Association of urinary albumin excretion with insulin resistance in Japanese subjects: impact of gender difference on insulin resistance.

OBJECTIVE: To investigate the relationship between homeostasis model assessment for insulin resistance (HOMA-R) and urinary albumin excretion in Japanese and clarify gender difference in albuminuria-related insulin resistance. METHODS: The subject group consisted of 752 Japanese who had no history of diabetes, hypertension or dyslipidemia. After anthropometric examination, fasting blood samples were obtained to determine plasma glucose (FPG), lipids and HOMA-R. The urinary excretion of albumin in the first void urine was expressed as the creatinine ratio (ACR, mg/gCr). Estimated glomerular filtration rate (eGFR) was calculated from serum creatinine using the formula for Japanese. RESULTS: HOMA-R showed a significant correlation with ACR, and the correlation between HOMA-R and ACR was evident in the subjects with central obesity, whereas no significant correlation was found in the non-obese subjects. There was no correlation between HOMA-R and eGFR. HOMA-R increased according to the quintile of ACR and followed a significant trend. This association was obvious in males; however, in females there was no significant trend. Multiple regression analysis revealed that HOMA-R showed a significant correlation with age, waist circumference, blood pressure and serum triglyceride. In addition, ACR exhibited an independent association with HOMA-R. The association of HOMA-R and ACR was observed only in males, and was not present in females. CONCLUSION: Microalbuminuria is associated with insulin resistance in Japanese, where central obesity might play an essential role. This association is gender-specific suggesting the involvement of sex hormones in the pathogenesis of albuminuria-related insulin resistance.

Association of polymorphism of estrogen receptor-alpha gene with circulating levels of adiponectin in postmenopausal women with type 2 diabetes.

AIM: Menopause is a risk factor for cardiovascular disease (CVD) in women because of the reduction in endogenous estrogen. Recently, single nucleotide polymorphisms (SNPs) of the estrogen receptor alpha (ESR-1) gene (c.454-397T>C) associated with the prognosis of myocardial infarction in postmenopausal women were identified; however, the mechanism by which genetic variation of ESR-1 contributes to the pathogenesis of CVD is unknown. Circulating levels of adipokines and inflammatory cytokines predict CVD risk; hence, this study aimed to investigate whether ESR-1 genotypes (c.454-397T>C) might influence circulating levels of adipokines and inflammatory cytokines in postmenopausal women with type 2 diabetes. METHODS: Sixty-three postmenopausal women with type 2 diabetes were recruited. Serum levels of adiponectin, resistin, interleukin-6 (IL-6), and high-sensitive C-reactive protein (hs-CRP) were determined. RESULTS: The genotype of ESR-1 was closely associated with serum adiponectin, which was decreased in subjects with the T allele and was lowest in those with the T/T genotype. Multiple logistic regression analysis revealed independent contribution of the homozygote for the T allele to low serum levels of adiponectin. CONCLUSION: The T allele of the c.454-397T>C SNP of ESR-1 is associated with low serum levels of adiponectin, which may lead to a high risk of CVD in postmenopausal women.

Involvement of the Rho/Rho kinase signaling pathway in platelet-derived growth factor BB-induced vascular endothelial growth factor expression in diabetic rat retina.

PURPOSE: To examine the role played by the Rho/Rho kinase pathway in the platelet-derived growth factor BB (PDGF-BB)-induced expression of vascular endothelial growth factor (VEGF) in the diabetic rat retina. METHODS: Male Sprague-Dawley rats were made diabetic by a single intraperitoneal injection of streptozotocin. Diabetic rats and PDGF-BB-exposed primary cultured porcine retinal pericyte cells (PRPCs) were treated with fluvastatin, an HMG-CoA reductase inhibitor, and fasudil, a selective Rho kinase inhibitor. The retinal expression of VEGF was determined by reverse transcriptase-polymerase chain reaction (RT-PCR). The mRNA expression of VEGF and the activation of Rho A were studied by Northern and Western blot analyses. RESULTS: RT-PCR showed that in rats that were diabetic for 4 weeks VEGF mRNA expression levels were 1.8-fold those in control rats. This enhanced expression was blocked by treatment with fluvastatin or fasudil. Exposure of PRPCs to PDGF-BB increased their VEGF mRNA expression threefold, and fluvastatin suppressed this effect. Fluvastatin also suppressed the PDGF-BB-induced activation of Rho GTPase in PRPCs. CONCLUSIONS: The Rho/Rho kinase pathway may be involved in the upregulation of VEGF expression in the diabetic retina, suggesting that fasudil might be useful for the prevention of diabetic retinopathy.

The Rho-kinase inhibitor, fasudil, attenuates diabetic nephropathy in streptozotocin-induced diabetic rats.

This study aimed to investigate the effect of the Rho-kinase inhibitor fasudil on the development of diabetic nephropathy and clarify a contribution of the Rho/Rho-kinase pathway to the pathogenesis of diabetic nephropathy. Diabetes was induced in male Sprague-Dawley rats with an intraperitoneal injection of streptozotocin. Animals were then divided into the following 4 groups; normal control rats, diabetic rats, diabetic rats administered fasudil orally and diabetic rats administered fluvastatin (3-hydroxy-methylglutaryl coenzyme A reductase inhibitor, statin) orally. After 1 month of treatment, neither fasudil nor statin had any influence on blood glucose or blood pressure in diabetic rats. While urinary excretion of albumin and 8-hydroxydeoxyguanosine (8-OHdG) was increased in diabetic rats, both of these increases were abolished by fasudil and statin. Rho activity was enhanced in the renal cortex of diabetic rats compared to normal controls, and this enhancement was abolished by statin treatment. Expression of transforming growth factor-beta (TGF-beta) and connective tissue growth factor (CTGF) mRNA was up-regulated in the renal cortex of diabetic rats, and this was abolished by fasudil as well as statin. Expression of NOX4 mRNA (catalytic subunit of NAD(P)H oxidase) was up-regulated in the renal cortex of diabetic rats, an effect which was also abolished by fasudil as well as statin. The present study demonstrates that the Rho/Rho-kinase pathway is involved in up-regulation of TGF-beta, CTGF and NAD(P)H oxidase in diabetic kidney. We conclude that suppression of the Rho/Rho-kinase pathway could be a new strategy for the treatment of diabetic nephropathy.