Ferulic acid prevents pathological and functional abnormalities of the kidney in Otsuka Long-Evans Tokushima Fatty diabetic rats.

We investigated the preventive effects of ferulic acid (FA) and alpha-tocopherol (AT) on the progression of diabetic nephropathy. Otsuka Long-Evans Tokushima Fatty (OLETF) and Long-Evans Tokushima Otsuka (LETO) rats were used as type 2 diabetes and non-diabetes models, respectively. Two-thirds of the OLETF rats were fed 0.2% FA-containing or 0.5% AT-containing chow. Diabetic nephropathy was assessed based on urinary protein excretion and pathological changes which were scored based on the percentages of extracellular matrix area in the glomerular area. Furthermore, renal messenger RNA (mRNA) expression of intercellular adhesion molecule-1 (ICAM-1), cyclooxygenase-2 (COX-2) and transforming growth factor-beta1 (TGF-beta1) was quantified by real-time polymerase chain reaction. After 12 weeks of FA- or AT-supplementation, urinary protein in untreated-OLETF group was significantly higher than that in LETO group, thus FA-supplementation significantly decreased urinary protein excretion. Pathological scores in FA-supplemented group were significantly lower than those in untreated OLETF group. Supplementation with either FA or AT significantly prevented the elevation of TGF-beta1 mRNA expression caused by diabetes. Treatment with neither FA nor AT had a significant effect on COX-2 or ICAM-1 mRNA expressions. We have demonstrated the preventative effects of FA on diabetic nephropathy via suppression of TGF-beta1 upregulation, furthermore FA may be more potent than AT.

Peripheral nerve functions may deteriorate parallel to the progression of microangiopathy in diabetic patients.

Our aim was to obtain information to help in the early detection of impaired nerve function and to assess the severity of diabetic symmetric polyneuropathy (DPN). Various somatic and autonomic nerve functions in 40 diabetics and 20 age-matched healthy volunteers were evaluated using six objective examinations: nerve conduction study, quantitative vibratory perception threshold, heart rate variability, Valsalva test, head-up tilt and quantitative sudomotor axonal reflex test (QSART). The diabetics were divided into three groups according to the severity of their microangiopathy. The nerve function data and level of impairment were compared between a healthy control and three diabetic groups. The relationships between nerve function data and clinical background were also examined using multivariate analysis. Results were as follows: (1) all nerve dysfunctions seemed to develop parallel to the progression of microangiopathy, (2) reduced nerve conduction velocity and elevated vibratory perception thresholds in the feet might be early detectable signs of DPN, (3) vasomotor and sudomotor sympathetic functions and cardiovagal functions seemed to deteriorate with the appearance of microangiopathy, (4) lowered compound muscle action potential seemed to appear at the advanced microangiopathic condition, (5) hypohydrosis was closely related to diabetic foot ulcers. In conclusion, nerve dysfunction in diabetics might generally progress with microangiopathy from somatic sensory nerve dysfunction to autonomic nerve dysfunction and then to somatic motor nerve dysfunction. Sympathetic sudomotor dysfunction might be a sensitive predictor of diabetic foot ulcer.

Increased gene expression of antioxidant enzymes in KKAy diabetic mice but not in STZ diabetic mice.

Oxidative stress and the gene expression at the transcriptional level of antioxidant enzymes were investigated in two models of diabetes in mice. We used KKAy mice as a model of obese insulin-resistant diabetes, and streptozotocin-induced diabetic mice (STZ mice) as a model of insulin-deficient diabetes. C57BL mice and saline-injected ICR mice were used as the respective non-diabetic controls. To assess oxidative damage, plasma malonedialdehyde (MDA), urine 8-isoprostane and 8-hydroxy deoxyguanosine (8-OHdG) were measured. The mRNA expression of antioxidant enzymes, superoxide dismutase 1 (SOD-1) and glutathione peroxidase 1 (GPx-1) in the kidney and heart were quantified using a real-time polymerase chain reaction. The KKAy mice demonstrated moderate hyperglycemia and hyperlipidemia, and the STZ mice showed severe hyperglycemia and hypolipidemia. The KKAy mice, but not the STZ mice, showed elevated plasma MDA relative to the non-diabetic controls. Urine 8-isoprostane and 8-OHdG in both diabetic mouse groups increased significantly. The urine oxidative stress markers in the severely hyperglycemic STZ mice were higher than those in the moderately hyperglycemic KKAy mice. Although GPx-1 and SOD-1 showed elevated mRNA expression in the KKAy mice in the kidney and heart, in the STZ mice they did not increase compared to the controls. The compensatory up-regulation of the mRNA expression of antioxidant enzymes may be impaired in the insulin-deficient severely hyperglycemic state.

Rice bran extract prevents the elevation of plasma peroxylipid in KKAy diabetic mice.

Oxidative stress is now considered to be a key factor in the development of diabetes and its complications. In this study, we examined the anti-oxidative effects of a crude lipophilic rice bran extract, Ricetrienol, which contains alpha-tocopherol, tocotrienol and phytosterol, in obese diabetic KKAy mice. We used KKAy mice fed a normal diet (DM group) or a diet including 0.1% Ricetrienol (RT group), and non-diabetic C57BL mice (C group). After 6 weeks, body weight, HbA1c, plasma glucose, lipids, peroxylipid (malonedialdehyde, MDA), alpha-tocopherol and glutathione peroxidase 1 (GPx) mRNA expression in the kidney were measured. At 1 week and at the end of the experimental period, urine 8-isoprostane and 8-hydroxy deoxyguanosine (8-OHdG) were also measured. Ricetrienol administration did not affect hyperglycemia, body weight or hyperlipidemia. Plasma MDA, urine 8-isoprostane and 8-OHdG in the DM group were significantly increased compared with the C group and the elevation of plasma MDA was significantly suppressed by 0.1% Ricetrienol. GPx mRNA expression was significantly increased in the RT group when compared with the C group. Plasma alpha-tocopherol in the RT group was significantly higher than that in the DM group. These findings suggest that Ricetrienol exerts a protective effect against oxidative damage in diabetes mellitus.

History of obesity as a risk factor for both carotid atherosclerosis and microangiopathy.

As a westernized lifestyle becomes widespread in Japan, the number of individuals with obesity, as well as type 2 diabetes, is rapidly increasing. In this investigation, we studied the prevalence of obesity and its association with the development of diabetic macroangiopathy and microangiopathy. The clinical records of 634 patients in our hospital with type 2 diabetes were surveyed. The relationship between obesity and diabetic retinopathy and nephropathy and macroangiopathy (carotid artery intima-media thickness, IMT) was examined using univariate and multivariate analysis. A body mass index (BMI) > or = 25 kg/m2 was used as the diagnostic criterion for obesity. The prevalence of obesity at the time of the survey was 35% and a history of obesity was reported in 70% of the survey population. Multiple regression analysis revealed that the maximum BMI was significantly correlated with IMT thickening. The prevalence of nephropathy in previously obese patients was significantly higher than in non-obese patients. The maximum BMI was significantly associated with the development of retinopathy and nephropathy, as shown by logistic regression analysis. This suggests that a history of obesity may be an important risk factor for the development of micro- and macroangiopathy in Japanese with type 2 diabetes.