Makoto Ohara

Relationship between daily and day-to-day glycemic variability and increased oxidative stress in type 2 diabetes

AIMS To determine the association of daily and day-to-day glucose variability with oxidative stress. METHODS This was a cross-sectional analysis of 68 patients with type 2 diabetes mellitus (T2DM) over 72h of continuous glucose monitoring. Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) were measured before breakfast on day 1. Glucose variability, mean glucose level (MGL), mean amplitude of glycemic excursions (MAGE), mean of daily differences (MODD) in glucose levels and area under the postprandial plasma glucose curve (AUCPP) were measured on days 2 and 3. Plasma oxidant capacity against N,N-diethylparaphenylenediamine was measured with the diacron-reactive oxygen metabolites (d-ROMs) test on day 1. RESULTS Overall, 66.2% males with the mean age of 63.2±12.6years, diabetes duration of 12.9±10.4years, and HbA1c level of 8.1±1.6% (65±17mmol/mol) were included. MGL (r=0.330), HbA1c (r=0.326), MAGE (r=0.565), MODD (r=0.488), and AUCPP (r=0.254) exhibited significant correlations with d-ROMs and not FPG; these correlations remained significant after adjustment for clinical factors (sex, age, duration of diabetes, smoking habit, insulin use, statin use, angiotensin II receptor blocker use, BMI, LDL-C, HDL-C, TG, eGFR, and systolic blood pressure) (R2=0.268, R2=0.268, R2=0.417, R2=0.314, and R2=0.347, respectively). MAGE was significantly correlated with MODD (r=0.708) and MAGE and MODD were independently correlated with d-ROMs by multivariate analysis. CONCLUSIONS Therefore, oxidative stress is associated with daily and day-to-day glucose variability in patients with T2DM.

Correlation between postprandial bile acids and body fat mass in healthy normal-weight subjects☆

BACKGROUND Bile acids (BAs) play important roles in glucose regulation and energy homeostasis via G protein-coupled receptors, such as enteroendocrine L cell TGR5. The aim of the present study was to investigate the relationship between postprandial BA levels and body composition after ingestion of a standard test meal. METHODS Eleven healthy subjects of normal weight (body-mass index, 22.0 ± 1.6 kg/m(2) [mean ± SD]), ingested a 400-kcal test meal, and blood samples were obtained from them before ingestion and every 30 min for 120 min after ingestion. The BA fractions were measured with high-performance liquid chromatography. To evaluate body composition, body impedance analysis was performed 1h before ingestion of the test meal. RESULTS Concentrations of both total BA and total glycine-conjugated BA (GCBA) at 30, 60, 90, and 120 min after test-meal ingestion were significantly higher than those at baseline. The body-mass index was correlated with total GCBA at baseline. Moreover, body fat mass was correlated with total GCBA at 30 min (r=-0.688, P=0.019) and 60 min (r=-0.642, P=0.033) and with total BA at 30 min (r=-0.688, P=0.019) and 60 min (r=-0.642, P=0.033). CONCLUSION The postprandial BA response is inversely related with body fat mass in healthy subjects of normal weight.

Association Between Pulse Wave Velocity and a Marker of Renal Tubular Damage (N-Acetyl-β-D-Glucosaminidase) in Patients Without Diabetes

The authors assessed the association between the ratio of urinary activity of N‐acetyl‐β‐D‐glucosaminidase (NAG) to creatinine and the brachial‐ankle pulse wave velocity (baPWV) in patients without overt diabetes mellitus (DM). This was a cross‐sectional study of 233 patients who had an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 and no history of kidney disease. Patients were divided into two groups: high NAG group (>5.8 U/g creatinine) and low NAG group (≤5.8 U/g creatinine). Mean baPWVs of the high NAG group were significantly higher than those of the low NAG group in both the eGFR ≥30 and <60 tertiles and the eGFR ≥60 and <90 tertiles. The baPWV was positively correlated with NAG in all patients (r=0.341, P<.001). Stepwise multivariate regression analysis showed that the baPWV was significantly related with NAG, age, and systolic blood pressure. Elevated NAG is related to elevated arterial stiffness in patients without DM.

Change in urinary N-acetyl-β-d-glucosaminidase levels relevant to postprandial glycemic control conditions in subjects without diabetes mellitus.

BACKGROUND To assess the relationship between the serum level of 1,5-anhydroglucitol (1,5-AG), a marker of postprandial hyperglycemia, and the ratio of the urinary activity of N-acetyl-β-d-glucosaminidase to creatinine (NAG index) in subjects without diabetes mellitus (DM). METHODS This was a cross-sectional study with 495 subjects without DM who had an estimated glomerular filtration rate≥30ml/min/1.73m(2). Subjects were divided into tertiles based on serum 1,5-AG levels: high (>21.0μg/ml), middle (14.0-21.0μg/ml), and low (<14.0μg/ml). Adjusted odds ratios for an elevated urinary NAG index (>5.8U/g creatinine) according to the HbA1c (≤5.4%, 5.5%-5.9%, and 6.0%-6.4%) and 1,5-AG tertiles were calculated. RESULTS The NAG index was negatively correlated with the serum 1,5-AG level in all subjects. The slopes of the regression lines for these variables did not differ significantly between elderly (≥65y) and nonelderly subjects. As compared with high 1,5-AG and HbA1c≤5.4%, the odds ratios for an elevated urinary NAG index increased progressively to 7.71 across the categories of low 1,5-AG and HbA1c of 6.0% to 6.4%. CONCLUSION Poor control of postprandial glucose is related to an elevated urinary NAG index in persons without DM.

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).

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.

Combination Therapy with a Sodium-Glucose Cotransporter 2 Inhibitor and a Dipeptidyl Peptidase-4 Inhibitor Additively Suppresses Macrophage Foam Cell Formation and Atherosclerosis in Diabetic Mice

Dipeptidyl peptidase-4 inhibitors (DPP-4is), in addition to their antihyperglycemic roles, have antiatherosclerotic effects. We reported that sodium-glucose cotransporter 2 inhibitors (SGLT2is) suppress atherosclerosis in a glucose-dependent manner in diabetic mice. Here, we investigated the effects of combination therapy with SGLT2i and DPP-4i on atherosclerosis in diabetic mice. SGLT2i (ipragliflozin, 1.0 mg/kg/day) and DPP-4i (alogliptin, 8.0 mg/kg/day), either alone or in combination, were administered to db/db mice or streptozotocin-induced diabetic apolipoprotein E-null (Apoe−/−) mice. Ipragliflozin and alogliptin monotherapies improved glucose intolerance; however, combination therapy did not show further improvement. The foam cell formation of peritoneal macrophages was suppressed by both the ipragliflozin and alogliptin monotherapies and was further enhanced by combination therapy. Although foam cell formation was closely associated with HbA1c levels in all groups, DPP-4i alone or the combination group showed further suppression of foam cell formation compared with the control or SGLT2i group at corresponding HbA1c levels. Both ipragliflozin and alogliptin monotherapies decreased scavenger receptors and increased cholesterol efflux regulatory genes in peritoneal macrophages, and combination therapy showed additive changes. In diabetic Apoe−/− mice, combination therapy showed the greatest suppression of plaque volume in the aortic root. In conclusion, combination therapy with SGLT2i and DPP4i synergistically suppresses macrophage foam cell formation and atherosclerosis in diabetic mice.

Change of carotid intima-media thickness is associated with age in elderly Japanese patients without a history of cardiovascular disease.

The present study aimed to evaluate the relationship between the change of carotid intima‐media thickness (CIMT) and clinical characteristics in Japanese patients without a history of cardiovascular disease.

Analysis of pancreatic volume in acute-onset, slowly-progressive and fulminant type 1 diabetes in a Japanese population

A decrease in the size of the pancreas is observed in islet autoantibody‐positive non‐diabetic donors and acute‐onset type 1 diabetes irrespective of the diabetes duration. Little is known, however, about the relationship between the size of the pancreas and type 1 diabetes subtypes, including fulminant type 1 diabetes.