Chie Ohmura

Effect of metformin on advanced glycation endproduct formation and peripheral nerve function in streptozotocin-induced diabetic rats

The effects of metformin treatment on advanced glycation endproduct formation and peripheral nerve function in streptozotocin-induced diabetic rats were examined. Streptozotocin-induced diabetic rats were treated with low dose metformin (50-65 mg kg(-1) daily) or high dose metformin (500-650 mg kg(-1) daily) for 10 weeks. While the metformin-untreated diabetic group showed a significant increase of advanced glycation endproducts (6.1-fold in the lens, 1.6-fold in the sciatic nerve, 2.3-fold in the renal cortex, and 1.9-fold in plasma; all P < 0.01) compared with the healthy control group, both metformin-treated groups had significantly less advanced glycation endproduct deposition. The % decrease in the diabetes-induced increase in advanced glycation endproduct formation by low and high dose metformin treatment was 25% and 72% in the lens (both P < 0.01), 31% and 42% in the sciatic nerve (both P < 0.05), and 16% and 33% in the renal cortex (P < 0.05 and P < 0.01), respectively. However, the plasma advanced glycation endproduct level showed no significant difference from that in the untreated diabetic group, in spite of slight decrease in plasma glucose and glycated hemoglobin levels in the metformin-treated groups. The diabetes-induced sciatic nerve conduction velocity deficits were improved by 46% and 42% by low and high dose metformin treatment, respectively (both P < 0.01). These data suggest that metformin may have a direct antiglycative action, which in turn contributes to amelioration of peripheral nerve function. Thus, metformin treatment may be effective in the prevention of diabetic complications through not only lowering plasma glucose, but also directly inhibiting advanced glycation endproduct formation.

Combination of the Framingham Risk Score and Carotid Intima-Media Thickness Improves the Prediction of Cardiovascular Events in Patients With Type 2 Diabetes

OBJECTIVE The aim of this study was to investigate whether carotid intima-media thickness (IMT) and brachial-ankle pulse wave velocity (baPWV) add value to the Framingham risk score (FRS) in predicting the development of cardiovascular diseases (CVDs) in type 2 diabetic patients with a negative history of CVD. RESEARCH DESIGN AND METHODS Type 2 diabetic patients (n = 783) were retrospectively recruited and followed for CVD. RESULTS During a 5.4-year follow-up period, 85 incidences of CVD were recorded (10.9%). After adjustment for conventional arterial risk factors, multivariate analysis with the Cox proportional hazards model identified IMT, but not baPWV, as a significant determinant of CVD. In addition, the combination of FRS with IMT, but not with baPWV, improved the prediction of CVD. CONCLUSIONS Carotid IMT is a significant predictor of CVD in asymptomatic type 2 diabetic patients, and the combination of FRS and IMT improves the prediction of CVD in these patients.

Clinical usefulness of measuring urinary polyol excretion by gas-chromatography/mass-spectrometry in type 2 diabetes to assess polyol pathway activity

INTRODUCTION Decreased myo-inositol levels and increased activity of the polyol pathway have been proposed to play a role in causing diabetic microvascular complications. There are few clinical methods for examining the activity of the polyol pathway in diabetic patients. We assessed the effect of changes in glycemic control on polyol pathway activity by measuring urinary polyol excretion. MATERIALS AND METHODS Gas-chromatography/mass-spectrometry (GC/MS) was used to assess the urinary excretion of glucose and polyols (myo-inositol, sorbitol, and fructose) in 50 patients who had type 2 diabetes without nephropathy and 20 healthy subjects. RESULTS In the diabetic patients with poor glycemic control, urinary sorbitol levels were significantly increased and urinary myo-inositol excretion was approximately 6.5-fold higher than in healthy controls (33.0+/-6.5 vs 221.7+/-45.9 mg/day, mean+/-SE, P<0.01). During strict glycemic control, some patients (Group A) showed simultaneous disappearance of glucosuria and normalization of the urinary excretion of myo-inositol (<50 mg/day) and, while others (Group B) showed delayed normalization of urinary myo-inositol excretion. Group B showed significantly higher urinary myo-inositol, sorbitol, and fructose excretion than Group A at the time of disappearance of glucosuria. These findings suggest that patients in Group B may have increased polyol pathway activity. CONCLUSION Even though short-term strict glycemic regulations were established in long-standing hyperglycemic diabetic patients, to normalize the once-exaggerated polyol pathway activities, it was essential to maintain glucosuria-free conditions for some period. Quantitation of urinary polyols using GC/MS appears to be a clinically useful method for assessing polyol pathway activity.

Different effects of two α-glucosidase inhibitors, acarbose and voglibose, on serum 1,5-anhydroglucitol (1,5AG) level

Serum 1,5-anhydroglucitol (1,5AG) is a useful glycemic marker in the control of diabetes; however, treated with alpha-glucosidase inhibitors (alpha-GIs), acarbose (Aca) and voglibose (Vog), it tends to show the discrepancy between serum 1,5AG and related glucose levels. Twenty patients were randomly assigned to adding Aca or Vog to the current treatment. We measured serum 1,5AG levels and other parameters of diabetic control before, 2 and 4 weeks after the alpha-GI treatment. We also measured urinary 1,5AG levels using gas chromatography/mass spectrometry (GC/MS). Glycated albumin, Hb(A1c), and fasting plasma glucose (FPG) levels were significantly decreased after 2 and 4 weeks of treatment, and the changes were similar in the two groups. Despite the similar urinary excretion of 1,5AG and other glycemic parameters, serum 1,5AG level was significantly lower in the Aca group than in the Vog group (3.4+/-0.5 vs. 7.9+/-1.2 microg/ml, P<.005; mean+/-S.E.) at the period of 4 weeks. Even in the same glycemic level, the less increase of serum 1,5AG after treatment with Aca might be due to a reduction of intestinal 1,5AG absorption via inhibition of alpha-amylase that features Aca.

Relationship between carotid atherosclerosis and erythrocyte membrane cholesterol oxidation products in type 2 diabetic patients

Oxidative stress is well known to play a critical role in atherosclerosis. This study investigated an appropriate marker of in vivo oxidative stress and whether it could predict macroangiopathy in diabetes. The lipid composition of erythrocyte membranes was analyzed in 64 type 2 diabetic patients using gas chromatography-mass spectrometry (GC/MS). After 3,5,7-cholestatriene (a cholesterol oxidation product) was detected, the peak height ratio of 3,5,7-cholestatriene to cholesterol was calculated. Carotid artery intima-media thickness (IMT) was measured to evaluate atherosclerosis. The IMT was independently associated with 3,5,7-cholestatriene (P<0.0001), age (P=0.0001), and HbA1c (P=0.05) by stepwise multiple regression analysis (R2=0.416, P<0.0001). When the subjects were divided into groups with or without carotid atherosclerosis, the 3,5,7-cholestatriene level was significantly higher in 37 subjects with atherosclerosis than in 27 subjects without it (0.41+/-0.22 vs. 0.16+/-0.16%, P<0.0001). Among 38 subjects with no clinical manifestations of macroangiopathy and long-term good glycemic control, the 3,5,7-cholestatriene level was also significantly higher in the patients with carotid atherosclerosis than in those without it (0.40+/-0.20 vs. 0.18+/-0.12%, P=0.0003). These data suggest that the 3,5,7-cholestatriene level in erythrocyte membrane lipids may be a useful predictor of subclinical atherosclerosis.

Relationship between olfactory dysfunction and cognitive impairment in elderly patients with type 2 diabetes mellitus.

AIMS Recent clinical studies identified the relation between olfactory dysfunction and cognitive impairment in the elderly without type 2 diabetes mellitus. The aim of the present study was to define the relation between olfactory function and cognition in elderly patients with type 2 diabetes mellitus. METHODS The study participants comprised 250 elderly (age, 68-77, median 72) Japanese outpatient with type 2 diabetes mellitus free of clinically-evident cognitive impairment. Olfactory and cognitive functions were evaluated by the Open Essence (OE) test and Mini-mental State Examination (MMSE), respectively. RESULTS Based on the MMSE score, 62.0%, 24.4%, and 13.6% of the participants were considered to have no impairment, possible cognitive impairment and probable dementia, respectively. The OE test score of the probable dementia group was significantly lower than other groups. Furthermore, age and serum uric acid were significantly higher in the probable dementia group than other groups. Simple correlation analysis showed positive correlation between the MMSE score and diastolic blood pressure, education, OE test score, total cholesterol, LDL cholesterol, folic acid, and negative correlation with age, HbA1c, aspartate aminotransferase, serum adiponectin and urinary albumin excretion. Multivariate regression analysis showed that OE test score correlated significantly and independently with MMSE score (standardized coefficients β=0.542, R(2)=0.478, P<0.01), in addition to education level, HbA1c and serum adiponectin. CONCLUSIONS The results suggested the association of olfactory dysfunction with cognitive impairment in elderly patients with type 2 diabetes mellitus.

Efficacy of low-dose metformin in japanese patients with type 2 diabetes mellitus

Abstract The goal of this study was to examine the antihyperglycemic effect of low-dose metformin in nonobese and obese Japanese patients with type 2 diabetes mellitus. After 3 months of reeducation and stabilization of diet therapy (25 kcal/kg of ideal body weight), metformin treatment was initiated. We administered metformin (500 to 750 mg daily) as monotherapy (n = 11) or in combination with a sulfonylurea (n = 14). After 6 months of treatment, the fasting plasma glucose level (mean ± SD) decreased from 190 ± 42 mg/dL to 155 ± 37 mg/dL and the glycated hemoglobin A 1c level (mean ± SD) from 8.8 ± 1.2% to 7.4 ± 1.0% in the monotherapy group. These same variables decreased from 218 ± 60 mg/dL to 162 ± 30 mg/dL and from 9.5 ± 1.2% to 8.4 ± 1.2% in the combination therapy group. All of these changes were statistically significant. Our results demonstrate that even low doses of metformin can improve hyperglycemia in Japanese patients with type 2 diabetes mellitus.

Switching from Twice-Daily Basal Insulin Injections to Once-Daily Insulin Degludec Injection for Basal-Bolus Insulin Regimen in Japanese Patients with Type 1 Diabetes: A Pilot Study.

The aim of this study was to investigate the efficacy of insulin degludec used for basal-bolus insulin regimen after switching from twice-daily basal insulin in Japanese patients with type 1 diabetes mellitus. The subjects were 22 type 1 diabetes patients treated with basal-bolus insulin regimen with twice-daily basal insulin. Basal insulin was switched to once-daily injection of insulin degludec with 10% dose reduction. HbA1c and fasting plasma glucose (FPG) were measured before and 12 weeks after switching. The frequency of hypoglycemic episodes, standard deviation (SD) of blood glucose, and mean of daily difference (MODD) were evaluated by continuous glucose monitoring (CGM) before and 4 weeks after switching. HbA1c and FPG before and 12 weeks after switching were comparable (HbA1c 8.5 ± 1.4 versus 8.7 ± 1.6%, P = 0.28; FPG 203.2 ± 81.2 versus 206.5 ± 122.4 mg/dL, P = 0.91). The frequency of hypoglycemia during nighttime was not significantly different at 4 weeks after switching (14.4 ± 17.0 versus 11.1 ± 15.0%, P = 0.45). In addition, SD and MODD before and 4 weeks after switching were also comparable. In conclusion, glycemic control under once-daily insulin degludec injection was almost comparable to that under twice-daily basal insulin injections in Japanese type 1 diabetes patients. This study was registered with ID: UMIN000010474.

Efficacy and safety of nateglinide plus vildagliptin combination therapy compared with switching to vildagliptin in type 2 diabetes patients inadequately controlled with nateglinide

To investigate the efficacy and safety of vildagliptin, a potent dipeptidyl peptidase‐4 inhibitor, as add‐on to nateglinide, compared with switching to vildagliptin in Japanese type 2 diabetes patients poorly controlled with nateglinide.

Repetitive Hypoglycemia Increases Circulating Adrenaline Level with Resultant Worsening of Intimal Thickening After Vascular Injury in Male Goto-Kakizaki Rat Carotid Artery

Hypoglycemia associated with diabetes management is a potential risk for cardiovascular diseases. However, the effect of hypoglycemic episodes including a surge of sympathetic activity on the progression of neointima formation after vascular injury remains largely unknown. In this study, insulin was injected intraperitoneally into nonobese diabetic Goto-Kakizaki (GK) rats, once every 3 days for 4 weeks after balloon injury of carotid artery to induce hypoglycemia. Then, we evaluated balloon injury-induced neointima formation. Insulin treatment enhanced neointima formation and increased the number of proliferating cell nuclear antigen (PCNA)-positive cells in the carotid artery. Injection of glucose with insulin prevented hypoglycemia and abrogated intimal thickening. Also, bunazosin, an α1 adrenergic receptor antagonist, prevented intimal thickening and accumulation of PCNA-positive cells induced by insulin treatment despite the presence of concomitant hypoglycemia and high adrenaline levels. Incubation of cultured smooth muscle cells with adrenaline resulted in a significant increase in their proliferation and G0/G1 to S phase progression, which was associated with activation of extracellular signal-regulated kinase, enhanced expression of cell cycle regulatory molecules such as cyclin D1, and cyclin E, and phosphorylation of retinoblastoma protein. These adrenaline-induced effects were abrogated by bunazosin. Our data indicated that increased adrenaline induced by repetitive hypoglycemia promotes intimal thickening and smooth muscle cell proliferation after endothelial denudation in GK rats.