Efficacy of high-intensity interval and continuous endurance trainings on cecal microbiota metabolites and inflammatory factors in diabetic rats induced by high-fat diet.

Physical exercise is known to modulate the intestinal microbiota composition and control the symptoms of metabolic syndrome. In this research, we intend to investigate and compare the effect of high-intensity interval and continuous endurance trainings (HIIT and CET) on cecal microbiota metabolites and inflammatory factors in diabetic rats. A number of Wistar rats were made diabetic by a high-fat diet and trained under two types of exercise protocols, HIIT and CET. After taking samples from the cecal tissue and serum of rats to reveal the effect of exercise, three microbial species from the Firmicute and Bacteroid phyla, which are the main types of intestinal microbes, and their metabolites include two short-chain fatty acids (SCFAs), butyrate and propionate and also, the inflammatory factors TLR4 and IL6 were analyzed through quantitative polymerase chain reaction (qPCR), high-performance liquid chromatography (HPLC), and Enzyme-linked immunosorbent assay (ELISA) methods. In general, exercise while increasing the representative of Firmicute has caused a relative reduction of Bacteroides and improved the concentration of SCFAs. In this regard, HIIT outperforms CET in up-regulating Akkermansia and Butyrivibrio expression, and butyrate and propionate metabolites concentration. Also, both exercises significantly reduced cecal expression of TLR4 and sera concentration of IL6 compared to the diabetic group, although the reduction rate was higher in the CET group than in HIIT. Our findings suggest that some symptoms of metabolic syndrome such as intestinal dysbiosis and the resulting metabolic disorders are better controlled by HIIT and inflammation by CET. Certainly, more extensive research on other contributing factors could help clarify the results.

The Anticancer Role of Cerium Oxide Nanoparticles by Inducing Antioxidant Activity in Esophageal Cancer and Cancer Stem-Like ESCC Spheres.

Introduction: Esophagus squamous cell carcinoma (ESCC) has a poor prognosis, a high rate of metastasis, and rapid clinical progression. One hypothesis is that therapeutic failure is due to the presence of cancer stem cells (CSC). Previous studies showed the anticancer effect of cerium oxide nanoparticles (CNP) in different cancer cells. In this study, we aim to evaluate the effect of cerium oxide nanoparticles on cell antioxidants, toxicity, as well as cell oxidant level in esophageal cancer (YM1) and cancer stem cell-like (CSC-LC) cell lines. Method: YM1 and CSC-LC spheres were treated with CNP at different concentrations. The cell viability was assessed by using the MTT test. Antioxidant levels (SOD (superoxide dismutase, CAT (catalase), thiol, and TAC (total antioxidant capacity)), antioxidant genes expression (SOD and CAT), ROS (reactive oxygen species), and MDA (malondialdehyde) levels were assessed in both cell lines. Results: CSC-LC had significantly elevated SOX4 and OCT4 pluripotent genes. The ROS and MDA levels were significantly reduced in both YM1 and CSC-LC spheres after treatment with CNP. Also, the antioxidant levels and expressions were elevated significantly in both cell lines after CNP treatment. Conclusion: These results suggest the potential anticancer effect of CNP by elevating antioxidant levels and expressions, and reducing oxidant levels.

High-Intensity Interval Training Improves Cardiac Function by miR-206 Dependent HSP60 Induction in Diabetic Rats.

Objective: A role for microRNAs is implicated in several biological and pathological processes. We investigated the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) on molecular markers of diabetic cardiomyopathy in rats. Methods: Eighteen male Wistar rats (260 ± 10 g; aged 8 weeks) with streptozotocin (STZ)-induced type 1 diabetes mellitus (55 mg/kg, IP) were randomly allocated to three groups: control, MICT, and HIIT. The two different training protocols were performed 5 days each week for 5 weeks. Cardiac performance (end-systolic and end-diastolic dimensions, ejection fraction), the expression of miR-206, HSP60, and markers of apoptosis (cleaved PARP and cytochrome C) were determined at the end of the exercise interventions. Results: Both exercise interventions (HIIT and MICT) decreased blood glucose levels and improved cardiac performance, with greater changes in the HIIT group (p < 0.001, η2: 0.909). While the expressions of miR-206 and apoptotic markers decreased in both training protocols (p < 0.001, η2: 0.967), HIIT caused greater reductions in apoptotic markers and produced a 20% greater reduction in miR-206 compared with the MICT protocol (p < 0.001). Furthermore, both training protocols enhanced the expression of HSP60 (p < 0.001, η2: 0.976), with a nearly 50% greater increase in the HIIT group compared with MICT. Conclusions: Our results indicate that both exercise protocols, HIIT and MICT, have the potential to reduce diabetic cardiomyopathy by modifying the expression of miR-206 and its downstream targets of apoptosis. It seems however that HIIT is even more effective than MICT to modulate these molecular markers.

The role of protein tyrosine phosphatase 1B (PTP1B) in the pathogenesis of type 2 diabetes mellitus and its complications.

Insulin resistance, the most important characteristic of the type 2 diabetes mellitus (T2DM), is mostly caused by impairment in the insulin receptor (IR) signal transduction pathway. Protein tyrosine phosphatase 1B (PTP1B), one of the main negative regulators of the IR signaling pathway, is broadly expressed in various cells and tissues. PTP1B decreases the phosphorylation of the IR resulting in insulin resistance in various tissues. The evidence for the physiological role of PTP1B in regulation of metabolic pathways came from whole-body PTP1B-knockout mice. Whole-body and tissue-specific PTP1B-knockout mice showed improvement in adiposity, insulin resistance, and glucose tolerance. In addition, the key role of PTP1B in the pathogenesis of T2DM and its complications was further investigated in mice models of PTP1B deficient/overexpression. In recent years, targeting PTP1B using PTP1B inhibitors is being considered an attractive target to treat T2DM. PTP1B inhibitors improve the sensitivity of the insulin receptor and have the ability to cure insulin resistance-related diseases. We herein summarized the biological functions of PTP1B in different tissues in vivo and in vitro. We also describe the effectiveness of potent PTP1B inhibitors as pharmaceutical agents to treat T2DM.

Effect of biotin supplementation on neuropathic pain induced by chronic constriction of the sciatic nerve in the rat.

BACKGROUND AND PURPOSE: Neuropathic pain is one of the most common types of chronic pain that is very difficult to treat. Numerous studies have shown the potential role of vitamins in relieving both hyperalgesia and allodynia. Based on the convincing evidence, this study was designed to evaluate the possible antinociceptive effect of biotin on neuropathic pain in rats. EXPERIMENTAL APPROACH: This study was performed on male Sprague Dawley rats weighing 200-300 g. Neuropathic pain was induced by tying the sciatic nerve. Chronic constriction injury (CCI) of the sciatic nerve resulted in hyperalgesia and allodynia. To measure the thermal hyperalgesia, the plantar test was used. Also to evaluate the cold and mechanical allodynia, acetone test and von Frey test were applied. Biotin (4, 8, and 16 mg/kg) was administered orally as two different treatment regimens, acute and chronic. FINDINGS/RESULTS: Acute oral administration of biotin (4, 8, and 16 mg/kg p.o.) on the 7th, 14th, and 21st postoperative days couldn't reduce pain sensitivity compared to the CCI group. However, following the oral administration of biotin (8 and 16 mg/kg p.o.) from the first day after the surgery until day 21, mechanical allodynia (P < 0.001) and heat hyperalgesia (P < 0.05) significantly relieved. CONCLUSION AND IMPLICATIONS: Our results suggest that biotin can be considered as a potential therapeutic for the treatment of neuropathic pain, and supplementation with this vitamin could reduce the required doses of analgesic drugs. However, further studies are needed to confirm this hypothesis.

Effects of N-acetylcysteine on Noise Exposure-induced Oxidative Stress and Depressive- and Anxiety-like Behaviors in Adult Male Mice.

INTRODUCTION: Depression and anxiety are the most common psychiatric disorders. These conditions widely occur in industrial societies and severely affect individuals' lives. N-Acetylcysteine (NAC) is a mucolytic compound with antioxidant and anti-inflammatory effects. This study aimed to investigate the potential therapeutic effects of NAC on chronic noise-induced depression- and anxiety-like behaviors in mice. METHODS: Fifty male BALB/c mice were randomly divided into 5 groups, as follows: control, noise90 dB, noise110 dB, noise 90+NAC, and noise 110+NAC groups. Animals in the noise groups were exposed to 90 dB 2 h/day and 110 dB 2 h/day for 30 days. The NAC groups received NAC (325 mg/kg P.O.) 20 min after being exposed to noise. To evaluate depressive- and anxiety-like behaviors, the examined mice were subjected to the Open Field Test (OFT), Sucrose Preference Test (SPT), Tail Suspension Test (TST), and Elevated Plus Maze (EPM) tasks. At the end of the behavioral tests, the study animals were sacrificed. Accordingly, the levels of Malondialdehyde (MDA), Total Antioxidant Capacity (TAC), Superoxide Dismutase (SOD), and Glutathione Peroxidase (GPx) were determined in the Hippocampus (HIP) and the Prefrontal Cortex (PFC). RESULTS: The obtained results suggested that noise exposure would induce anxiety- and depressive-like behaviors, being reversed by NAC administration. Moreover, chronic administration of NAC significantly increased antioxidant enzyme activities and reduced lipid peroxidation (MDA levels) in the PFC and HIP of noise-exposed mice. CONCLUSION: Our findings revealed that administrating NAC would reduce the adverse effects of noise on the brain and would exert anti-depressant and anxiolytic effects.

Positive Correlation between Circulating Fetuin-A and Severity of Coronary Artery Disease in Men.

OBJECTIVE: Fetuin-A serves a dual function; its high levels are associated with metabolic syndrome, type 2 diabetes, obesity, insulin resistance, and nonalcoholic fatty liver disease, and on the other hand, it serves as a potent inhibitor of ectopic vascular calcification. Due to the opposing findings, the aim of the current study was to investigate serum fetuin-A levels in men with coronary artery disease (CAD). METHODS: In the case-control study, anthropometric and biochemical parameters were determined in 83 men (43 CAD patients and 40 control subjects). At last, the serum fetuin-A levels were measured using the fetuin-A human enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: A significant difference was detected among the two groups for triglyceride and cholesterol levels (P=0.003 and P=0.002, respectively). The mean fetuin-A levels were determined 230.57 ± 63.76 and 286.35 ± 64.07 µg/ml for the control group and the CAD patients, respectively (P<0.001). Fetuin- A was significantly correlated to the severity of CAD (r 0.393, P<0.001) and associated with the risk of CAD in subjects (OR [CI] = 1. 144 [1.060-1. 235]; p = 0.001). A cut-off value of 237.4 µg/ml had good sensitivity (76.7%) and specificity (65.0%) for differentiating between two groups [area under curve (AUC) = 0.732 (CI=0.621-0.842); p < 0.001]. CONCLUSION: Our results indicated that fetuin-A levels were positively correlated to the severity of CAD. The findings suggest that there is a possible link between pathogenic mechanisms of atherosclerosis and fetuin-A; however, more investigations are needed in this regard.

High intensity interval training improves diabetic cardiomyopathy via miR-1 dependent suppression of cardiomyocyte apoptosis in diabetic rats.

PURPOSE: Diabetes and its complications such as diabetic cardiomyopathy still account for significant morbidity and mortality. High-quality evidence was shown the importance of exercise in controlling diabetes complications, but the molecular mechanism on diabetic cardiomyopathy is not yet fully understood. This study aimed to compare and investigate the effect of high intensity interval training (HIIT) and continuous endurance training (CET) on the signaling pathway of diabetic cardiomyopathy. METHODS: Hence, 21 Wistar rats with an average weight of 260 ± 10 g, after induction of diabetes (STZ 50 mg/kg BW) were randomly divided into three groups (control, CET and HIIT; n = 7). Training programs were conducted 5 days a week for 5 weeks. CET program was defined as running at 60% vVO2max for 30 min in each session and the HIIT program was defined as running at 85-90% vVO2max for 3 min followed by 1 min recovery (30-35% vVO2max), that was repeated four times in each session. The cardiac performance was analyzed via determination of end systolic and diastolic dimensions and the ejection fraction by echocardiography. To elucidate the responsible molecular mechanism of miR-1, IGF-1 and IGF-1R mRNA and apoptosis marker protein expression were investigated. RESULTS: Both training programs specifically HIIT, significantly reduced the blood glucose, enhanced heart performance, reduced miR-1 expression, induced IGF-1 and IGF-1R expression and reduced apoptotic protein expression. CONCLUSION: We showed that HIIT is more effective than CET for reduction of diabetic cardiomyopathy as a complication of diabetes in animal models through suppressing miR-1 and its downstream apoptosis pathway.

High-Intensity Interval Training Reversed High-Fat Diet-Induced M1-Macrophage Polarization in Rat Adipose Tissue via Inhibition of NOTCH Signaling.

INTRODUCTION: There is accumulating evidence on the beneficial effect of exercise intervention in the management of metabolic disorders; however, the molecular mechanism is still unclear. Here, the current study aimed to compare the effect of high-intensity interval training (HIIT) and continuous endurance training (CET) on serum and adipose-tissue markers of M1/M2 macrophage polarization. METHODS: A total of 45 healthy male Wistar rats were divided into groups of normal chow (n=10) and high-fat diet (HFD) (n=35). Then, rats receiving the HFD were randomly divided into four groups. Training programs were performed for 5 days/week over 10 weeks. The CET protocol included 30 minutes running at 50%-60% of VO2max. The HIIT protocol consisted of five repeated intervals of 2-minute sprints on the treadmill at 80%-90% VO2max workload with 1 minute's 30%-35% VO2max interval for each rat. Then, biochemical parameters were assessed. Macrophage-polarization markers were assessed at mRNA and protein levels by real-time PCR and Western blotting, respectively. RESULTS: Both exercise-training programs, especially HIIT, reversed increased serum biochemical parameters (glucose, triglycerides, cholesterol, Homeostatic Model Assessment of Insulin Resistance, and hsCRP), M1-polarization markers (circulating IL6, TNFα, and adipose-tissue mRNA expression of IL6, TNFα and iNOS), M2 markers (CD206, CD163, and IL10 expression), as well as pIκKB, pNFκB, and NICD expression in HFD-induced diabetes. CONCLUSION: Our findings suggest that despite devoting less time, the HIIT workout is a more effective intervention for diabetes management. Moreover, HIIT reverses HFD-induced macrophage polarization by targeting the NFκB and NOTCH signaling pathways.

Serum C1q/TNF-Related Protein-2 (CTRP2) Levels are Associated with Coronary Artery Disease.

Recent studies have shown that complement C1q tumor necrosis factor related proteins (CTRPs) such as adiponectin, have different regulatory roles on the cardiovascular system. CTRP2 is the most similar to adiponectin and one of the best characterized beneficial adipokines important in the regulation of whole body metabolism. However, there were no studies about the relationship between CTRP2 and Coronary artery disease (CAD). This study aimed to evaluate the serum CTRP2 levels in patient with Coronary artery disease. In this study, a total of 82 participants who underwent vascular angiography were included. All of subjects were male. According to their coronary angiography results, all participants were divided into CAD group (n = 42) and control group (n = 40). Serum CTRP2 levels were determined quantitatively with enzyme-linked immunosorbent assay (ELISA). Our study for the first time showed that the CTRP2 levels were higher in CAD patients (1.79 ± 1.46 ng/mL) compared to control subjects (1.08 ± 0.78 ng/mL; p = 0.001). The levels of CTRP2 also were positively correlated with severity of CAD (r = 0.356, p = 0.001). In addition, logistic regression analysis indicated that CTRP2 had an independent association with the risk of CAD (OR [CI] = 3.366 [1.605-7.060]; p = 0.001). Increased levels of CTRP2 in CAD patients were independently associated with the progression of the CAD, it might be regarded as a novel biomarker for assessing the risk of CAD; however, more study is required in this regard.

High-intensity interval training (HIIT) effectively enhances heart function via miR-195 dependent cardiomyopathy reduction in high-fat high-fructose diet-induced diabetic rats.

Aims: Regarding the fact that up-regulation of miR-195 in diabetic hearts has a potential role in diabetic cardiomyopathy, the present study investigated whether continuous endurance training (CET) and high-intensity interval training (HIIT) reduces miR-195 expression and which exercise is effective in this regard.Methods: Diabetes was induced by high-fat high-fructose diet (HFHFD). Then, the rats were sub-divided into three categories; sedentary (HFHFD + SED), continuous endurance training (HFHFD + CET), and high-intensity interval training group (HFHFD + HIIT). After eight weeks of running, expression of miR-195 and myocardial function were evaluated.Results: HIIT effectively decreases the expression of miR-195 and increases the expression of Sirt1 and BCL-2 in diabetic rats compared with CET. Our results showed that HIIT compared with CET increases left ventricular ejection fraction (LVEF%) and fractional shortening (FS%).Conclusions: Our results indicated that exercise, especially HIIT is an appropriate strategy for reducing miR-195 and improving myocardial function in diabetic rats compared with CET.

Differential expressions of SIRT1, SIRT3, and SIRT4 in peripheral blood mononuclear cells from patients with type 2 diabetic retinopathy.

This study investigated the mRNA and protein levels of SIRT1, SIRT3, and SIRT4 in peripheral blood mononuclear cells (PBMCs) from type 2 diabetes patients with retinopathy (diabetic retinopathy (DR) patients) (n = 86) and those without retinopathy (n = 103). The mRNA expression of SIRT1 and SIRT3 was found to be significantly higher in diabetic patients with retinopathy compared to those without retinopathy. Notably, protein levels of SIRT1, SIRT3, and SIRT4 were higher in patients with DR compared with controls after adjusting for diabetes duration and taking metformin (p = .001 for SIRT1; p = .001 for SIRT3; p = .005 for SIRT4). In the logistic model, there was a significant association between SIRT3 and DR (p = .0001) independent of age and sex and hyperglycaemia markers including FBS, HbA1c, and diabetic duration. These findings suggest an emerging role of sirtuins in the pathogenesis of retinopathy, but further studies are necessary to establish this concept.

Cardioprotective effects of omega-3 fatty acids and ascorbic acid improve regenerative capacity of embryonic stem cell-derived cardiac lineage cells.

One of the major issues in cell therapy of myocardial infarction (MI) is early death of engrafted cells in a harsh oxidative stress environment, which limits the potential therapeutic utility of this strategy in the clinical setting. Increasing evidence implicates beneficial effects of omega-3 fatty acids including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and ascorbic acid (AA) in cardiovascular diseases, in particular their role in ameliorating fibrosis. In the current study, we aim to assess the cytoprotective role of EPA + DHA and AA in protecting embryonic stem cell (ESC)-derived cardiac lineage cells and amelioration of fibrosis. Herein, we have shown that preincubation of the cells with EPA + DHA + AA prior to H2 O2 treatment attenuated generation of reactive oxygen species (ROS) and enhanced cell viability. Gene expression analysis revealed that preincubation with EPA + DHA + AA followed by H2 O2 treatment, upregulated heme oxygenase-1 (HO-1) along with cardiac markers (GATA4, myosin heavy chain, α isoform [MYH6]), connexin 43 [CX43]) and attenuated oxidative stress-induced upregulation of fibroblast markers (vimentin and collagen type 1 [Col1]). Alterations in gene expression patterns were followed by marked elevation of cardiac troponin (TNNT2) positive cells and reduced numbers of vimentin positive cells. An injection of EPA + DHA + AA-pretreated ESC-derived cardiac lineage cells into the ischemic myocardium of a rat model of MI significantly reduced fibrosis compared to the vehicle group. This study provided evidence that EPA + DHA + AA may be an appropriate preincubation regimen for regenerative purposes. © 2019 BioFactors, 45(3):427-438, 2019.

The effects of quercetin supplementation on metabolic and hormonal parameters as well as plasma concentration and gene expression of resistin in overweight or obese women with polycystic ovary syndrome.

The aim of this study was to investigate the effect of quercetin on metabolic and hormonal parameters as well as plasma concentration and gene expression of resistin in overweight or obese women with polycystic ovary syndrome (PCOS). In this randomized, double-blind, placebo-controlled trial, 78 overweight or obese women (25 ≤ BMI ≤ 40 kg/m2 , 20-40 years) with PCOS were recruited. Patients were randomized to receive 1,000 mg/day quercetin or placebo for 12 weeks. Resistin plasma concentration and gene expression in peripheral blood mononuclear cells, parameters of glucose homeostasis, circulatory testosterone, luteinizing hormone (LH), and sex hormone-binding globulin, and anthropometries were assessed at baseline and at the end of the study. Following supplementation, quercetin significantly decreased resistin concentration (2.07 ± 0.23 vs. 2.88 ± 0.40 ng/ml, p < 0.001) and mRNA level (0.64 ± 0.58 vs. 1 ± 0.56 fold change, p = 0.008), compared with placebo group. Moreover, testosterone (0.72 ± 0.15 vs. 0.76 ± 0.12 ng/ml, p = 0.001) and LH (8.05 ± 2.88 vs. 8.77 ± 1.99 mIU/ml, p = 0.035) concentrations were significantly lower in quercetin compared with placebo group. Fasting blood glucose (p < 0.001), insulin (p = 0.02), and homeostatic model assessment of insulin resistance (p = 0.009) decreased within the quercetin group; however, no significant differences were observed compared with the placebo group (p = 0.074, p = 0.226, p = 0.22, respectively). Quercetin supplementation decreased resistin plasma levels and gene expression, and testosterone and LH concentration in overweight or obese women with PCOS.

Aerobic endurance training improves nonalcoholic fatty liver disease (NAFLD) features via miR-33 dependent autophagy induction in high fat diet fed mice.

Due to changes in life style, obesity and obesity related complication such as insulin resistance, type 2 diabetes and non-alcoholic fatty liver disease caused worldwide health problems. Regular exercise has been frequently prescribed to combat metabolic complication of obesity but its molecular mechanism has not been fully illustrated. We investigated molecular mechanism of lipid lowering effect of exercise training in high fat diet fed mice by focusing on miR-33 expression and autophagy pathway. 24 mice were assigned to normal chow (NC) (n=8), high-fat diet (HFD) (n=16) group and subjected to NC and HFD for 13-weeks. HFD groups were divided to sedentary (HFD n=8) or continuous endurance training (HFD+CET, n=8) subgroups. The HFD+CET mice were subjected to treadmill running for 10-weeks in 23-week HFD course. HFD increased body weight, fasting blood sugar, triglyceride, cholesterol, aspartate aminotransferase (AST), alanine aminotransferase (ALT), liver lipogenic genes expression and reduced miR-33 mRNA expression and autopahgy pathway while training program reversed them. Exogenous miR-33 mimic sequence induced autophagy and reduced lipogenesis in HepG2 cells. Autophagy induction by rapamycin reduced lipogenesis and autophagy inhibition by chloroquine, enhanced lipogenesis in HepG2 cells. These findings suggest that aerobic exercise training as a non-pharmacological therapy exerts its lipid lowering effects by miR-33 dependent autophagy induction.

Oral Quercetin Supplementation Enhances Adiponectin Receptor Transcript Expression in Polycystic Ovary Syndrome Patients: A Randomized Placebo-Controlled Double-Blind Clinical Trial.

OBJECTIVES: Polycystic ovary syndrome (PCOS), an ovarian-pituitary axis androgen disorder, is a common endocrine disease in women. Obesity-induced androgenesis and imbalance of adipokine secretion may lead to some metabolic features of PCOS. The beneficial effects of polyphenolic compounds such as quercetin have been reported, however, the underlying molecular mechanism is not entirely understood. In the present study, we investigated the effect of quercetin supplementation on the expression of adiponectin receptors at the transcript level in peripheral blood mononuclear cells (PBMC) samples of PCOS patients. MATERIALS AND METHODS: In this randomized clinical trial, 84 PCOS subjects were randomly assigned to two groups; the treatment group received 1 g quercetin (two 500 mg capsules) daily for 12 weeks and the control group received placebo. To examine the effect of quercetin supplementation on PCOS patients in addition to biochemical and anthropometric assessments, the expression of ADIPOR1 and ADIPOR2 at the transcript level and AMPK level were determined by quantitative reverse transcription-polymerase chain reaction (RT-qPCR) and ELISA assays respectively. RESULTS: Oral quercetin supplementation significantly increased ADIPOR1 and ADIPOR2 transcript expression by 1.32- and 1.46-fold respecetively (P<0.01). In addition, quercetin supplementation enhanced AMPK level by 12.3% compared with the control group (P<0.05). CONCLUSIONS: Oral quercetin supplementation improves the metabolic features of PCOS patients by upregulating the expression of adiponectin receptors and AMPK (Registration Number: IRCT2013112515536N1).

The association between bone turnover markers and microvascular complications of type 2 diabetes.

BACKGROUND: Global epidemic of diabetes is a serious health care concern because of its complications and consequently reduced life expectancy and increased morbidity. However, the bone turnover and thus bone health may be affected or even compromised by diabetes and its complications. The aim of this study was to assess whether bone turnover markers are associated with diabetes micro-vascular complications. METHODS: A total of 204 type 2 diabetes patients (104 patients with diabetic micro-vascular complications (retinopathy and/or nephropathy) as a case group and 100 patients without retinopathy and/or nephropathy) as a control group were recruited in this case-control study. The biochemical and metabolic parameters and bone turnover markers were assessed in all patients. RESULTS: Our findings showed serum levels of osteocalcin (OC) (p = 0.0001) and, carboxy-terminal collagen crosslinks (CTX) (p = 0.006) were higher in diabetic patients with both diabetic retinopathy and nephropathy compared with control group. However, there was no significant difference in serum levels of procollagen I aminoterminal propeptide (P1NP) between diabetic patients with diabetic retinopathy (DR) and/or diabetic nephropathy (DN) compared with control. In diabetes patients with complications, there were significant negative correlation between OC and CTX with estimated-glomerular filtration rate (e-GFR) and also positive correlation between each bone marker (OC and CTX) and PTH levels (p = 0.0001) and BUN (p = 0.0001). In a general linear model, after adjusting for age, sex and BMI, and microvascular complications, there was not any significant association between three bone turnover markers and metabolic markers including fasting glucose, insulin, and lipid profile. Among kidney markers, there were significant positive associations between serum levels of CTX and OC with BUN (p < 0.05) as well as PTH (p < 0.0001). CONCLUSIONS: Our data suggest the possible role of PTH and BUN levels in modulating bone turnover markers in diabetic patients.

Molecular and cellular mechanisms linking inflammation to insulin resistance and ß-cell dysfunction.

Obesity is a major public health problem worldwide, and it is associated with an increased risk of developing type 2 diabetes. It is now commonly accepted that chronic inflammation associated with obesity induces insulin resistance and ß-cell dysfunction in diabetic patients. Obesity-associated inflammation is characterized by increased abundance of macrophages and enhanced production of inflammatory cytokines in adipose tissue. Adipose tissue macrophages are suggested to be the major source of local and systemic inflammatory mediators such as tumor necrosis factor α, interleukin (IL)-1ß, and IL-6. These cytokines induce insulin resistance in insulin target tissues by activating the suppressors of cytokine signaling proteins, several kinases such as c-Jun N-terminal kinase, IκB kinase ß, and protein kinase C, inducible nitric oxide synthase, extracellular signal-regulated kinase, and protein tyrosine phosphatases such as protein tyrosine phosphatase 1B. These activated factors impair the insulin signaling at the insulin receptor and the insulin receptor substrates levels. The same process most likely occurs in the pancreas as it contains a pool of tissue-resident macrophages. High concentrations of glucose or palmitate via the chemokine production promote further immune cell migration and infiltration into the islets. These events ultimately induce inflammatory responses leading to the apoptosis of the pancreatic ß cells. In this review, the cellular and molecular players that participate in the regulation of obesity-induced inflammation are discussed, with particular attention being placed on the roles of the molecular players linking inflammation to insulin resistance and ß-cell dysfunction.

SH2 domain-containing inositol 5-phosphatase (SHIP2) inhibition ameliorates high glucose-induced de-novo lipogenesis and VLDL production through regulating AMPK/mTOR/SREBP1 pathway and ROS production in HepG2 cells.

Hepatic de-novo lipogenesis and production of triglyceride rich very low density lipoprotein (VLDL) is increased in the state of insulin resistance, however, the role of a negative regulator of the insulin signaling pathway, the SH2 domain-containing inositol 5-phosphatase (SHIP2) in this process, remains unknown. In the present study, we studied the molecular mechanisms linking SHIP2 expression to metabolic dyslipidemia using overexpression or suppression of SHIP2 gene in HepG2 cells exposed to high glucose (33 mM). The results showed that high glucose induced SHIP2 mRNA and protein levels in HepG2 cells. Overexpression of the dominant negative mutant SHIP2 (SHIP2-DN) ameliorated high glucose-induced de-novo lipogenesis and secretion of apoB containing lipoprotein in HepG2 cells, as demonstrated by a reduction in both secreted apoB and MTP expression, and decreased triglyceride levels and the expression of lipogenic genes such as SREBP1c, FAS and ACC. Overexpression of the SHIP2-DN decreased high glucose-induced apoB containing lipoproteins secretion via reduction in ROS generation, JNK phosphorylation and Akt activation. Furthermore, using the specific inhibitor and activator, it was found that the AMPK/mTOR/SREBP1 is the signaling pathway that mediates the effects of SHIP2 modulation on hepatic de-novo lipogenesis. Taken together, these findings suggest that SHIP2 is an important regulator of hepatic lipogenesis and lipoprotein secretion in insulin resistance state.

Inhibition of SH2-domain-containing inositol 5-phosphatase (SHIP2) ameliorates palmitate induced-apoptosis through regulating Akt/FOXO1 pathway and ROS production in HepG2 cells.

The serine-threonine kinase Akt regulates proliferation and survival by phosphorylating a network of protein substrates; however, the role of a negative regulator of the Akt pathway, the SH2-domain-containing inositol 5-phosphatase (SHIP2) in apoptosis of the hepatocytes, remains unknown. In the present study, we studied the molecular mechanisms linking SHIP2 expression to apoptosis using overexpression or suppression of SHIP2 gene in HepG2 cells exposed to palmitate (0.5 mM). Overexpression of the dominant negative mutant SHIP2 (SHIP2-DN) significantly reduced palmitate-induced apoptosis in HepG2 cells, as these cells had increased cell viability, decreased apoptotic cell death and reduced the activity of caspase-3, cytochrome c and poly (ADP-ribose) polymerase. Overexpression of the wild-type SHIP2 gene led to a massive apoptosis in HepG2 cells. The protection from palmitate-induced apoptosis by SHIP2 inhibition was accompanied by a decrease in the generation of reactive oxygen species (ROS). In addition, SHIP2 inhibition was accompanied by an increased Akt and FOXO-1 phosphorylation, whereas overexpression of the wild-type SHIP2 gene had the opposite effects. Taken together, these findings suggest that SHIP2 expression level is an important determinant of hepatic lipoapotosis and its inhibition can potentially be a target in treatment of hepatic lipoapoptosis in diabetic patients.