Supplementation with Ashitaba (Angelica keiskei) Yellow Stem Exudate Prevents Aging-Induced Thrombotic Tendencies and Systemic Inflammation Without Affecting Body Weight Gain in Mice.

Angelica keiskei Koidzumi (Ashitaba) is a traditional folk medicine and health supplement in Japan. Ashitaba yellow stem exudate (AYE) contains abundant chalcones and thus has the potential to treat and prevent many pathological states such as cancer, inflammation, obesity, diabetics, thrombosis, and hypertension. Levels of plasminogen activator inhibitor 1 (PAI-1), a key regulator of the fibrinolytic system, increase with age in mouse plasma. Therefore, we aimed to determine the effects of AYE on plasma thrombotic parameters in aging mice. Long-term (52 weeks) AYE supplementation significantly decreased age-induced increases of PAI-1 in mouse plasma. Supplementation with AYE decreased levels of the acute-phase and fibrinolytic protein plasma plasminogen, and significantly decreased those of tumor necrosis factor α. These results suggested that continuous intake of AYE throughout life decreases age-induced systemic inflammation and prevents thrombotic tendencies without affecting body weight gain in aged mice. Our findings showed that supplementing diets with AYE might help to prevent thrombotic diseases in elderly individuals.

Relationship between adiponectin multimer levels and subtypes of cerebral infarction.

AIM: Serum adiponectin levels are decreased in patients with cerebral infarction. Adiponectin in circulation exists in three isoforms: high molecular weight (HMW), medium molecular weight (MMW), and low molecular weight (LMW) adiponectin. We measured serum levels of total adiponectin and adiponectin multimers (HMW, MMW, and LMW) in patients with cerebral infarction and compared the serum levels of the three adiponectin multimers in stroke subtypes. We also evaluated the clinical value of adiponectin multimer levels as a biomarker for cerebral infarction. METHODS: We assessed a total of 132 patients with cerebral infarctions. The serum levels of total and adiponectin multimers were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: The total and HMW adiponectin levels were significantly lower in atherothrombotic infarction (AI) than in cerebral embolism (CE) (total, p < 0.05; HMW, p < 0.05). In male patients, the MMW adiponectin level was significantly lower in the lacunar infarction (LI) group than in the AI group (p < 0.05). The LMW adiponectin level was significantly lower in the AI group than in the LI and CE groups (LI, p < 0.001; CE, p = 0.001). However, there were no significant differences in adiponectin multimer levels among the stroke subtypes in female subjects. Additionally, in female patients with AI and LI, the LMW adiponectin levels were negatively associated with C-reactive protein (CRP; AI, p < 0.05; LI, p < 0.05). CONCLUSION: These findings suggest that a decrease in adiponectin is associated with AI and that serum LMW adiponectin level represents a potential biomarker for AI.

Ashitaba (Angelica Keiskei) Exudate Prevents Increases in Plasminogen Activator Inhibitor-1 Induced by Obesity in Tsumura Suzuki Obese Diabetic Mice.

Angelica keiskei koidzumi (ashitaba) is consumed as a traditional folk medicine and health food in Japan. Ashitaba extract contains abundant flavonoids containing chalcones. Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological inhibitor of tissue plasminogen activator. Excessive amounts of PAI-1 in plasma disrupt the fibrinolytic balance and promote a prothrombotic state with which thrombosis and cardiovascular diseases are associated. In the present study, we investigated the effects of ashitaba yellow exudate (AE) on enhanced PAI-1 levels in Tsumura Suzuki obese diabetic (TSOD) mice. AE significantly decreased food efficiency and plasma PAI-1 in TSOD mice but did not affect lean control Tsumura Suzuki nonobese (TSNO) mice. AE also decreased some parameters in the plasma, such as glucose, insulin, tumor necrosis factor alpha (TNF-α) and gains in body weight, subcutaneous, mesenteric fat weight in TSOD mice but had little effect on these parameters in TSNO mice. Levels of adipose PAI-1 were significantly higher in TSOD than in TSNO mice. Major sources of plasma PAI-1 are thought to be adipose tissue and liver. AE significantly suppressed PAI-1 protein levels in the livers of both TSOD and TSNO mice. These results suggest that AE decreased plasma PAI-1 levels by suppressing both the adipose tissue retention of PAI-1 protein and liver PAI-1 production in TSOD mice. Supplementing the diet with AE might help to prevent thrombotic diseases or alleviate the risk of thrombotic diseases as well as to suppress metabolic state in obese individuals.

Serum IFN-λ3 Levels Correlate with Serum Hepatitis C Virus RNA Levels in Symptomatic Patients with Acute Hepatitis C.

BACKGROUND: Recent genome-wide association studies demonstrated that 2 single nucleotide polymorphisms (SNPs), upstream of the interferon-λ (IFNL) 3 gene, are associated with the spontaneous clearance of hepatitis C virus (HCV) in symptomatic patients with acute hepatitis C (AHC). Although these 2 SNPs, rs8099917 and rs12979860, have established their significant roles in the innate immunity response to spontaneously clear HCV in patients with AHC, the detailed mechanisms of their roles remain largely unknown. AIM: This study is aimed at clarifying the factors affecting IFNL3 production and assessing the roles of IFNL3 in AHC. MATERIALS AND METHODS: A total of 21 AHC patients who visited the hospital within 10 days after symptom onset were assessed. As controls, 23 healthy volunteers (HVs) were examined. Serum IFNL3 levels were quantified using an in-house, IFNL3-specific chemiluminescence enzyme immunoassay (CLEIA) kit. Serum IFNL1, IFN-α, IFN-ß, and IFN-γ induced protein-10 (IP-10) levels were assayed using commercial enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: At baseline, serum IFNL3 levels were higher in AHC patients than in HVs (p < 0.0001). The higher levels in AHC patients did not differ between patients with the rs8099917 TT genotype and those with the non-TT (TG/GG) genotype (p = 0.546). Serial measurement of serum IFNL3 levels did not predict the outcome of conventional AHC. However, serum IFNL3 levels at baseline correlated positively with the HCV RNA levels (p = 0.005). Following HCV eradication, serum IFNL3 levels reduced to within the range obtained for HVs. Baseline serum IFNL1 levels did not differ significantly between AHC patients and HVs (p = 0.284). Serum levels of IFNL1 and IFNL3 at baseline also showed no correlative power (p = 0.288). Serum IFN-α and IFN-ß were detected together with remarkably high serum IFNL3 levels in only one patient who progressed to acute liver failure (ALF). CONCLUSION: These findings indicate that serum IFNL3 levels at baseline are higher in AHC patients regardless of the rs8099917 polymorphism, and primary HCV infection triggers the production of IFNL3. As a first line of defense in the innate immune system against invading HCV, increased IFNL3 levels play an important role, but serum IFNL3 levels are not the principal determinant of the clinical course of conventional AHC.

Usefulness of Cytokeratin-18M65 in Diagnosing Non-Alcoholic Steatohepatitis in Japanese Population.

OBJECTIVE: The aim of this study was to evaluate cytokeratin-18M65 (CK-18M65) for distinguishing between simple steatosis (SS) and non-alcoholic steatohepatitis (NASH) against healthy individuals (HIs) in Japanese population. METHODS: The serum from 24 HIs, 21 patients with SS and 20 patients with NASH were examined. Serum CK-18M65 was measured by enzyme-linked immunosorbent assay. RESULTS: Aspartate aminotransferase was significantly different between NASH patients and HIs with p < 0.0001 (SS patients and HIs: p < 0.0001), as was alanine aminotransferase between NASH patients and HIs with p < 0.0001 (SS patients and HIs: p < 0.0001). Serum CK-18M65 increased in a stepwise fashion in HIs and also in SS and NASH patients. Multivariate logistic regression analysis revealed that NASH could be diagnosed with the use of CK-18M65 alone (p = 0.0285, OR 1.0038, 95% CI 1.0004-1.0073). At the optimal cut-off level of 548 U/l, CK-18M65 had an AUC value of 0.7369, 60.00% sensitivity and 85.70% specificity. In patients with NASH, no significant difference was observed between low fibrosis (Stage 0-1, 794.30 ± 454.41, n = 10) and high fibrosis (Stage 2-3, 809.70 ± 641.43, n = 10; p = 0.5967) and between slight steatosis (<33%, 512.89 ± 229.65, n = 9) and moderate steatosis (≥33%, 655.13 ± 480.78, n = 32) in patients with non-alcoholic fatty liver disease (NAFLD; p = 0.7647) with the use of CK-18M65. CONCLUSION: Serum CK-18M65 distinguished NASH from SS, but could not assess the severity of steatosis in NAFLD patients or the grade of fibrosis in NASH patients in Japanese population.

Two chalcones, 4-hydroxyderricin and xanthoangelol, stimulate GLUT4-dependent glucose uptake through the LKB1/AMP-activated protein kinase signaling pathway in 3T3-L1 adipocytes.

4-Hydroxyderricin (4HD) and xanthoangelol (XAG) are major components of n-hexane/ethyl acetate (5:1) extract of the yellow-colored stem juice of Angelica keiskei. 4-Hydroxyderricin and XAG have been reported to increase glucose transporter 4 (GLUT4)-dependent glucose uptake in 3T3-L1 adipocytes, but the detailed mechanism of this phenomenon remains unknown. This present study was aimed at clarifying the detailed mechanism by which 4HD and XAG increase GLUT4-dependent glucose uptake in 3T3-L1 adipocytes. Both 4HD and XAG increased glucose uptake and GLUT4 translocation to the plasma membrane. 4-Hydroxyderricin and XAG also stimulated the phosphorylation of 5' adenosine monophosphate-activated protein kinase (AMPK) and its downstream target acetyl-CoA carboxylase. In addition, phosphorylation of liver kinase B1 (LKB1), which acts upstream of AMPK, was also increased by 4HD and XAG treatment. Small interfering RNA knockdown of LKB1 attenuated 4HD- and XAG-stimulated AMPK phosphorylation and suppressed glucose uptake. These findings demonstrate that 4HD and XAG can increase GLUT4-dependent glucose uptake through the LKB1/AMPK signaling pathway in 3T3-L1 adipocytes.

Salusin-ß, an antimicrobially active peptide against Gram-positive bacteria.

Salusin-ß has been detected in numerous mammalian tissues and has been shown to have various effects on the cardiovascular system. In this study, we showed that salusin-ß exhibited potent antibacterial activity against Gram-positive microorganisms such as Bacillus subtilis NBRC 3513, Bacillus megaterium ATCC 19213, Staphylococcus aureus NBRC 12732, and Staphylococcus epidermidis NBRC 12933. A cytoplasmic membrane-depolarizing assay using the DiSC3(5) dye revealed that the addition of 4 nmol/mL of salusin-ß caused the leakage of fluorescence dye from Staphylococcus aureus NBRC 12732. The antimicrobial potency and circular dichroism (CD) spectroscopy of five analogs related to salusin-ß were examined to determine structure-function relationships in its N- and C-terminal regions. The results obtained suggest that the N-terminal sequences of the salusin-ß molecule are important for the expression of the potent antimicrobial activity of this peptide. A profile corresponding to that of the α-helix conformation was observed in the salusin-ß solution.

Factors of response to pegylated interferon/ribavirin combination therapy and mechanism of viral clearance.

OBJECTIVES: This study explores viral factors of the interferon (IFN) and ribavirin (RBV) resistance-determining region (IRRDR), the IFN sensitivity-determining region (ISDR) and the core protein, and host factor interleukin 28B associated with response to pegylated IFN (PEG-IFN) and RBV combination therapy, and the correlation of viral and host factors with IFN-λ1. METHODS: A total of 58 patients underwent PEG-IFN/RBV combination therapy for 48 weeks. The pretreatment factors associated with rapid virological response (RVR) and sustained virological response (SVR) were analyzed. Pretreatment IFN-λ1 serum levels were compared with the viral and host factors. RESULTS: Univariate analysis showed that IRRDR ≥6 and ISDR ≥2 were significant pretreatment predictors of RVR, and multivariate analysis identified IRRDR ≥6 and hemoglobin as significant predictors of SVR. Pretreatment IFN-λ1 was significantly higher in the SVR group than in the non-SVR group and also in the IRRDR ≥6 group than in the IRRDR ≤5 group. CONCLUSIONS: IRRDR ≥6 was the only significant predictor of SVR and was correlated with IFN-λ1. High serum levels of IFN-λ1 may be conducive to effective PEG-IFN/RBV combination therapy because of the immunomodulatory system.

Prediction of response to pegylated interferon/ribavirin combination therapy for chronic hepatitis C genotypes 2a and 2b and high viral load.

OBJECTIVE: We investigated the impact of host genetics represented by the single nucleotide polymorphism (SNP) of the IL28B gene and viral genetic variations within the nonstructural protein 5A (NS5A) [including the interferon (IFN)/ribavirin (RBV) resistance-determining region (IRRDR) and the IFN sensitivity-determining region (ISDR)] on the outcome of pegylated IFN and RBV (PEG-IFN/RBV) treatment. METHODS: Sixty-six patients infected with hepatitis C virus (HCV)-2a or HCV-2b who received PEG-IFN/RBV for 24 weeks were examined. RESULTS: In HCV-2a, the major genotype of IL28B SNP showed a tendency toward association with sustained virological response (SVR) and rapid virological response (RVR), and four or more mutations in IRRDR (IRRDR[2a] ≥4) and one or more mutations in ISDR plus its carboxyl-flanking region (ISDR/+C[2a] ≥1) were significantly associated with SVR and RVR. In HCV-2b, one or more mutations in the N-terminal part of IRRDR (IRRDR/N[2b] ≥1) were significantly associated with RVR. Multivariate analysis identified the major genotype of IL28B SNP and IRRDR[2a] ≥4 as independent predictive factors of SVR in HCV-2a, with IRRDR[2a] ≥4 being more powerful than the IL28B SNP. Also, IRRDR[2a] ≥4 in HCV-2a and IRRDR/N[2b] ≥1 in HCV-2b were significant determiners of RVR. CONCLUSION: The NS5A sequence heterogeneity and IL28B SNP are useful factors to predict the sensitivity to PEG-IFN/RBV therapy in HCV-2a and HCV-2b infections.

Outcome of double-filtration plasmapheresis plus interferon treatment in nonresponders to pegylated interferon plus ribavirin combination therapy.

OBJECTIVES: We assessed the outcome of double-filtration plasmapheresis (DFPP) combined with pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy in patients infected with hepatitis C virus (HCV)-1b whose HCV had not disappeared during PEG-IFN/RBV combination therapy, or who had relapsed after the end of the therapy. Additionally, we investigated factors predictive of sustained virological response (SVR), including host and viral genetic factors, to DFPP plus IFN/RBV therapy. METHODS: A total of 40 patients infected with HCV-1b whose HCV virus had not been eradicated by previous PEG-IFN/RBV therapy were enrolled for treatment by DFPP plus IFN/RBV. Rapid virological response (RVR) and SVR were assessed, and pretreatment factors associated with SVR - the interleukin (IL)28B gene, the IFN/RBV resistance-determining region (IRRDR) and the IFN sensitivity-determining region (ISDR) - were analyzed. RESULTS: Of the 40 patients, 9 (23%) achieved RVR and 10 (25%) achieved SVR. The significant factors associated with SVR were IL28B major and RVR, as assessed by multivariate analysis (p = 0.0182, p = 0.0005). CONCLUSION: Patients whose HCV is not eradicated by previous PEG-IFN/RBV would be good candidates for combined DFPP and IFN/RBV retreatment provided they demonstrate IL28B major and have achieved RVR.

Serum allograft inflammatory factor-1 is a novel marker for diabetic nephropathy.

AIMS: Recent studies have identified macrophage-mediated injury as an important component in the development of diabetic nephropathy. The aim of this study was to investigate the correlations between serum allograft inflammatory factor-1 (AIF-1) concentration, which is a marker of activated macrophages, and diabetic nephropathy. METHODS: Serum AIF-1 concentrations were measured in 284 patients with type 2 diabetes. We evaluated relationships of serum AIF-1 concentrations to degree of urinary albumin excretion (UAE) or estimated glomerular filtration rate (eGFR) in univariate and multivariate linear regression analyses. RESULTS: Serum AIF-1 concentrations positively correlated with logarithm of UAE (r=0.260, P<0.0001), whereas serum AIF-1 concentrations inversely correlated with eGFR (r=-0.312, P<0.0001). Mean serum AIF-1 concentration was higher in patients with macroalbuminuria than that in patients with normoalbuminuria (P=0.0001) or that in patients with microalbuminuria (P=0.0093). In multivariate linear regression analyses, serum AIF-1 concentrations were independently correlated with logarithm of UAE (ß=0.213, P=0.0120) and with eGFR (ß=-0.286, P=0.0011). CONCLUSIONS: Serum AIF-1 concentration correlated with albuminuria and eGFR in patients with type 2 diabetes and it could be a marker of diabetic nephropathy as well as activated macrophages.

The serum concentration of allograft inflammatory factor-1 is correlated with metabolic parameters in healthy subjects.

Obesity is associated with low-grade chronic inflammation characterized by inflamed adipose tissue with increased infiltration of macrophages. The aim of this study was to investigate the correlations between the serum concentration of allograft inflammatory factor-1 (AIF-1), which is a marker of activated macrophages, and metabolic parameters. The serum AIF-1 concentrations were measured in 303 healthy subjects (163 men and 140 women). We then evaluated the relationships between the serum AIF-1 concentrations and metabolic parameters, including fasting plasma glucose levels, serum lipid concentration, uric acid concentration, and waist circumference. The serum AIF-1 concentrations positively correlated with levels of fasting plasma glucose (r = 0.159, P =.0056), hemoglobin A(1c) (r = 0.169, P = .0032), triglycerides (r = 0.137, P = .0172), and uric acid (r = 0.146, P = .0108) and with waist circumference (r = 0.221, P = .0001) and body mass index (r = 0.185, P = .0012), whereas the serum AIF-1 concentrations inversely correlated with high-density lipoprotein cholesterol level (r = -0.178, P = .0019). Stepwise multiple regression analysis demonstrated that hemoglobin A(1c) level (ß = .133, F = 5.490, P < .05) and waist circumference (ß = .197, F = 11.954, P < .05) were independent predictors of the serum AIF-1 concentrations. The serum AIF-1 concentrations correlated with clinical and biochemical metabolic parameters. Allograft inflammatory factor-1 may be a significant predictor of activated macrophages as well as cardiovascular disease in humans.

Correlation between insulin resistance and outcome of pegylated interferon and ribavirin therapy, hepatic steatosis, hepatic fibrosis in chronic hepatitis C-1b and high viral load.

BACKGROUND/AIMS: Insulin resistance (IR) has been reported to be an independent predictor of treatment outcome in chronic hepatitis C patients. METHODS: We analyzed the relationship between IR and the outcome of pegylated interferon and ribavirin (PEG-IFN/RBV) therapy, taking into account host factors of body mass index and histological index, such as rate of fatty change and fibrosis. Japanese patients (n = 30; 19 men and 11 women; median age 60.0 ± 8.7 years) with chronic hepatitis C-1b with a high viral load were treated with PEG-IFN-α2b/RBV for 48 weeks. RESULTS: Sustained virological response (SVR) was seen in 60% (18/30) and non-SVR in 40% (12/30). HOMA-IR (homeostasis model of assessment-insulin resistance index) at the start and at 24 weeks of treatment showed no statistical difference between SVR and non-SVR. Correlation was observed between HOMA-IR and body mass index (r = 0.45, p = 0.013). Among 20 patients, steatosis and fibrosis were assessed by biopsy. Correlation was observed between HOMA-IR and steatosis (r = 0.57, p = 0.0093), whereas no correlation was observed between HOMA-IR and fibrosis. CONCLUSION: A larger prospective study is needed to clarify the role of IR in the outcome of PEG-IFN/RBV combination therapy and hepatic fibrosis in Japanese patients.

Double-Filtration Plasmapheresis plus Interferon-ß for HCV-1b Patients with Non-Sustained Virological Response to Previous Combination Therapy.

BACKGROUND AND AIMS: Double-filtration plasmapheresis (DFPP) together with interferon (IFN) administration produces a substantial reduction in the viral load during the early stages of treatment. METHODS: Based on their responses to previous pegylated IFN and ribavirin (PEG-IFN/RBV) therapy, 20 patients were divided into null virological response (NVR; n = 12) and relapse (n = 8) groups. DFPP was used in combination with IFN-ß/RBV with subsequent administration of PEG-IFN-α2a/RBV therapy (DFPP + IFN-ß/RBV then PEG-IFN/RBV). Early viral dynamics was assessed, focusing especially on complete early virological response (cEVR) associated with sustained virological response. Additionally, the interleukin 28B gene, the IFN/RBV resistance-determining region, the IFN sensitivity-determining region and the core regions were analyzed. RESULTS: Rapid virological response was achieved in 0% (0/12) of NVR and in 75% (6/8) of relapse patients, with a significant difference between the two groups (p = 0.001). Similarly, cEVR was achieved in 8% (1/12) of NVR and in 88% (7/8) of relapse patients, with a significant difference between the two groups (p = 0.037). By multivariate logistic regression analysis, interleukin-28B major was a significant determiner of cEVR (odds ratio = 24.19, p = 0.037). CONCLUSION: DFPP + IFN-ß/RBV then PEG-IFN/RBV therapy is indicated more for relapse than for NVR patients.

The effect of dopamine agonists: the expression of GDNF, NGF, and BDNF in cultured mouse astrocytes.

In Parkinson's disease, cell death is selectively induced in mesencephalic nigral dopaminergic neurons. At present, no disease modifying therapy or radical treatment has been found for this disease. Some dopamine agonists may have a neuroprotective action in cultured cells and animal models. In the present study, we examined stimulating effects of a non-ergoline D(2) dopamine agonist, ropinirole, on synthesis/secretion of neurotrophic factors, including NGF, BDNF, and GDNF, in cultured mouse astrocytes. These effects were compared with those of ergoline dopamine agonists, SKF-38393, a D(1) agonist, bromocriptine, D(2) agonist, and apomorphine, D(1)/D(2) agonist. Ropinirole elevated GDNF levels to 4-fold, and NGF levels to 6.3-fold, compared with the control group. Of the dopamine agonists examined, ropinirole produced and secreted more GDNF than a 1.8-fold greater amount of apomorphine, a lesser amount of bromocriptine, or a 2.8-fold greater amount of SKF-38393, which served as the control group.

Effect of pioglitazone on various parameters of insulin resistance including lipoprotein subclass according to particle size by a gel-permeation high-performance liquid chromatography in newly diagnosed patients with type 2 diabetes.

Pioglitazone is an insulin-sensitizing agent that has been reported to have anti-arteriosclerotic effects. The aim of this study was to obtain a better understanding of the mechanism involved in the insulin sensitizing effect of pioglitazone. A total of 50 newly diagnosed patients with type 2 diabetes were enrolled in this study and divided into two groups, 25 of who were treated with 15 mg/day pioglitazone and 25 with 500 mg/day metformin for 12 weeks. Changes in various parameters of insulin resistance including lipoprotein subclass according to particle size determined by high performance liquid chromatography, as well as glucose metabolism, were monitored to determine the relationship between lipoprotein subclass and other insulin resistance parameters. Both pioglitazone and metformin treatment were associated with significant reductions in hyperglycemia, HOMA-IR and HbA1c levels. Pioglitazone treatment, but not metformin treatment resulted in significant reductions in serum large very low-density lipoprotein (VLDL: 44.5-64.0 nm) and increases in serum adiponectin levels (both <0.001). In the pioglitazone group, the change in large VLDL levels correlated positively with changes in HbA1c (r=0.468, P=0.0174), HOMA-IR (r=0.593, P=0.0014), very small LDL (r=0.714, P<0.0001) and net electronegative charged modified-LDL (r=0.412, P=0.0399), and inversely with changes in adiponectin level (r=-0.526, P=0.0061). The results in this study suggest that the hypoglycemic effect of pioglitazone is achieved mainly through improvement of hepatic insulin resistance, and that pioglitazone may have an antiatherosclerotic effect by decreasing serum atherogenic modified-LDL and by increasing adiponectin.

Telmisartan, an angiotensin II type 1 receptor blocker, prevents the development of diabetes in male Spontaneously Diabetic Torii rats.

To assess the beneficial effects of the angiotensin II type 1 receptor blocker telmisartan on a non-obese animal model of reduced function and mass of islet beta-cells prior to the development of diabetes, Spontaneously Diabetic Torii (SDT) rats were treated with telmisartan at 8 weeks of age. At 24 weeks of age, the treatment with telmisartan dose-dependently ameliorated hyperglycemia and hypoinsulinemia, and high-dose (5 mg/kg/day) treated SDT rats did not developed diabetes. Real-time RT-PCR analysis revealed that treatment with high-dose telmisartan reduced mRNA expression of local renin-angiotensin system (RAS) components, components of NAD(P)H oxidase, transforming growth factor-beta1 and vascular endothelial growth factor in the pancreas of male SDT rats. Immunohistochemical and Western blot analyses revealed that treatment with telmisartan also reduced expression of p47(phox). These results suggest that treatment with telmisartan reduces oxidative stress by local RAS activation and protects against islet beta-cell damage and dysfunction. These findings provide at least a partial explanation for the reduced incidence of new-onset diabetes that has been observed in several clinical trials involving angiotensin II type 1 receptor blockers and ACE inhibitors.

Serum brain-derived neurotrophic factor in patients with type 2 diabetes mellitus: Relationship to glucose metabolism and biomarkers of insulin resistance.

OBJECTIVES: The aims of this study were to measure serum levels of brain-derived neurotrophic factor (BDNF) in patients with type 2 diabetes mellitus (T2DM) and to investigate the association of these BDNF levels with biomarkers of glucose metabolism and insulin resistance. DESIGN AND METHODS: We studied 112 patients with T2DM and 80 age- and gender-matched control subjects. RESULTS: Serum BDNF levels were significantly lower in patients with T2DM compared to control subjects (15.5+/-5.2 ng/mL vs. 20.0+/-7.3 ng/mL, P<0.01). In patients with T2DM, BDNF levels were significantly higher in females than in males (P<0.01). In the female patients, BDNF was positively related to immunoreactive insulin (IRI) (rho=0.458, P<0.05) and HOMA-R (rho=0.444, P<0.05). Stepwise multiple regression analysis showed a significant relationship between BDNF and IRI (F=5.294, P<0.05) in female patients with diabetes. CONCLUSIONS: These findings suggest that BDNF may contribute to glucose metabolism.