (MT group, n = 22) and less than 8000 steps (LT group, n = 22) and found that the reduction in TG and BP was observed only in the MT group. CONCLUSIONS: Walking with a pedometer is effective for improving metabolic parameters, such as TG and blood pressure, but is not sufficient to increase adiponectin levels in Japanese men.

The relationship of percent body fat by bioelectrical impedance analysis with blood pressure, and glucose and lipid parameters.

The objective of this study was to clarify the clinical significance and usefulness of measuring percent body fat (PBF) when compared with body mass index (BMI) in the Japanese population. A total of 2,483 Japanese individuals (1,380 men and 1,103 women) who underwent a medical checkup from 1999-2002 were employed. PBF was determined using bioelectrical impedance analysis (BIA). Relationships of age, BMI and PBF with several metabolic parameters, including blood pressure, lipids and plasma glucose levels were assessed in both genders separately. In men, PBF was a stronger determinant of total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C) and triglycerides (TG) compared with age and BMI, whereas in women, age was the strongest determinant of TC and LDL-C. In both genders, BMI was the strongest determinant of serum HDL-C among age, PBF and BMI. Based on these data, we suggest that measuring PBF by BIA is superior to BMI for predicting TC, LDL-C and TG in Japanese men.

Raloxifene promotes adipocyte differentiation of 3T3-L1 cells.

To explore the possibility that raloxifene might influence an adipocyte differentiation and lipogenesis, we studied the effects of raloxifene on the expression of adiponectin and other peroxisome proliferator-activated receptor gamma targeting genes using the 3T3-L1 adipocytes. With standard adipogenic inducers, we added raloxifene at various doses for the adipocyte differentiation. Higher doses of raloxifene facilitated lipid accumulation of the 3T3-L1 cells. We next examined the differentiating and differentiated adipocytes and found that raloxifene augmented mRNA levels of adiponectin, adipocyte-specific fatty acid binding protein, and lipoprotein lipase dose-dependently in both. These effects were opposite those of 17beta-estradiol treatment. These findings suggest that raloxifene promotes adipocyte differentiation, providing a novel insight into the treatment of postmenopausal metabolic syndrome with hypoadiponectinemia.

Effects of fenofibrate therapy on plasma ubiquinol-10 and ubiquinone-10 levels in Japanese patients with hyperlipidemia and type 2 diabetes mellitus.

STUDY OBJECTIVE: To assess the effects of fenofibrate therapy on concentrations of plasma ubiquinol-10 and ubiquinone-10-the reduced and oxidized forms, respectively, of coenzyme Q(10). DESIGN: Prospective, open-label, non-controlled study. SETTING: University clinic and laboratory. PATIENTS: Eighteen patients with hyperlipidemia and type 2 diabetes mellitus. INTERVENTION: Patients received fenofibrate 150 mg/day for 12 weeks. MEASUREMENTS AND MAIN RESULTS: Metabolic parameters were assessed 4, 8, and 12 weeks after the start of fenofibrate treatment. Plasma ubiquinol-10 and ubiquinone-10 levels were measured by reverse-phase high-performance liquid chromatography. At 4, 8, and 12 weeks, significant reductions in fasting triglyceride levels and significant increases in high-density lipoprotein cholesterol levels were noted. Total cholesterol, low-density lipoprotein cholesterol, fasting plasma glucose, and adiponectin levels, however, did not change significantly. Plasma ubiquinol-10 concentrations significantly increased after 8 and 12 weeks (p<0.05 for both), whereas ubiquinone-10 concentrations tended to decrease, especially at 12 weeks. CONCLUSION: Our findings suggest that fenofibrate may help produce energy or prevent oxidation by increasing plasma ubiquinol-10 concentration; this effect may protect against the development and progression of atherosclerosis. In addition, treatment with fenofibrate demonstrated a favorable effect on serum lipid parameters.

Association of coronary artery ectasia with plasma insulin levels in Japanese men of heterozygous familial hypercholesterolemia with the low-density lipoprotein receptor gene mutation K790X.

BACKGROUND: Hyperinsulinemia is widely believed to be an important coronary risk factor. We investigated the effect of plasma insulin levels on the development of coronary ectasia in Japanese men with heterozygous familial hypercholesterolemia (FH). METHODS: A cross-sectional study was conducted in 20 FH men with the LDL receptor mutation (K790X) [age 42.3+/-2.8 years old, body mass index (BMI) 24.6+/-0.7 kg/m2, total cholesterol (TC) 8.68+/-0.36 mmol/l, triglycerides (TG) 1.76+/-0.23 mmol/l, high-density lipoprotein cholesterol (HDL-C) 0.977+/-0.065 mmol/l]. Subjects with diabetes mellitus were excluded. Plasma insulin levels, either fasting or during oral glucose tolerance test, were compared between subjects with and without coronary artery ectasia. RESULTS: FH subjects with coronary ectasia had significantly higher fasting plasma insulin levels than those without (12.6+/-1.4 vs. 7.7+/-0.5 mU/l; p<0.05). Also, plasma insulin levels during oral glucose tolerance test tended to be higher in the former than in the latter. CONCLUSIONS: Plasma insulin level could be an important determinant of the development of coronary artery ectasia in Japanese heterozygous FH men.

An LMNA variant is associated with dyslipidemia and insulin resistance in the Japanese.

Nuclear lamins A and C are encoded by LMNA and are present in terminally differentiated cells. Rare mutations in LMNA were shown to cause familial partial lipodystrophy, a syndrome characterized by regional loss of adipose tissue, glucose intolerance, and dyslipidemia, making LMNA a candidate gene for insulin-resistant diabetes. The aim of this study was to investigate whether genetic variation in LMNA can influence the risk of type 2 diabetes in a Japanese cohort. First, we performed mutational screening of LMNA by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and sequence analysis in 8 insulin-resistant males with acanthosis nigricans who were not lipodystrophic. One known single nucleotide polymorphism, 1908C/T, was found in exon 10. We subsequently screened samples of 171 nondiabetic and 164 type 2 diabetic male subjects for the presence of the 1908C/T polymorphism by PCR-restriction fragment length polymorphism (RFLP). The frequency of subjects with the 1908T allele tended to be higher in the diabetic group than in the nondiabetic group; however, the difference was not significant (43.9% v 32.2%) (P =.084). Carriers of the 1908T allele, both among diabetics and nondiabetics, showed significantly higher fasting insulin, triglycerides (TG), total cholesterol (TC), and lower high-density lipoprotein-cholesterol (HDL-C) levels than those of the 1908C/C subjects. These results suggest the LMNA 1908C/T single nucleotide polymorphism (SNP) is not associated with the prevalence of type 2 diabetes, although it may be a factor predisposing to insulin resistance and dyslipidemia in some Japanese.

Impact of serum retinol-binding protein 4 levels on regulation of remnant-like particles triglyceride in type 2 diabetes mellitus.

Background. Although retinol-binding protein 4 (RBP4) associates with insulin resistance and remnant-like particles triglyceride (RLP-TG) elevated in the insulin resistant state, few data exist regarding the relationship between RBP4 and RLP-TG. Subjects and Methods. The study included 92 Japanese type 2 diabetic mellitus (T2DM) male patients (age 60.5 ± 13.6 years, body mass index (BMI) 24.7 ± 4.1 kg/m(2), waist circumference (WC) 88.4 ± 10.7 cm, and HbA1c (NGSP) 7.2 ± 1.9%). Patients on medications affecting insulin sensitivity, including fibrates, biguanides, and thiazolidinedione, were excluded. Visceral fat area (VFA) and subcutaneous fat area (SFA) were measured by computed tomography. Results. RBP4 levels showed a significant positive correlation with RLP-TG (r = 0.2544 and P = 0.0056), TG (r = 0.1852 and P = 0.041), RLP-TG/TG (r = 0.23765 and P = 0.0241), and age (r = -0.2082 and P = 0.0219), although there was no significant correlation with VFA, SFA, adiponectin levels, or homeostasis model of assessment insulin resistance (HOMA-R). Multiple regression analysis revealed that RBP4 was an independent determinant of RLP-TG (P = 0.0193) but was not a determinant of TG. Conclusions. RBP4 correlates positively with serum RLP-TG independent of fat accumulation in T2DM. RBP4 may regulate remnant metabolism independent of glycemic control in T2DM.

Reassessment of the cutoff values of waist circumference and visceral fat area for identifying Japanese subjects at risk for the metabolic syndrome.

In the new world-wide criteria for metabolic syndrome (MetS) by the International Diabetes Federation (IDF) in 2006, the Japanese is the only ethnicity in which the recommended waist circumference (WC) cutoff value is higher in women (>or=90cm) than in men (>or=85cm), and its validity appears to be controversial. We investigated the optimal cutoff points for the diagnosis of central obesity in Japanese men and women, using the receiver operating characteristic (ROC) curve analysis for both of WC and visceral fat area (VFA) in 1870 middle-aged Japanese. VFA was superior to WC and Body mass index (BMI) for discriminating the subjects with two or more nonadipose components of MetS. The optimal cutoff points of VFA and WC were 132.6cm(2) and 89.8cm for men and 91.5cm(2) and 82.3cm for women. The stratifications of MetS components more than 1.0 in average occurred more steeply by the accumulation of VFA in women than in men. In conclusion, setting the cutoff points of WC and VFA lower values in women than in men for the definition of central obesity is needed to identify the subjects with MetS in Japanese, as in other Asian populations.

Association of LMNA 1908C/T polymorphism with cerebral vascular disease and diabetic nephropathy in Japanese men with type 2 diabetes.

OBJECTIVE: The LMNA 1908C/T polymorphism has been reported to be associated with dyslipidaemia, metabolic syndrome, adipose tissue metabolism and obesity phenotypes, suggesting that this polymorphism presents an increased risk of atherosclerosis and vascular diseases. However, there have been no previous reports on the relationship between the LMNA 1908C/T polymorphism and vascular diseases. The aim of this study therefore was to investigate the association between the LMNA 1908C/T polymorphism and the prevalence of vascular disease in Japanese patients with type 2 diabetes. DESIGN: A cross-sectional, hospital-based study of diabetic complications with an LMNA gene background. PATIENTS: One hundred and sixty-six Japanese men with type 2 diabetes. Measurements LMNA 1908C/T polymorphism (by polymerase chain reaction restriction fragment length polymorphism, PCR-RFLP); diabetic retinopathy (by standard fundus photography); diabetic nephropathy (by urinary albumin excretion rate); diabetic neuropathy (by signs, symptoms and/or nerve conduction velocity); coronary heart disease (by symptoms of typical chest pain and/or history of myocardial infarction, and ischaemic electrocardiographic alteration and/or coronary artery bypass graft surgery); cerebral vascular disease (by ultrasonography, computed tomography and/or magnetic resonance imaging). RESULTS: Carriers of the LMNA 1908T allele manifested a significantly higher prevalence of diabetic nephropathy and cerebral vascular disease than carriers of the C allele. Multiple regression analysis showed that the LMNA 1908T allele tended to be associated with cerebral vascular disease, but was independent of age, hypertension, total cholesterol or triglyceride [odds ratio (OR) 7.03, P=0.0611]. Similarly, the LMNA 1908T allele showed a significant association with diabetic nephropathy, not independent of total cholesterol or triglyceride. CONCLUSIONS: The LMNA 1908C/T polymorphism plays an important role in the development of cerebral vascular disease and diabetic nephropathy in Japanese men with type 2 diabetes.

Association between CTLA-4 +49 A/G polymorphism and type 1B diabetes in Japanese population.

+49 A/G polymorphism of CTLA-4 gene has been suggested to be associated with type 1 diabetes in some populations. However, a functional significance of the +49 A/G polymorphism is unknown, because it is believed the polymorphism does not affect the function of the CTLA-4 molecule. In this study, we examined the +49 A/G polymorphism of the CTLA-4 gene in 30 Japanese type 1 diabetic patients (14 type 1B and 16 type 1A) and 40 non-diabetic subjects in a case-control study, and stratified patients according to genotype of the polymorphism. The distribution of genotype frequencies differed between type 1 diabetic patients and controls (p<0.01). When the subjects were subdivided into type 1A and type 1B subgroups, a significant difference in G allele frequency was found only between type 1B patients and controls, whereas G allele frequency tended to be higher in type 1A diabetic patients than controls. Type 1B patients displayed more severe metabolic decompensation (higher plasma glucose concentration, lower urinary C-peptide levels, higher insulin requirement, and higher serum amylase levels), and were found to be more prone to diabetic ketoacidosis than type 1A patients. After stratification by genotype, differences in urinary C-peptide and serum amylase levels between type 1A and type 1B patients were found to be due to differences in the GG genotype subgroup, whereas in the AG subgroup those differences disappeared. In conclusion, the +49 A/G polymorphism of CTLA-4 gene was associated with the occurrence of type 1B diabetes in a Japanese population, and type 1B diabetics with a GG genotype were associated with more severe cell dysfunction than their type 1A counterparts.

Two novel mutations of PTEN gene in Japanese patients with Cowden syndrome.

Cowden syndrome (CS), also known as multiple hamartoma syndrome, is an autosomal dominant cancer syndrome associated with high risk of breast and thyroid cancer. In three unrelated Japanese CS patients, three PTEN germline mutations were identified, including two novel ones: 589A --> T, resulting in Lys197Stop, and 219-222delAAGA. We also detected a previously reported mutation: 697C --> T, resulting in Arg233Stop. Reports from Western countries have indicated that approximately two-thirds of mutations are found in exons 5, 7, and 8, which is almost the same frequency as found in Japanese CS. No genotype-phenotype correlations have been found in CS patients from 21 Japanese families.