Insulin resistance is a marker for increased risk of Non-Insulin- Dependent Diabetes (NIDDM), Gestational Diabetes (GDM), hypertension, and cardiovascular disease, and is a major cause of glucose intolerance in NIDDM and GDM. However, the degree to which insulin sensitivity is determined by genetic and environmental factors is unknown, and molecular mechanisms causing insulin resistance have not been fully elucidated. In the previous cycle, the P1 found that insulin resistance in NIDDM was due to depletion of GLUT 4 glucose transporters (the major insulin- responsive isoform) in adipocytes, while GLUT 4 levels were normal in skeletal muscle indicating that either GLUT 4 translocation (to the cell surface) or functional activity was impaired. The overall goal in the proposed studies is to define the heritability of insulin resistance and to identify mechanisms which reduce glucose transport system activity in humans with and without insulin-resistant disease processes. Heritability of insulin resistance will be assessed by measuring maximally-stimulated glucose uptake in monozygotic and dizygotic twins, and estimating genetic variance based on intraclass differences and model-fitting path analyses. Muscle fiber composition and GLUT 4 content, resting metabolic rate, and body composition will also be measured so that interrelationships can be assessed within the context of the MZ/DZ twin model. Other studies will characterize molecular mechanisms causing insulin resistance in NIDDM and GDM. In NIDDM, adipocytes will be studied to determine whether nuclear proteins suppress GLUT 4 gene transcription, and the responsible cis and trans elements """"""""will be identified. Studies in skeletal muscle will demonstrate whether insulin resistance in NIDDM and GDM is due to impaired translocation or reduced activity of GLUT 4. GLUT 4 recruitment will be measured by exploiting our ability to biopsy muscle fibers held at fixed length and to photolabel (3H-ATB-BMPA) cell-surface GLUT 4. GLUT 4 activity will be assessed in native membrane vesicles and after reconstitution in synthetic liposomes. Preliminary data in GDM indicate that GLUT 4 accumulates in an alternative membrane compartment where it then becomes refractory to insulin-mediated translocation in adipocytes. This defect will be further characterized in both fat (GDM) and muscle (NIDDM and GDM) by biochemically analyzing immuno-purified GLUT 4 vesicles including their content of small molecular weight G-proteins (smg's), assessing the subcellular distribution of other insulin-regulated proteins (GLUT 1, IGF 11 receptors), and morphologically localizing GLUT 4 using immuno- gold/EM. Finally, insulin-mediated recruitment and activity of GLUT 4 will be assessed in muscle biopsies from two groups of MZ twins concordant for upper and lower quartiles of insulin sensitivity to determine if mechanisms causing insulin resistance in subjects without overt disease are similar to those operative in diabetes. Major hypotheses are supported by preliminary data and include: 1) Insulin resistance is a highly inherited trait due in part to genetic factors which determine skeletal muscle fiber composition and GLUT 4 content; 2) In NIDDM, specific transcription factors in adipocytes repress GLUT 4 gene transcription; 3) In NIDDM and GDM, insulin resistance in skeletal muscle is due to impaired insulin-mediated translocation of GLUT 4 to the cell surface; 4) the translocation defect is associated with abnormal subcellular localization of GLUT 4 vesicles and smg's. Thus, these studies will combine basic and clinical research methodologies to directly study heritability and mechanisms of human insulin resistance, and will further elucidate the pathogenesis and role of insulin resistance in human diseases.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Metabolism Study Section (MET)
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Medical University of South Carolina
Internal Medicine/Medicine
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Ma, Elizabeth; Fu, Yuchang; Garvey, W Timothy (2018) Relationship of Circulating miRNAs with Insulin Sensitivity and Associated Metabolic Risk Factors in Humans. Metab Syndr Relat Disord 16:82-89
Kang, Minsung; Liu, Xiaobing; Fu, Yuchang et al. (2018) Improved systemic metabolism and adipocyte biology in miR-150 knockout mice. Metabolism 83:139-148
Guo, Fangjian; Garvey, W Timothy (2017) Cardiometabolic Disease Staging Predicts Effectiveness of Weight-Loss Therapy to Prevent Type 2 Diabetes: Pooled Results From Phase III Clinical Trials Assessing Phentermine/Topiramate Extended Release. Diabetes Care 40:856-862
Garvey, W Timothy (2017) Comment on Cefalu et al. Update and Next Steps for Real-World Translation of Interventions for Type 2 Diabetes Prevention: Reflections From a Diabetes Care Editors' Expert Forum. Diabetes Care 2016;39:1186-1201. Diabetes Care 40:e21-e22
Ma, Elizabeth; Ingram, Katherine H; Milne, Ginger L et al. (2017) F2-Isoprostanes Reflect Oxidative Stress Correlated With Lean Mass and Bone Density but Not Insulin Resistance. J Endocr Soc 1:436-448
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
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
Chandler-Laney, Paula C; Schneider, Camille R; Gower, Barbara A et al. (2016) Association of late-night carbohydrate intake with glucose tolerance among pregnant African American women. Matern Child Nutr 12:688-98
Garvey, W Timothy (2016) Ablation of the Duodenal Mucosa as a Strategy for Glycemic Control in Type 2 Diabetes: Role of Nutrient Signaling or Simple Weight Loss. Diabetes Care 39:2108-2110
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

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