{"id":160,"date":"2015-04-02T13:44:56","date_gmt":"2015-04-02T13:44:56","guid":{"rendered":"https:\/\/www.gersztenlab.com\/?page_id=160"},"modified":"2015-07-02T17:41:16","modified_gmt":"2015-07-02T17:41:16","slug":"cardiometabolic-risk-factors-2","status":"publish","type":"page","link":"https:\/\/www.gersztenlab.com\/our-research\/cardiometabolic-risk-factors-2\/","title":{"rendered":"FHS scientists: \u201cNew Cardiometabolic Risk Factors in the Framingham Heart Study\u201d"},"content":{"rendered":"<p>Metabolic diseases present particular difficulty for clinicians because they are often present for years before becoming clinically apparent.\u00a0 We investigated whether metabolite profiles can predict the development of diabetes in the Framingham Heart Study.<strong>\u00a0 <\/strong>Five branched-chain and aromatic amino acids had highly-significant associations with future diabetes, while a combination of three amino acids strongly predicted future diabetes by up to 12 years (&gt;5-fold increased risk for individuals in top quartile).\u00a0 Our findings in over 1100 individuals underscore the potential importance of amino acid metabolism early in the pathogenesis of diabetes, and suggest that amino acid profiles could aid in diabetes risk assessment.\u00a0<\/p>\n<p>In a \u201clipidomics\u201d analysis in the Framingham Heart Study, we found that lipids of relatively lower carbon number and double bond content were associated with an increased risk of diabetes, whereas lipids of higher carbon number and double bond content were associated with decreased risk.\u00a0 To explore potential mechanisms that modulate the distribution of plasma lipids, we also performed lipid profiling in the setting of perturbational experiments in MGH patients, including oral glucose tolerance testing, pharmacologic interventions such and acute exercise testing.\u00a0 Lipids associated with increased diabetes risk (particularly triacylglycerols or TAGs) fell in response to insulin action; in turn, these TAGs were elevated in the setting of insulin resistance.\u00a0 These studies identify a novel relationship between lipid acyl-chain content and diabetes risk, demonstrate how lipidomic profiling could also aid in clinical risk assessment beyond standard risk factors, and highlight enzymes including specific lipid elongases and desaturases for further exploration in the context of diabetes.<\/p>\n<p>Most recently, we completed an analysis of \u201cintermediate\u201d metabolites (organic acids, purines, pyrimidines and other compounds) using a novel method.\u00a0 The intermediate metabolite most strongly associated with incident DM was 2-aminoadipic acid (2-AAA). Individuals with elevated levels of 2-AAA had as much as a 4-fold higher risk of developing new-onset DM. We also replicated these findings in the Malmo Diet and Cancer Study. Of note, levels of 2-AAA were not correlated with other metabolite biomarkers of DM, such as BCAA and AroAA, suggesting they report on a distinct patho-physiological pathway. 2-AAA is a poorly characterized intermediary in lysine degradation, which can ultimately enter the TCA cycle via acetyl-CoA. In experimental studies, administration of 2-AAA lowered fasting plasma glucose levels in mice fed both standard chow and high fat diets. Further, 2-AAA treatment enhanced insulin secretion from both a pancreatic beta cell line as well as murine and human islets. These data highlight a novel metabolite not previously associated with T2D risk and a potential modulator of glucose homeostasis.<\/p>\n<p><span style=\"text-decoration: underline;\">Publications:<\/span><\/p>\n<p>Wang TJ, Larson MG, Vasan RS, Cheng S, Rhee EP, McCabe E, Lewis GD, Fox CS, Jacques PF, Fernandez C, O&#8217;Donnell CJ, Carr SA, Mootha VK, Florez JC, Souza A, Melander O, Clish CB, Gerszten RE. Metabolite profiles and the risk of developing diabetes.\u00a0 <em>Nature Medicine.<\/em> 2011 Mar 20. PMID:21423183<\/p>\n<p><em>Rhee EP, Cheng S, Larson MG, Walford GA, Lewis GD, McCabe E, Yang E, Farrell L, Fox CS, O\u2019Donnell CJ, Carr SA, Vasan RS, Florez JC, Clish CB, Wang TJ, Gerszten RE.\u00a0 Lipid profiling identifies a triacylglycerol signature of insulin resistance and improves diabetes prediction in humans. <\/em><em>Journal of Clinical Investigation<\/em>. 2011 Mar 14. pii: 44442. doi: 10.1172\/JCI44442. PMID:21403394<\/p>\n<p>Wang TJ, Ngo D, Psychogios N, Dejam A, Larson M, Ramachandran V, Ghorbani A, O&#8217;Sullivan J, Cheng S, Rhee EP, Sinha S, McCabe E, Fox C, O&#8217;Donnell C, Ho J, Florez J, Magnusson M, Pierce K, Souza A, Yu Y, Carter C, Light P, Melander O, Clish C, Gerszten RE. 2-Aminoadipic acid is a biomarker for diabetes risk. <em>Journal of Clinical Investigation<\/em> 2013 Oct 1;123(10):4309-17. PMID:24091325 PMCID:PMC3784523<\/p>\n<p>&nbsp;<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Metabolic diseases present particular difficulty for clinicians because they are often present for years before becoming clinically apparent.\u00a0 We investigated whether metabolite profiles can predict the development of diabetes in the Framingham Heart Study.\u00a0 Five branched-chain and aromatic amino acids had highly-significant associations with future diabetes, while a combination of three amino acids strongly predicted [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":196,"parent":8,"menu_order":3,"comment_status":"closed","ping_status":"closed","template":"","meta":{"_acf_changed":false,"footnotes":""},"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v22.4 - https:\/\/yoast.com\/wordpress\/plugins\/seo\/ -->\n<title>FHS scientists: \u201cNew Cardiometabolic Risk Factors in the Framingham Heart Study\u201d - Gerszten Lab<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.gersztenlab.com\/our-research\/cardiometabolic-risk-factors-2\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"FHS scientists: \u201cNew Cardiometabolic Risk Factors in the Framingham Heart Study\u201d - 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