Insulin sensitivity and Lp(α) concentrations in normoglycemic offspring of type 2 diabetic parents

BACKGROUND: Offspring of at least 1 parent with type 2 diabetes are more resistant to the insulin action, exhibit higher incidence of dyslipidemia and are more prone to cardiovascular diseases. The association between Lp(α) and coronary heart disease is well established. An association between Lp(α) concentration and insulin sensitivity was examined in this study. We investigated the serum LP(α) in 41 offspring of 41 families of type 2 diabetic subjects (group I) with normal glucose tolerance, compared to 49 offspring who their parents had no history of type 2 diabetes, matched for sex, age, BMI, WHR and blood pressure (group II). Serum Lp(α), triglycerides, insulin resistant index, HDL, LDL-cholesterol and insulin were measured. RESULTS: The offspring of type 2 diabetic subjects had higher fasting serum triglycerides (mean ± SD 199.3 ± 184.2 vs. 147.1 ± 67.9 ng/dl, p < 0.05) lower HDL-cholesterol (37.3 ± 9.0 vs. 44.6 ± 7.8, p < 0.001) and particularly higher Insulin resistance Index (HOMA-IR) (2.84 ± 1.39 vs. 1.67 ± 0.77, p < 0.001). They also had higher serum LP(α) concentration (15.4 ± 6.7 vs. 8.6 ± 6.0, p < 0.001). By simple linear analysis in the offspring of type 2 diabetic parents there was no correlation of Lp(α) concentration with insulin resistance index Homa-IR (r = 0,016 p = NS). CONCLUSIONS: We conclude that serum LP(α) is significantly increased in offspring of type 2 diabetic subjects but was not related to insulin sensitivity

Differential Expression of MicroRNAs in Adipose Tissue after Long-Term High-Fat Diet-Induced Obesity in Mice

Obesity is a major health concern worldwide which is associated with increased risk of chronic diseases such as metabolic syndrome, cardiovascular disease and cancer. The elucidation of the molecular mechanisms involved in adipogenesis and obesogenesis is of essential importance as it could lead to the identification of novel biomarkers and therapeutic targets for the development of anti-obesity drugs. MicroRNAs (miRNAs) have been shown to play regulatory roles in several biological processes. They have become a growing research field and consist of promising pharmaceutical targets in various fields such as cancer, metabolism, etc. The present study investigated the possible implication of miRNAs in adipose tissue during the development of obesity using as a model the C57BLJ6 mice fed a high-fat diet

Topiramate-Induced Modulation of Hepatic Molecular Mechanisms: An Aspect for Its Anti-Insulin Resistant Effect

Topiramate is an antiepileptic drug known to ameliorate insulin resistance besides reducing body weight. Albeit liver plays a fundamental role in regulation of overall insulin resistance, yet the effect of topiramate on this organ is controversial and is not fully investigated. The current work aimed to study the potential hepatic molecular mechanistic cassette of the anti-insulin resistance effect of topiramate. To this end, male Wistar rats were fed high fat/high fructose diet (HFFD) for 10 weeks to induce obese, insulin resistant, hyperglycemic animals, but with no overt diabetes. Two HFFD-groups received oral topiramate, 40 or 100 mg/kg, for two weeks. Topiramate, on the hepatic molecular level, has opposed the high fat/high fructose diet effect, where it significantly increased adiponectin receptors, GLUT2, and tyrosine kinase activity, while decreased insulin receptor isoforms. Besides, it improved the altered glucose homeostasis and lipid profile, lowered the ALT level, caused subtle, yet significant decrease in TNF-α, and boosted adiponectin in a dose dependent manner. Moreover, topiramate decreased liver weight/, visceral fat weight/, and epididymal fat weight/body weight ratios. The study proved that insulin-resistance has an effect on hepatic molecular level and that the topiramate-mediated insulin sensitivity is ensued partly by modulation of hepatic insulin receptor isoforms, activation of tyrosine kinase, induction of GLUT2 and elevation of adiponectin receptors, as well as their ligand, adiponectin, besides its known improving effect on glucose tolerance and lipid homeostasis

Nrf2 represses FGF21 during long-term high-fat diet - Induced obesity in mice

OBJECTIVE - Obesity is characterized by chronic oxidative stress. Fibroblast growth factor 21 (FGF21) has recently been identified as a novel hormone that regulates metabolism. NFE2-related factor 2 (Nrf2) is a transcription factor that orchestrates the expression of a battery of antioxidant and detoxification genes under both basal and stress conditions. The current study investigated the role of Nrf2 in a mouse model of long-term highfat diet (HFD)-induced obesity and characterized its crosstalk to FGF21 in this process. RESEARCH DESIGN AND METHODS - Wild-type (WT) and Nrf2 knockout (Nrf2-KO) mice were fed an HFD for 180 days. During this period, food consumption and body weights were measured. Glucose metabolism was assessed by an intraperitoneal glucose tolerance test and intraperitoneal insulin tolerance test. Total RNA was prepared from liver and adipose tissue and was used for quantitative real-time RT-PCR. Fasting plasma was collected and analyzed for blood chemistries. The ST-2 cell line was used for transfection studies. RESULTS - Nrf2-KO mice were partially protected from HFDinduced obesity and developed a less insulin-resistant phenotype. Importantly, Nrf2-KO mice had higher plasma FGF21 levels and higher FGF21 mRNA levels in liver and white adipose tissue than WT mice. Thus, the altered metabolic phenotype of Nrf2-KO mice under HFD was associated with higher expression and abundance of FGF21. Consistently, the overexpression of Nrf2 in ST-2 cells resulted in decreased FGF21 mRNA levels as well as in suppressed activity of a FGF21 promoter luciferase reporter. CONCLUSIONS - The identification of Nrf2 as a novel regulator of FGF21 expands our understanding of the crosstalk between metabolism and stress defense. © 2011 by the American Diabetes Association

Simvastatin activates Keap1/Nrf2 signaling in rat liver

Some of the statins’ pleiotropic actions have been attributed to their antioxidant activity. The Nrf2 transcription factor controls the expression of a number of protective genes in response to oxidative stress. In the present study, wistar rats, primary hepatocytes as well as ST2 cells, were employed to explore the potential role of Nrf2 in mediating the reported antioxidant effects of statins. Simvastatin triggered nuclear translocation of Nrf2 in rat liver and in primary rat hepatocytes in a mevalonate-dependent and cholesterol-independent way. In liver, nuclear extracts from simvastatin-treated rats, the DNA-binding activity of Nrf2, was significantly increased and the mRNA of two known targets of Nrf2 (HO-1 and GPX2) was induced. In ST2 cells stably transfected with constructs bearing Nrf2-binding site (antioxidant responsive element), simvastatin enhanced Nrf2-mediated transcriptional activity in a mevalonate-dependent and cholesterol-independent fashion. In conclusion, activation of Keap1/Nrf2 signaling pathway by simvastatin might provide effective protection of the cell from the deleterious effects of oxidative stress

Simvastatin lowers reactive oxygen species level by Nrf2 activation via PI3K/Akt pathway

The beneficial effects of HMG-CoA (3-hydroxy-3-methyl-glutaryl-CoA) reductase inhibitors (statins) have been attributed not only to their cholesterol lowering effect but also to their pleiotropic actions and especially to their anti-oxidant activity. Nrf2 (NF-E2-related factor 2) is a transcription factor that orchestrates the transcriptional response of cells to oxidative stressors and electrophilic xenobiotics. In this study, primary mouse embryonic fibroblasts from wild type or Nrf2 knock out C57B16J mice and ST-2 cells were used to investigate the implication of Nrf2 in the mediation of the anti-oxidant effects of statins and the possible involvement of PI3K/Akt pathway in this process. We show for the first time that simvastatin lowers reactive oxygen species (ROS) by activating Nrf2 through the PI3K/Akt pathway. (C) 2010 Elsevier Inc. All rights reserved

Brown Adipose Tissue Responds to Cold and Adrenergic Stimulation by Induction of FGF21

Fibroblast growth factor-21 (FGF21) is a pleiotropic protein involved in glucose, lipid metabolism and energy homeostasis, with main tissues of expression being the liver and adipose tissue. Brown adipose tissue (BAT) is responsible for cold-induced thermogenesis in rodents. The role of FGF21 in BAT biology has not been investigated. In the present study, wild-type C57BL/6J mice as well as a brown adipocyte cell line were used to explore the potential role of cold exposure and beta 3-adrenergic stimulation in the expression of FGF21 in BAT. Our results demonstrate that short-term exposure to cold, as well as beta 3-adrenergic stimulation, causes a significant induction of FGF21 mRNA levels in BAT, without a concomitant increase in FGF21 plasma levels. This finding opens new routes for the potential use of pharmaceuticals that could induce FGF21 and, hence, activate BAT thermogenesis. (C) 2011 The Feinstein Institute for Medical Research, www.feinsteininstitute.or