Circadian Rhythm of Subspecies of Low-Density Lipoprotein-Cholesterol and High-Density Lipoprotein-Cholesterol in Healthy Subjects and Patients with Type 2 Diabetes.

AIMS: We established automated assay kits for quantifying small dense low-density lipoprotein (sdLDL)-cholesterol (C), LDL-triglyceride (TG), and high-density lipoprotein (HDL)3-C, and apolipoprotein (apo)E-rich HDL-C, and these have been recognized as sensitive biomarkers for predicting coronary artery disease. We investigated the circadian rhythms of these novel lipids to determine if fasting is required to determine basal levels. METHODS: Forty-eight inpatients with type 2 diabetes and 19 healthy volunteers were studied. Blood samples were collected at seven time points, which were obtained after an overnight fast, before and 2 h after each meal, and before the next breakfast. sdLDL-C, LDL-TG, remnant-like particle (RLP)-C, TG-rich lipoprotein (TRL-C), HDL3-C, and apoE-rich HDL-C were measured by the homogeneous methods. NonHDL-C, large buoyant (lb)LDL-C and HDL2-C were calculated by subtracting sdLDL-C from LDL-C or HDL3-C from HDL-C, respectively. RESULTS: Serum TG levels were significantly increased after meals in both healthy participants and patients with diabetes. RLP-C and TRL-C were also increased postprandially. LDL-TG, LDL-C, nonHDL-C, HDL2,3-C, and apoE-rich HDL-C did not exhibit significant fluctuation during the day in healthy participants and patients with diabetes. sdLDL-C was slightly increased postprandially in subjects with diabetes (1-2 mg/dl, 3%-9%), though its increase was not significant compared to the baseline (fasting) level. Significant postprandial reduction was observed with LDL-C and lbLDL-C. There was no influence of statin therapy or oral anti-diabetes drugs on the circadian rhythm of LDL-C subspecies. CONCLUSIONS: Subtle postprandial increase in sdLDL-C is considered a negligible level in general clinical practice. Fasting is not mandatory to measure basal concentrations of LDL and HDL subspecies.

Effects of omarigliptin on glucose variability and oxidative stress in type 2 diabetes patients: A prospective study.

AIMS: To date, no clinical studies have compared once-weekly dipeptidyl peptidase 4 (DPP-4) inhibitors with once-daily DPP-4 inhibitors in terms of glucose variability (GV) and oxidative stress (OS). METHODS: Thirty-six patients with type 2 diabetes mellitus (T2DM) treated with once-daily DPP-4 inhibitors for at least 12 weeks were randomized to either continue once-daily DPP-4 inhibitors or receive omarigliptin, a once-weekly DPP-4 inhibitor, for 24 weeks. The primary end points were changes in the diacron-reactive oxygen metabolite (d-ROMs) test, a marker of OS, and GV using flash glucose monitoring. The secondary end point was changes in the diabetes treatment satisfaction questionnaire (DTSQ) scores. RESULTS: There were no significant group differences in d-ROMs and DTSQ scores after 24 weeks of treatments. However, omarigliptin was superior to once-daily DPP-4 inhibitors in controlling fasting plasma glucose (FPG) and time in range (TIR). Although FPG and TIR were unchanged at 24 weeks after switching to omarigliptin, these parameters increased in the group receiving maintenance therapy with once-daily DPP-4 inhibitors. No statistically significant changes in hemoglobin A1c were observed between the two groups. CONCLUSIONS: Our findings suggest that switching from once-daily DPP-4 inhibitors to omarigliptin may be efficacious for maintaining FPG and TIR in T2DM patients.

Glucose Variability is Independently Correlated with Serum Level of Pigment Epithelium-Derived Factor in Type 2 Diabetes.

INTRODUCTION: Pigment epithelium-derived factor (PEDF) may play a role in cardiometabolic disorders. The aim of this study was to investigate which biochemical and clinical parameters are independently associated with serum PEDF levels in patients with type 2 diabetes mellitus (T2DM). METHODS: We performed a cross-sectional analysis of 124 patients with T2DM who underwent continuous glucose monitoring (CGM) and blood chemistry analysis, including the diacron-reactive oxygen metabolites (d-ROMs) test and serum PEDF measurement (study 1). Then we investigated whether the changes in the studied biochemical and clinical parameters after 24 weeks of treatment (Δparameters) with anti-hyperglycemic agents, including sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, and/or insulin and anti-hypertensive drugs and statins, were independently correlated with change in PEDF (ΔPEDF) in 52 of the patients with T2DM for whom there was sufficient serum samples to perform the post-treatment analysis (study 2). Serum levels of PEDF were measured with an enzyme-linked immunosorbent assay. CGM metrics were calculated on days 2 and 3. Oxidative stress was evaluated using the d-ROMs test. RESULTS: Body mass index (BMI), triglycerides, fasting C-peptide, mean amplitude of glycemic excursions (MAGE), urinary albumin-to-creatinine ratio (UACR), and d-ROMs were positively associated with serum PEDF level, and high-density lipoprotein cholesterol (HDL-C) and estimated glomerular filtration rate (eGFR) were inversely associated with serum PEDF level. Because these parameters were correlated with each other, multivariate stepwise analysis was performed: eGFR, HDL-C, BMI, MAGE, and UACR remained significant (R2 = 0.452). Furthermore, ΔMAGE and Δd-ROMs were positively correlated with ΔPEDF in study 2. CONCLUSIONS: The results of this study suggest that MAGE may be independently correlated with elevations in serum PEDF level in patients with T2DM.

Pancreatic fat accumulation evaluated by multidetector computed tomography in patients with type 2 diabetes.

AIMS: To clarify the clinical impact of pancreatic fat volume on beta cell function in type 2 diabetes patients. MATERIALS AND METHODS: One hundred thirty two consecutive type 2 diabetic patients (mean age, 63.7 years) were enrolled in this cross-sectional study. Total pancreatic volume (TPV), pancreatic fat volume (PFV), and pancreatic parenchymal volume (PPV), and visceral fat volume were examined quantitatively with multidetector computed tomography using SYNAPSE VINCENT image analysis system (Fujifilm Inc., Tokyo, Japan). Pancreatic fat was identified using Hounsfield Units of less than zero. The capacity of insulin secretion was assessed by C-peptide immunoreactivity (CPR) index (100 × fasting CPR/fasting plasma glucose). Insulin sensitivity was evaluated using CPR-insulin resistance (20/fasting CPR × fasting plasma glucose). RESULTS: TPV, PFV, PPV, and visceral fat volume were significantly correlated with body weight (BW). PPV/BW, but not PFV/BW, significantly decreased with increasing duration of diabetes and aging. PFV/BW was positively associated with body mass index and visceral fat volume/BW. PFV/BW was significantly correlated with CPR index, while inversely associated with insulin sensitivity. CPR index, but not CPRinsulin resistance was progressively decreased in patients with a longer duration of diabetes. When patients were divided into two groups according to a median PFV/BW value, CPR index in high PFV/BW group with diabetes duration >5 years was significantly lower than those ≤5 years. However, duration-dependent decrease in CPR index was not observed in low PFV/BW group. CONCLUSIONS: Our present study suggests that PFV might predict the progression of beta cell dysfunction in patients with type 2 diabetes.

Association of Hemoglobin A1c, 1,5-Anhydro-D-Glucitol and Glycated Albumin with Oxidative Stress in Type 2 Diabetes Mellitus Patients: A Cross-Sectional Study.

INTRODUCTION: Oxidative stress plays a central role in the development and progression of vascular complications in patients with type 2 diabetes mellitus (T2DM). We have previously shown that markers of glucose variability evaluated by continuous glucose monitoring (CGM) are positively associated with oxidative stress in patients with T2DM. However, the evaluation of the glycemic variability by CGM remains a time- and money-consuming procedure. Therefore, this study investigated the independent correlates of oxidative stress among various other clinical markers routinely measured in primary care. METHODS: This was a retrospective cross-sectional study with 234 T2DM patients to examine which clinical variables, including 1,5-anhydro-D-glucitol (1,5-AG) and glycated albumin (GA), were independently associated with oxidative stress. Oxidative stress was measured using the diacron-reactive oxygen metabolites (d-ROMs) test. The relationships between d-ROMs and clinical factors, such as blood glucose, glycated hemoglobin (HbA1c), 1,5-AG, GA, lipid parameters, and blood pressure, were examined. RESULTS: Multiple stepwise regression analysis revealed that 1,5-AG (inversely), GA, triglycerides, use of metformin and being female were independently associated with d-ROMs. When patients with T2DM were stratified into two groups with HbA1c < 8.0% and HbA1c ≥ 8.0%, 1,5-AG (inversely), HbA1c, use of metformin and being female were independently associated with d-ROMs in diabetes patients with HbA1c < 8.0%, whereas GA, fasting plasma glucose and being female were independently associated with d-ROMs in patients with HbA1c ≥ 8.0%. CONCLUSION: Our present study suggests that 1,5-AG and GA are the strongest correlates of oxidative stress in patients with well and poorly controlled T2DM, respectively.

Relationship between glucose variability evaluated by continuous glucose monitoring and clinical factors, including glucagon-stimulated insulin secretion in patients with type 2 diabetes.

AIMS: To evaluate the clinical factors affecting daily and day-to-day glucose variability by using continuous glucose monitoring. METHODS: We performed a cross-sectional analysis of patients with type 2 diabetes mellitus (T2DM) who underwent a glucagon stimulation test (GST) with 72 h of continuous glucose monitoring. Daily glucose variability was evaluated by mean amplitude of glycemic excursions [MAGE], percentage coefficient of variation for glucose (%CV), and day-to-day glucose variability (mean of daily differences [MODD]) by using continuous glucose monitoring. Correlations of clinical factors, including insulin secretion ability by the GST with MAGE, %CV, and MODD, were analyzed. RESULTS: In 83 T2DM with insulin therapy, age and hemoglobin A1c (HbA1c) correlated with MAGE and %CV, fasting plasma glucose with MAGE and MODD, and increment of C-peptide immunoreactivity (ΔCPR) by GST correlated inversely with MAGE, %CV, and MODD. In 126 T2DM without insulin therapy, age, diastolic blood pressure, and triglycerides correlated with MODD, HbA1c with MAGE and MODD, and ΔCPR inversely correlated with %CV. Use of α-glucosidase inhibitors inversely correlated with %CV, whereas that of sulfonylurea was associated with MAGE and %CV. CONCLUSIONS: These results suggest that ΔCPR correlated with stability of glycemic control, whereas poorly controlled diabetes is associated with increase in glucose variability. α-glucosidase inhibitors may be superior to sulfonylureas in reducing the glucose variability in T2DM.

Association of glucose and blood pressure variability on oxidative stress in patients with type 2 diabetes mellitus and hypertension: a cross-sectional study.

BACKGROUND: The present study evaluated the effects of glucose and blood pressure (BP) variability on oxidative stress in patients with type 2 diabetes mellitus (T2DM) and hypertension. METHODS: A total of 60 inpatients with T2DM underwent continuous glucose monitoring (CGM) and ambulatory BP monitoring (ABPM). Oxidative stress was estimated using the diacron-reactive oxygen metabolites (d-ROMs) test. Glucose variability, mean glucose level, percentage coefficient of variation for glucose, mean amplitude of glycemic excursions (MAGE), and area under the postprandial plasma glucose curve were determined through CGM. BP variability was assessed by measuring average BP, standard deviation (SD) of systolic and diastolic BP, and coefficient of variation (CV) of systolic and diastolic BP during daytime and nighttime ABPM. RESULTS: Participants had a mean age of 64.5 ± 13.3 years with the duration of the disease 13.9 ± 12.4 years and HbA1c of 8.5 ± 1.2%. Univariate analysis showed that MAGE, nighttime SDs of systolic and diastolic BP, and nighttime CV of systolic BP were significantly correlated with d-ROMs. Further, stepwise multiple regression analysis identified MAGE, nighttime SD and CV of diastolic BP, estimated glomerular filtration rate, and smoking as independent contributors to d-ROMs. CONCLUSIONS: Oxidative stress was associated with daily glucose and nighttime diastolic BP variability in patients with T2DM and hypertension.Trial registration UMIN Clinical Trial Registry UMIN000035615, Registered January 22, 2019-retrospectively registered.

Effect of Dulaglutide Versus Liraglutide on Glucose Variability, Oxidative Stress, and Endothelial Function in Type 2 Diabetes: A Prospective Study.

INTRODUCTION: To compare the effect of dulaglutide and liraglutide on oxidative stress and endothelial function in patients with type 2 diabetes mellitus (T2DM). METHODS: Twenty-two patients with T2DM who received treatment with liraglutide for at least 12 weeks were randomized to either continue liraglutide or receive dulaglutide for 24 weeks. The primary end points were changes in the diacron-reactive oxygen metabolite (d-ROMs) test, as a marker of oxidative stress, and endothelial function, as determined by the reactive hyperemia index (RHI). The secondary end points were changes in body weight (BW), glucose variability, diabetes treatment satisfaction questionnaire (DTSQ) score, and eating behavior. RESULTS: There were no significant differences in changes in d-ROMs and logarithmic-scaled RHI (L-RHI) between the two groups after 24 weeks of treatment. Notably, the treatment with dulaglutide was superior to that with liraglutide in terms of mean glucose levels and mean amplitude of glycemic excursions following the 24-week treatment. However, in this regard, the outcome following the treatment with dulaglutide was maintained, whereas that with the treatment with liraglutide was aggravating. The DTSQ score for "convenience" improved in the dulaglutide group. No statistically significant changes in fasting plasma glucose, hemoglobin A1c, and BW were observed between the two groups. CONCLUSION: We showed that once-weekly dulaglutide was comparable to once-daily liraglutide in terms of oxidative stress and endothelial function. Switching from liraglutide to dulaglutide improved convenience by decreasing the number of injections without deteriorating glucose metabolism. TRIAL REGISTRATION: This trial was registered with the University Hospital Medical Information Network (UMIN no. 000034353) on 10 October 2018.

Improvements of ambient hyperglycemia and glycemic variability are associated with reduction in oxidative stress for patients with type 2 diabetes.

AIMS: We aimed to evaluate which parameters of improvement in glucose metabolism reduce oxidative stress for patients with Type 2 diabetes mellitus (T2DM). METHODS: Sixty-seven outpatients with T2DM underwent 72 h of continuous glucose monitoring (CGM) and were measured for oxidative stress before and after a 24-week intervention with the following targets: fasting plasma glucose (FPG), <130 mg/dl; postprandial plasma glucose (PPG), <180 mg/dl; and glycated hemoglobin (HbA1c), <7% (53 mmol/mol). The mean glucose level (MGL), mean amplitude of glycemic excursions (MAGE), mean of daily differences (MODD), percentage coefficient of variation for glucose (%CV) and area under the postprandial plasma glucose curve (AUCPP) were calculated from the CGM data. Oxidative stress was estimated using the diacron-reactive oxygen metabolites (d-ROMs) test. Finally, the association between the improvements in glucose metabolism and oxidative stress was evaluated. RESULTS: FPG, MGL, HbA1c, MAGE, MODD, %CV, AUCPP, and d-ROMs significantly improved after 24 weeks of intervention. The change in d-ROMs was significantly correlated with that in FPG (r = 0.414), MGL (r = 0.402), HbA1c (r = 0.271), MAGE (r = 0.457), MODD (r = 0.371), and AUCPP (r = 0.352). The correlation of the change in d-ROMs with that in FPG, MAGE, and MODD and the use of glucose-like peptide 1 receptor agonists and statins remained significant after adjustment for other markers of diabetes control (multiple R2 = 0.406). CONCLUSIONS: Improvements in glucose metabolism, including FPG and daily and day-to-day glucose variability, were all correlated with reduced oxidative stress for patients with T2DM.

Comparison of liraglutide plus basal insulin and basal-bolus insulin therapy (BBIT) for glycemic control, body weight stability, and treatment satisfaction in patients treated using BBIT for type 2 diabetes without severe insulin deficiency: A randomized prospective pilot study.

AIMS: We examined whether 0.9 mg/day liraglutide plus basal insulin (Lira-basal) is superior to basal-bolus insulin therapy (BBIT) for type 2 diabetes (T2DM) without severe insulin deficiency as determined by glucagon stimulation. METHODS: Fifty patients receiving BBIT were enrolled in this 24-week, prospective, randomized, open-labeled study. After excluding subjects with fasting C-peptide immunoreactivity (CPR) < 1.0 ng/mL and CPR increase < 1.0 ng/mL at 6 min post glucagon injection, 25 were randomly allocated to receive Lira-basal (n = 12) or continued BBIT (n = 13). Primary endpoint was change in HbA1c. Secondary endpoints were changes in body weight (BW), 7-point self-monitored blood glucose (SMBG), and Diabetes Treatment Satisfaction Questionnaire status (DTSQs) scores. RESULT: The Lira-basal group demonstrated reduced HbA1c, whereas the BBIT group showed no change. BW was reduced in the Lira-basal group but increased in the BBIT group. The Lira-basal group also exhibited significantly reduced pre-breakfast and pre-lunch SMBG. DTSQs scores improved in the Lira-basal group but not the BBIT group. Plasma lipids, liver function, and kidney function were not significantly changed in either group. CONCLUSIONS: Lira-basal therapy is superior to BBIT for T2DM without severe insulin deficiency. This study was registered with UMIN Clinical Trials Registry (UMIN000028313).