Impact of Serum Retinol-Binding Protein 4 Levels on Regulation of Remnant-Like Particles Triglyceride in Type 2 Diabetes Mellitus

13301乙第2063号博士（医学）金沢大学博士論文要旨Abstract 以下に掲載：Journal of Diabetes Research Vol. 2013, Article ID 143515 pp.1-5 2013. Hindawi Publishing Corporation. 共著者：Naoto Yamaaki, Kunimasa Yagi, Junji Kobayashi, Atsushi Nohara, Naoko Ito, Akimichi Asano, Kaoru Nakano, Jianhui Liu, Takuya Okamoto, Yukiko Mori, Azusa Ohbatake, Satoko Okazaki, Yoshiyu Takeda, Masakazu Yamagish

Decreased ADP-Ribosyl Cyclase Activity in Peripheral Blood Mononuclear Cells from Diabetic Patients with Nephropathy

Aims/hypothesis. ADP-ribosyl-cyclase activity (ADPRCA) of CD38 and other ectoenzymes mainly generate cyclic adenosine 5’diphosphate-(ADP-) ribose (cADPR) as a second messenger in various mammalian cells, including pancreatic beta cells and peripheral blood mononuclear cells (PBMCs). Since PBMCs contribute to the pathogenesis of diabetic nephropathy, ADPRCA of PBMCs could serve as a clinical prognostic marker for diabetic nephropathy. This study aimed to investigate the connection between ADPRCA in PBMCs and diabetic complications. Methods. PBMCs from 60 diabetic patients (10 for type 1 and 50 for type 2) and 15 nondiabetic controls were fluorometrically measured for ADPRCA based on the conversion of nicotinamide guanine dinucleotide (NGD+) into cyclic GDP-ribose. Results. ADPRCA negatively correlated with the level of HbA1c (P = .040, R2 = .073), although ADPRCA showed no significant correlation with gender, age, BMI, blood pressure, level of fasting plasma glucose and lipid levels, as well as type, duration, or medication of diabetes. Interestingly, patients with nephropathy, but not other complications, presented significantly lower ADPRCA than those without nephropathy (P = .0198) and diabetes (P = .0332). ANCOVA analysis adjusted for HbA1c showed no significant correlation between ADPRCA and nephropathy. However, logistic regression analyses revealed that determinants for nephropathy were systolic blood pressure and ADPRCA, not HbA1c. Conclusion/interpretation. Decreased ADPRCA significantly correlated with diabetic nephropathy. ADPRCA in PBMCs would be an important marker associated with diabetic nephropathy

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/m2, 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. © 2013 Naoto Yamaaki et al

Clinical Study 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 ( = 0.2544 and = 0.0056), TG ( = 0.1852 and = 0.041), RLP-TG/TG ( = 0.23765 and = 0.0241), and age ( = −0.2082 and = 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 ( = 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

Comparison of effects of bezafibrate and fenofibrate on circulating proprotein convertase subtilisin/kexin type 9 and adipocytokine levels in dyslipidemic subjects with impaired glucose tolerance or type 2 diabetes mellitus: Results from a crossover study

金沢大学医学系研究科Background: Bezafibrate and fenofibrate show different binding properties against peroxisome proliferator-activated receptor subtypes, which could cause different clinical effects on circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and on various metabolic markers. Methods: An open, randomized, four-phased crossover study using 400 mg of bezafibrate or 200 mg of fenofibrate was performed. Study subjects were 14 dyslipidemia with impaired glucose tolerance or type 2 diabetes mellitus (61 ± 16 years, body mass index (BMI) 26 ± 3 kg/m2, total cholesterol (TC) 219 ± 53 mg/dL, triglyceride (TG) 183 ± 83 mg/dL, high-density lipoprotein-cholesterol (HDL-C) 46 ± 8 mg/dL, fasting plasma glucose 133 ± 31 mg/dL and HbA1c 6.2 ± 0.8%). Subjects were given either bezafibrate or fenofibrate for 8 weeks, discontinued for 4 weeks and then switched to the other fibrate for 8 weeks. Circulating PCSK9 levels and other metabolic parameters, including adiponectin, leptin and urine 8-hydroxy-2′-deoxyguanosine (8-OHdG) were measured at 0, 8, 12 and 20 weeks. Results: Plasma PCSK9 concentrations were significantly increased (+39.7% for bezafibrate and +66.8% for fenofibrate, p < 0.001) in all patients except for one subject when treated with bezafibrate. Both bezafibrate and fenofibrate caused reductions in TG (-38.3%, p < 0.001 vs. -32.9%, p < 0.01) and increases in HDL-C (+18.0%, p < 0.001 vs. +11.7%, p < 0.001). Fenofibrate significantly reduced serum cholesterol levels (TC, -11.2%, p < 0.01; non-HDL-C, -17.3%, p < 0.01; apolipoprotein B, -15.1%, p < 0.01), whereas bezafibrate significantly improved glucose tolerance (insulin, -17.0%, p < 0.05) and metabolic markers (γ-GTP, -38.9%, p < 0.01; adiponectin, +15.4%, p < 0.05; urine 8-OHdG/Cre, -9.5%, p < 0.05). Conclusion: Both bezafibrate and fenofibrate increased plasma PCSK9 concentrations. The addition of a PCSK9 inhibitor to each fibrate therapy may achieve beneficial cholesterol lowering along with desirable effects of respective fibrates. © 2011 Elsevier Ireland Ltd. All rights reserved

The relationship between patients’ perception of type 2 diabetes and medication adherence: a cross-sectional study in Japan

Abstract Background The self-management of type 2 diabetes mellitus (T2DM), which involves adherence to medical instructions on diet and nutritional advice, physical activity, medication regimen, and weight and stress management, is necessary for the treatment of T2DM. In this study, we investigated the relationship between patients’ perceptions of their disease and their adherence to their medications. And we attempted to determine whether distinct subphenotypes of behavioral change of medication adherence can be discerned based on a patients’ perceptions. Method A cross-sectional study using a questionnaire was conducted among 157 patients with T2DM from October 2015 to September 2017. Questionnaires were administered to assess the participants’ demographic and clinical characteristics, medication adherence, diabetes knowledge, and perception of being diabetic. Principal component analysis (PCA) and cluster analyses were performed to classify medication adherence patterns in the total cohort. Multiple regression analyses were performed to identify the determinant factors of medication adherence. Results PCA showed the interpretable medication adherence of patients with diabetes by using component 1 (“accessibility to medical treatment”) and component 2 (“status of taking medicines”). We identified four groups that show significantly different medication adherence by using cluster analysis on the basis of the two components. Multiple regression analysis showed that body mass index (BMI), family history of diabetes, one factor of patient’s perception (living an orderly life), and diabetes knowledge were found to be significant predictors of medication adherence in patients with T2DM. Conclusions In patients with T2DM, the patient’s diabetes perception of “living an orderly life” is associated with medication adherence. A poor adherence group may be able to change their adherence to diabetes treatment by developing the perception of “living an orderly life.

Improved Glycemic Control through Robot-Assisted Remote Interview for Outpatients with Type 2 Diabetes: A Pilot Study

Background and Objectives: Our research group developed a robot-assisted diabetes self-management monitoring system to support Certified Diabetes Care and Education Specialists (CDCESs) in tracking the health status of patients with type 2 diabetes (T2D). This study aimed to evaluate the impact of this system on glycemic control and to identify suitable candidates for its use. Materials and Methods: After obtaining written informed consent from all participants with T2D, the CDCESs conducted remote interviews with the patients using RoBoHoN. All participants completed a questionnaire immediately after the experiment. HbA1c was assessed at the time of the interview and two months later, and glycemic control status was categorized as either “Adequate” or “Inadequate” based on the target HbA1c levels outlined in the guidelines for adult and elderly patients with type 2 diabetes by the Japan Diabetes Society. Patients who changed their medication regimens within the two months following the interview were excluded from the study. Results: The clinical characteristics of the 28 eligible patients were as follows: 67.9 ± 14.8 years old, 23 men (69%), body mass index (24.7 ± 4.9 kg/m2), and HbA1c levels 7.16 ± 1.11% at interview and two months later. Glycemic control status (GCS) was Adequate (A) to Inadequate (I): 1 case; I to A: 7 cases; A to A good: 14 cases; I to I: 6 cases (p-value = 0.02862 by Chi-square test). Multiple regression analyses showed that Q1 (Did RoBoHoN speak clearly?) and Q7 (Was RoBoHoN’s response natural?) significantly contributed to GCS, indicating that the naturalness of the responses did not impair the robot-assisted interviews. The results suggest that to improve the system in the future, it is more beneficial to focus on the content of the conversation rather than pursuing superficial naturalness in the responses. Conclusions: This study demonstrated the efficacy of a robot-assisted diabetes management system that can contribute to improved glycemic control