Relationship between serum indirect bilirubin levels and skeletal muscle mass in older male and female patients with type 2 diabetes.

OBJECTIVE: We previously showed that low serum bilirubin levels are associated with disability in quality of daily living in older patients with diabetes. However, the underlying mechanism is not fully understood. The aim of this study is to assess the relationship between serum bilirubin levels and skeletal muscle mass in older patients with type2 diabetes. METHODS: A total of 272 older patients with type2 diabetes (152 male and 120 female) aged 60 years and over were continuously recruited from April 2020 to July 2020. Body composition was evaluated by bioelectrical impedance analysis. The skeletal muscle mass index (SMI) was calculated as appendicular muscle mass divided by height squared (m2). RESULTS: The SMI was markedly lower in old-old patients (aged 75 years and over) than in young-old patients (aged 60-74 years) in both male and female (7.1 ± 0.8 kg/m2 vs 7.6 ± 0.9 kg/m2, P<0.001; 5.5 ± 0.9 kg/m2 vs 6.3 ± 0.8 kg/m2, P<0.001, respectively). Multivariate regression analysis showed that the SMI was associated with body mass index (BMI) (p<0.001) and age (p = 0.048) in male young-old patients, while it was associated with BMI (p<0.001), age (p = 0.008), and serum indirect bilirubin levels (p = 0.038) in male old-old patients. In female, the SMI was associated with BMI (p<0.001) and age (p = 0.042) in young-old patients and associated with BMI alone (p<0.001) in old-old patients. CONCLUSION: Serum indirect bilirubin levels may be associated with the decreased skeletal muscle mass in male older patients (aged 75 years and over) with type 2 diabetes.

A simplified prediction model for end-stage kidney disease in patients with diabetes.

This study aimed to develop a simplified model for predicting end-stage kidney disease (ESKD) in patients with diabetes. The cohort included 2549 individuals who were followed up at Kyushu University Hospital (Japan) between January 1, 2008 and December 31, 2018. The outcome was a composite of ESKD, defined as an eGFR < 15 mL min-1 [1.73 m]-2, dialysis, or renal transplantation. The mean follow-up was 5.6 [Formula: see text] 3.7 years, and ESKD occurred in 176 (6.2%) individuals. Both a machine learning random forest model and a Cox proportional hazard model selected eGFR, proteinuria, hemoglobin A1c, serum albumin levels, and serum bilirubin levels in a descending order as the most important predictors among 20 baseline variables. A model using eGFR, proteinuria and hemoglobin A1c showed a relatively good performance in discrimination (C-statistic: 0.842) and calibration (Nam and D'Agostino [Formula: see text]2 statistic: 22.4). Adding serum albumin and bilirubin levels to the model further improved it, and a model using 5 variables showed the best performance in the predictive ability (C-statistic: 0.895, [Formula: see text]2 statistic: 7.7). The accuracy of this model was validated in an external cohort (n = 5153). This novel simplified prediction model may be clinically useful for predicting ESKD in patients with diabetes.

Clinical usefulness of human serum nonmercaptalbumin to mercaptalbumin ratio as a biomarker for diabetic complications and disability in activities of daily living in elderly patients with diabetes.

BACKGROUND: Oxidative stress may play an important role in the development of diabetic complications. The ratio of human nonmercaptalbumin (HNA; oxidized form) to human mercaptalbumin (HMA; reduced form) has attracted attention as an indicator for systemic redox states. In this study, we measured the ratio in elderly patients with diabetes and evaluated its association with diabetic complications and disability in activities of daily living (ADL disability). METHODS: One hundred twenty-six elderly patients with diabetes, aged 70 years and older, under medical care at Yukuhashi Central Hospital from April 2018 to June 2018, were continuously recruited. HNA%, defined as HNA / (HNA + HMA) × 100, was measured by a high-performance liquid chromatography method. First, multivariate regression analysis was performed to evaluate which variables were significant determinants for HNA%. Next, to evaluate the association of HNA% with ADL disability, logistic regression analysis in various models was performed. Then we plotted the receiver operating characteristic (ROC) curve and calculated the under area the curve (AUC), sensitivity, and specificity in each model. RESULTS: In elderly patients with diabetes, multiple regression analysis showed that serum bilirubin levels and albumin levels, both of which are major endogenous anti-oxidants, and chronic renal failure (or proliferative nephropathy) were significantly associated with HNA%, suggesting that HNA% may be a good biomarker for oxidative stress in those patients. We then evaluated the association of HNA% with ADL disability in various logistic regression models. Model using only HNA% showed that it was a significant determinant for ADL disability (OR 1.158, 95% CI 1.077-1.244, P < 0.001). Model using HNA% and age showed that both variables were significant determinants for ADL disability (OR 1.160, 95% CI 1.069-1.258, P < 0.001; OR 1.258, 95% CI 1.110-1.427, P < 0.001, respectively). ROC analysis showed that the AUC of HNA% alone was 0.765. The AUC of model using HNA% and age was further increased to 0.866. CONCLUSIONS: HNA% was significantly associated with diabetic complications and ADL disability, thereby may be clinically useful as an oxidative stress marker in elderly patients with diabetes.

A diabetic patient in whom Hb Weesp was incidentally detected when her HbA1c level was measured.

The level of glycated hemoglobin A1c (HbA1c) is widely used to monitor long-term glycemic control in patients with diabetes mellitus. There are more than 30 methods for measuring HbA1c levels. In recent times, high-performance liquid chromatography (HPLC) has become the most commonly used method in Japan. However, HPLC-based HbA1c level measurements do not accurately reflect glycemic control in the presence of Hb variants. We report the case of a patient with type 2 diabetes mellitus, who was incidentally found to having an extremely rare Hb variant. A 69-year-old Japanese female visited our clinic and was diagnosed with diabetes mellitus. Her HbA1c level, which was measured using HPLC at our clinic, could not be determined. DNA sequencing revealed a heterozygous mutation in the α1 globin gene (HBA1: c.301C > T, p.Leu101Phe). Hb Weesp was detected. Many Hb variants have been reported; however, to the best of our knowledge, this is only the second report about Hb Weesp in the world and the first from Japan. Clinicians should consider the possibility of Hb variants in cases in which abnormal elution patterns are detected during the measurement of HbA1c using HPLC.

Serum bilirubin level is a strong predictor for disability in activities in daily living (ADL) in Japanese elderly patients with diabetes.

Elderly patients with diabetes are at increased risk of frailty and disability in activities of daily living (ADL). Recent evidence has shown that oxidative stress is associated with these conditions. In this cross-sectional study, we aimed to assess whether serum level of bilirubin, a strong endogenous antioxidant, can predict ADL disability in elderly patients with diabetes. Forty elderly patients aged 70 years and older with diabetes and ADL disability and 158 elderly patients with diabetes and without ADL disability were continuously recruited. Multivariate logistic regression models showed that serum bilirubin level was a significant predictor for ADL disability. Receiver operating characteristic analysis showed that the area under the curve (AUC) of serum bilirubin level alone for ADL disability was 0.887 (95% CI 0.837-0.936, P < 0.001) and the cut-off value was 0.4 mg/dL (sensitivity = 88.0% and specificity = 65.0%). The predictive ability was further increased by the addition of age (AUC = 0.921) or addition of age, body mass index, red blood cell count, cerebrovascular disease and chronic renal failure (AUC = 0.953). In conclusion, low serum bilirubin level is a strong predictive biomarker for ADL disability in elderly patients with diabetes, and its clinical utility is suggested.

Variation of fasting serum C-peptide level after admission in Japanese patients with type 2 diabetes mellitus.

BACKGROUND: The aim of this study was to evaluate the variation of fasting serum C-peptide (S-CPR) levels, as a marker for endogenous insulin secretion after admission in Japanese patients with type 2 diabetes mellitus (T2DM). METHODS: S-CPR levels together with other metabolic factors were measured in 234 T2DM patients twice: at the beginning and at the end of admission for the control of blood sugar levels. As a result, patients were classified into two groups according to their changes of S-CPR (DeltaS-CPR), which consisted of patients whose S-CPR levels had decreased (group D) and increased (group I) after admission. RESULTS: Patients allocated to group I showed younger age, shorter duration of diabetes, and lower basal S-CPR level compared to group D. Conversely, patients in group D showed higher levels of high-sensitivity C-reactive protein (HS-CRP) and brachial-ankle pulse wave velocity compared to group I, suggesting patients in this group are prone to atherosclerosis. DeltaS-CPR was positively correlated with the change of body mass index, waist circumference, and triglycerides in group D. On the other hand, DeltaS-CPR was negatively correlated with the change of HS-CRP in group I, indicating residual beta-cell function could be recovered by the amelioration of inflammatory status in pancreatic islets. CONCLUSIONS: It is plausible that Japanese T2DM patients could be classified according to the variation of S-CPR after admission. Evaluation of basal and the variation of S-CPR could provide advantageous information for the management of diabetes mellitus or related disorders.

Attenuated metabolic effect of waist measurement in Japanese female patients with type 2 diabetes mellitus.

Waist circumference (WC) was measured in 200 Japanese patients with type 2 diabetes mellitus (T2DM: male 106, female 94, mean age 61 years old) who had been admitted in our hospital, and relationship with various risk factors to predict future cardiovascular disease (CVD) was analyzed. There was a positive and statistically significant trend in WC levels with an increasing number of CVD risk factors in male patients, whereas no significant trend of WC was observed in female patients. The receiver operator characteristic (ROC) curve for WC to predict the presence of two or more risk factors of CVD depicted greater area under the curve in male patients (0.732) than that in female patients (0.571). Apart from positive correlation with fasting serum C-peptide (S-CPR) and log-transformed high-sensitivity C-reactive protein (log HS-CRP) in both genders, WC was positively correlated with log-transformed triglyceride (log TG), systolic and diastolic blood pressure (SBP and DBP) and negatively with HDL-cholesterol (HDL-C) in male patients, whereas it was negatively correlated with HbA1c and fasting plasma glucose (FPG) in female patients. The change of WC after administration (DeltaWC) was correlated with DeltaS-CPR, DeltaLDL-C, DeltaSBP and DeltaDBP in male patients, while no relationship was observed in female patients. In conclusion, WC is a reliable marker to predict future CVD events at least in Japanese male, but not female patients with T2DM.

Indicators for the efficacy of pioglitazone before and during treatment in Japanese patients with type 2 diabetes.

BACKGROUND: The aim of this study is to explore appropriate indicators for the efficacy of pioglitazone (Pio) before and during treatment of Japanese patients with type 2 diabetes mellitus (T2DM). METHODS: Forty-eight Japanese patients with T2DM (22 men, 26 women, 60 +/- 2 years old) were enrolled and treated with 15 mg/day of Pio for 12 weeks. Before and after the treatment, various parameters were evaluated regarding the efficacy of Pio. Patients who had a reduction in hemoglobin A1c (HbA1c) of >1% after 12 weeks of treatment were defined as responders. RESULTS: Twenty-two patients were classified as responders. In the responder group, age, fasting plasma glucose (FPG), and percentage female were significantly (P < 0.05) higher compared with the non-responder group. In logistic regression analysis, female sex and higher FPG were selected as explanatory variables for the efficacy of Pio. Furthermore, the change of HbA1c (DeltaHbA1c) was positively correlated with that of fasting C-peptide level (DeltaCPR) and log-transformed high-sensitivity C-reactive protein (Deltalog HS-CRP), and negatively correlated with that of high-density lipoprotein cholesterol (DeltaHDL-C) and log-transformed adiponectin (Deltalog AP). In multiple stepwise regression analysis, DeltaCPR, Deltalog HS-CRP, and Deltalog AP (or DeltaFPG) were selected as explanatory variables for DeltaHbA1c. CONCLUSIONS: We concluded that Pio is likely to show favorable effects on blood glucose control especially in female patients with higher FPG levels. Administration of Pio ameliorates blood glucose control accompanied by the increase of AP and the decrease of CPR or HS-CRP, suggesting that Pio exerts its beneficial effects through the enhancement of AP, which leads to suppression of inflammation and amelioration of insulin resistance.

High-sensitivity C-reactive protein in Japanese patients with type 2 diabetes.

OBJECTIVE: To assess the relationship between high-sensitivity (HS) C-reactive protein (CRP) and metabolic syndrome (MetS) or atherosclerosis and to assess effects of strict metabolic control on the degree of inflammation and MetS in patients with type 2 diabetes. RESEARCH METHODS AND PROCEDURES: Four hundred thirteen patients with diabetes were enrolled in the cross-sectional study. Of these 413 patients, 161 patients were further admitted for 2.4 +/- 0.4 weeks (mean +/- SD) to investigate the change in HS-CRP or other parameters under strict metabolic control. RESULTS: Log-transformed HS-CRP value (log HS-CRP) was strongly correlated with BMI (r = 0.448, p < 0.01). Log HS-CRP was also correlated with the presence of MetS or each component of MetS. Furthermore, a positive significant trend in HS-CRP levels was shown with an increasing number of MetS components (p < 0.05). Log HS-CRP showed a significant positive correlation with carotid artery intima-media thickness (IMT) (r = 0.152, p < 0.01). In multiple step-wise regression analysis, BMI, hemoglobin A(1c), right IMT, duration of diabetes, and triglyceride were selected as explanatory variables for log HS-CRP (R2 = 0.412). Under strict metabolic control, HS-CRP was significantly (p < 0.01) lower, together with lower levels of other markers for MetS. The change in HS-CRP was significantly correlated with the change in BMI (r = 0.161, p = 0.04). DISCUSSION: In subjects with type 2 diabetes, HS-CRP levels are related to MetS and subclinical atherosclerosis. Strict weight management and metabolic control were associated with a reduction in HS-CRP levels, and changes in HS-CRP were related to changes in weight, supporting the hypothesis that lifestyle modification reduces inflammation and the risk of CHD.

Genome-wide linkage analysis of type 2 diabetes mellitus reconfirms the susceptibility locus on 11p13-p12 in Japanese.

Type 2 diabetes mellitus is a heterogeneous disorder, and the development of type 2 diabetes mellitus is associated with both insulin secretion defect and insulin resistance. The primary metabolic defect leading to type 2 diabetes mellitus has been thought to be varied among populations, especially in Japanese and Caucasians. Here, we have done the genome-wide scan for type 2 diabetes mellitus using 102 affected Japanese sib-pairs to identify the genetic factors predisposing to type 2 diabetes mellitus. Nonparametric linkage analysis showed one suggestive evidence for linkage to 11p13-p12 [D11S905: two-point maximum LOD score (MLS) of 2.89 and multipoint MLS of 2.32] and one nominally significant evidence for linkage to 6q15-q16 (D6S462: two-point MLS of 2.02). Interestingly, the 11p13-p12 region was reported to be a susceptibility locus for Japanese type 2 diabetes mellitus with suggestive evidence of linkage, and D11S905 was within 5 cM to D11S935 with the highest MLS in the previous linkage analysis reported. The only overlapped susceptibility region with suggestive evidence of linkage for Japanese type 2 diabetes mellitus was D11S935-D11S905 among the three reports including this study. These results taken together suggest that a susceptibility gene for type 2 diabetes mellitus in Japanese will reside in 11p13-p12.

Glucosamine-induced beta-cell dysfunction: a possible involvement of glucokinase or glucose-transporter type 2.

INTRODUCTION: The mechanism for beta-cell dysfunction induced by glucosamine has not yet fully been investigated previously. AIM: To investigate the effects of glucosamine on insulin release or gene expression related to glucose metabolism in rat islets cultured with glucosamine for 24 hours. METHODOLOGY: After islets were cultured with glucosamine or diazoxide, we measured glucose- or arginine-induced insulin release by using radioimmunoassay (RIA) and gene expressions by semiquantitative polymerase/chain reaction. RESULTS: Coculture with glucosamine inhibited 27 mmol/L glucose-induced insulin release with no effects on 20 mmol/L arginine-induced insulin release. Coculture with diazoxide did not restore the impaired glucose-induced insulin release. In glucosamine-cultured islets, glucose-transporter type 2 or glucokinase mRNA expression decreased, whereas hexokinase mRNA increased. Phosphofructokinase-A, pyruvate dehydrogenase E1alpha, or pyruvate carboxylase mRNA was not affected by the addition of glucosamine. Pancreatic and duodenal homeobox-1, preproinsulin, or p21 (induced by oxidative stress) mRNA expression did not change, whereas uncoupling protein 2 mRNA, which plays an important role in thermogenesis, decreased in glucosamine-cultured islets. CONCLUSION: These data imply that glucosamine impairs glucose-induced insulin release probably through the inhibition of glucose metabolism.

Lysophosphatidylcholine inhibits the expression of prostacyclin stimulating factor in cultured vascular smooth muscle cells.

We have cloned a prostacyclin (PGI2) stimulating factor (PSF), which stimulates PGI2 production by vascular endothelial cells. Previous study demonstrated the reduced PSF expression in the coronary arteries from the patients with ischemic heart disease. To clarify the mechanism of reduced PSF expression in atherosclerosis, we examined the effect of lysophosphatidylcholine (lysoPC), a main component of oxidized low density lipoprotein (LDL), on PSF expression in cultured vascular smooth muscle cells. LysoPC reduced PSF expression dose-dependently. Whereas neither phosphatidylcholine nor native LDL affects the PSF expression. Calphostin C, a protein kinase C (PKC) inhibitor, restored the reduction of PSF expression by lysoPC. These results suggest that lysoPC-induced reduction of PSF expression is mediated by PKC activation and is playing a role in the initiation and progression of atherosclerotic lesions.