1.
Modulating DDAH/NOS Pathway to Discover Vasoprotective Insulin Sensitizers.
Lai, L, Ghebremariam, YT
Journal of diabetes research. 2016;:1982096
Abstract
Insulin resistance syndrome (IRS) is a configuration of cardiovascular risk factors involved in the development of metabolic disorders including type 2 diabetes mellitus. In addition to diet, age, socioeconomic, and environmental factors, genetic factors that impair insulin signaling are centrally involved in the development and exacerbation of IRS. Genetic and pharmacological studies have demonstrated that the nitric oxide (NO) synthase (NOS) genes are critically involved in the regulation of insulin-mediated glucose disposal. The generation of NO by the NOS enzymes is known to contribute to vascular homeostasis including insulin-mediated skeletal muscle vasodilation and insulin sensitivity. By contrast, excessive inhibition of NOS enzymes by exogenous or endogenous factors is associated with insulin resistance (IR). Asymmetric dimethylarginine (ADMA) is an endogenous molecule that competitively inhibits all the NOS enzymes and contributes to metabolic perturbations including IR. The concentration of ADMA in plasma and tissue is enzymatically regulated by dimethylarginine dimethylaminohydrolase (DDAH), a widely expressed enzyme in the cardiovascular system. In preclinical studies, overexpression of DDAH has been shown to reduce ADMA levels, improve vascular compliance, and increase insulin sensitivity. This review discusses the feasibility of the NOS/DDAH pathway as a novel target to develop vasoprotective insulin sensitizers.
2.
Sensing of nutrients and microbes in the gut.
Bishu, S
Current opinion in gastroenterology. 2016;(2):86-95
Abstract
PURPOSE OF REVIEW Sensing of nutrients and microbes in the gut are fundamental processes necessary for life. This review aims to provide an overview of the basic background and new data on cellular nutrient, energy, and microbe sensors. RECENT FINDINGS The nutrient sensors 5' adenosine monophosphate-activated protein kinase, activating transcription factor 4 and mechanistic target of rapamycin (mTOR) are critical in control of the cell cycle. Recent data demonstrate their role in metabolic syndrome, in cell growth, and as therapeutic targets. Regulation of mTOR by the amino acids is the subject of intense investigation. Recent studies have further elucidated the exact mechanism of amino acid-dependent mTOR regulation. Pathogen recognition receptors (PRRs) are receptors that recognize conserved microbial molecules. New data demonstrate how lymphocyte-specific PRRs are necessary to maintain homeostasis. Moreover, new studies explore the role of PRRs in controlling the gut bacterial and fungal microbiome. SUMMARY Nutrient sensing molecules are central to cell growth and metabolism and are implicated in cancer and the metabolic syndrome. Regulation of nutrient sensors is complex, and may be amenable to therapeutic targeting. Microbial sensors play critical roles in homeostasis and maintenance of the gut fungal and bacterial microbiome.
3.
Controversies surrounding the clinical potential of cinnamon for the management of diabetes.
Rafehi, H, Ververis, K, Karagiannis, TC
Diabetes, obesity & metabolism. 2012;(6):493-9
Abstract
Obesity levels have increased significantly in the past five decades and are predicted to continue rising, resulting in important health implications. In particular, this has translated to an increase in the occurrence of type II diabetes mellitus (T2D). To alleviate associated problems, certain nutraceuticals have been considered as potential adjuncts or alternatives to conventional prescription drugs. Cinnamon, a commonly consumed spice originating from South East Asia, is currently being investigated as a potential preventative supplement and treatment for insulin resistance, metabolic syndrome and T2D. Extensive in vitro evidence has shown that cinnamon may improve insulin resistance by preventing and reversing impairments in insulin signalling in skeletal muscle. In adipose tissue, it has been shown that cinnamon increases the expression of peroxisome proliferator-activated receptors including, PPARγ. This is comparable to the action of commonly used thiazolinediones, which are PPAR agonists. Studies have also shown that cinnamon has potent anti-inflammatory properties. However, numerous human clinical trials with cinnamon have been conducted with varying findings. While some studies have showed no beneficial effect, others have indicated improvements in cholesterol levels, systolic blood pressure, insulin sensitivity and postprandial glucose levels with cinnamon. However, the only measurement consistently improved by cinnamon consumption is fasting glucose levels. While it is still premature to suggest the use of cinnamon supplementation based on the evidence, further investigation into mechanisms of action is warranted. Apart from further characterization of genetic and epigenetic changes in model systems, systematic large-scale clinical trials are required. In this study, we discuss the mechanisms of action of cinnamon in the context of T2D and we highlight some of the associated controversies.
4.
Growth signals, inflammation, and vascular perturbations: mechanistic links between obesity, metabolic syndrome, and cancer.
Hursting, SD, Hursting, MJ
Arteriosclerosis, thrombosis, and vascular biology. 2012;(8):1766-70
Abstract
Nearly 35% of adults and 20% of children in the United States are obese, defined as a body mass index ≥ 30 kg/m(2). Obesity, which is accompanied by metabolic dysregulation often manifesting in the metabolic syndrome, is an established risk factor for many cancers. Within the growth-promoting, proinflammatory environment of the obese state, cross talk between macrophages, adipocytes, and epithelial cells occurs via obesity-associated hormones, cytokines, and other mediators that may enhance cancer risk and progression. This review synthesizes the evidence on key biological mechanisms underlying the obesity-cancer link, with particular emphasis on obesity-associated enhancements in growth factor signaling, inflammation, and vascular integrity processes. These interrelated pathways represent possible mechanistic targets for disrupting the obesity-cancer link.