Insulin resistance is central to the pathogenesis of Type 2 Diabetes (T2DM) and the Metabolic Syndrome, and drugs or lifestyle interventions that increase insulin sensitivity constitute effective therapy and prevention. Thiazolidinedione drugs (TZDs) act through agonism of nuclear transcription factors (i.e., PPAR?) to enhance insulin sensitivity;however, TZD therapy is associated with adverse effects, including weight gain and heart failure. These untoward effects limit clinical utility, and highlight the need for alternative insulin-sensitizing medications that can act directly on muscle. We will study the NR4A family of orphan nuclear receptors, which were identified as differentially expressed genes on our human muscle cDNA microarrays. Extensive preliminary data indicate that: (i) NR4A3 is expressed at lower levels in insulin-resistant humans and rodents;(ii) TZDs induce NR4A3 suggesting that NR4A3 may be downstream of TZD action;(iii) MCK-NR4A3 transgenic mice exhibit an insulin sensitive phenotype;(iv) an increase in NR4A3 receptors can augment insulin signaling and stimulation of glucose transport;(v) PGA2 acts to increase insulin sensitivity in a NR4A3 dependent manner. To pursue these novel observations, our overall goal is to increase our understanding of the role of NR4A receptors in modulating insulin action, their role in human insulin resistance, and their rationale as a therapeutic drug target. To achieve this goal, we will apply our laboratory's capacity for translational research including human metabolism, human muscle and adipose tissue biopsies, transgenic mice, and cultured cell systems. Based on extensive preliminary data, the specific aims are: (1) Assess expression of NR4A receptors in muscle and fat in insulin sensitive, insulin resistant, and T2DM humans, before and after weight loss and TZD treatment, and in insulin resistant rodent models. (2) Establish metabolic role of NR4A3 by phenotyping transgenic mice with specific hyperexpression of NR4A3 in skeletal muscle. In both human and mouse, NR4A expression will be assessed for its ability to affect insulin sensitivity and substrate metabolism at the level of whole body and individual cells and tissues. (3) Determine mechanisms by which NR4A3 regulates insulin action by studying stable hyperexpression and shRNA- mediated suppression of NR4A3 in cultured muscle and adipose cells. These studies will address our preliminary data indicating that NR4A3 modulates insulin-stimulated glucose transport, GLUT4 translocation, and insulin-mediated phosphorylation of signaling molecules. (4) Identify lipid mediator agonists of NR4A3 based on preliminary data indicating that PGA2 increases insulin sensitivity in a NR4A3 dependent manner. Thus, this work will elucidate novel molecules and pathophysiologic processes contributing to insulin resistance, and develop new potential drug targets for the treatment and prevention of diabetes and cardiometabolic disease.
Insulin resistance is a critical factor causing Type 2 Diabetes and the Metabolic Syndrome. Treatment of insulin resistance can prevent diabetes and control blood sugars in patients who already have the disease;however, the available medications have serious side effects which limit their use. This research will elucidate, for the first time, the role of a novel family of orphan nuclear transcription factors (NR4A) in the cause of insulin resistance, and their potential as targets for new drugs to treat and prevent Type 2 Diabetes.
|Guo, Fangjian; Garvey, W Timothy (2016) Cardiometabolic disease risk in metabolically healthy and unhealthy obesity: Stability of metabolic health status in adults. Obesity (Silver Spring) 24:516-25|
|Zhang, Wei; Hartmann, Riley; Tun, Hein Min et al. (2016) Deletion of the Toll-Like Receptor 5 Gene Per Se Does Not Determine the Gut Microbiome Profile That Induces Metabolic Syndrome: Environment Trumps Genotype. PLoS One 11:e0150943|
|Zhang, Wei; Wu, Mengrui; Kim, Teayoun et al. (2016) Skeletal Muscle TRIB3 Mediates Glucose Toxicity in Diabetes and High- Fat Diet-Induced Insulin Resistance. Diabetes 65:2380-91|
|Steverson Jr, Dennis; Tian, Ling; Fu, Yuchang et al. (2016) Tribbles Homolog 3 Promotes Foam Cell Formation Associated with Decreased Proinflammatory Cytokine Production in Macrophages: Evidence for Reciprocal Regulation of Cholesterol Uptake and Inflammation. Metab Syndr Relat Disord 14:7-15|
|Guo, Fangjian; Garvey, W Timothy (2015) Development of a Weighted Cardiometabolic Disease Staging (CMDS) System for the Prediction of Future Diabetes. J Clin Endocrinol Metab 100:3871-7|
|Garvey, W Timothy (2015) The conundrum of whole foods versus macronutrient composition in assessing effects on insulin sensitivity. Am J Clin Nutr 101:1109-10|
|Grams, J; Garvey, W Timothy (2015) Weight Loss and the Prevention and Treatment of Type 2 Diabetes Using Lifestyle Therapy, Pharmacotherapy, and Bariatric Surgery: Mechanisms of Action. Curr Obes Rep 4:287-302|
|Thalacker-Mercer, Anna E; Ingram, Katherine H; Guo, Fangjian et al. (2014) BMI, RQ, diabetes, and sex affect the relationships between amino acids and clamp measures of insulin action in humans. Diabetes 63:791-800|
|Shalaurova, Irina; Connelly, Margery A; Garvey, W Timothy et al. (2014) Lipoprotein insulin resistance index: a lipoprotein particle-derived measure of insulin resistance. Metab Syndr Relat Disord 12:422-9|
|Guo, Fangjian; Moellering, Douglas R; Garvey, W Timothy (2014) The progression of cardiometabolic disease: validation of a new cardiometabolic disease staging system applicable to obesity. Obesity (Silver Spring) 22:110-8|
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