The overall aim of this application is to determine the mechanism(s) by which common genetic variation in TCF7L2, recently associated with type 2 diabetes alters glucose metabolism. We wish to do so in order to develop rational approaches for the prevention and treatment of diabetes. Type 2 diabetes is a common metabolic disorder that arises out of a complex interaction between genes and the environment. It is proceeded by pre-diabetes where affected subjects have elevated fasting or postprandial glucose concentrations but do not fulfill the criteria for the diagnosis of diabetes. Individuals with prediabetes are at high risk of progression to diabetes. Analysis of participants in the diabetes prevention program has also independently confirmed that common variants in TCF7L2 are associated with increased risk of diabetes among persons with impaired glucose tolerance. Although there is some understanding as to how variation in KCNJ11 and PPARG alters glucose metabolism, little is known about how TCF7L2 alters glucose homeostasis. TCF7L2 is a transcription factor that may modulate signaling pathways necessary for blood glucose homeostasis. It has been shown that individuals with the disease-associated variant(s) of this gene secrete less insulin during an oral glucose tolerance test (OGTT). However, despite the reproducible association of this genetic locus with type 2 diabetes, there is very little knowledge of how variation in this locus affects glucose homeostasis in humans with and without impaired fasting glucose and / or impaired glucose tolerance and ultimately how this gene contributes to the development of diabetes. The product of TCF7L2 is an important constituent of the wnt-signaling cascade that regulates proglucagon gene expression. The protein product of proglucagon is differentially processed in intestinal L cells to produce glucagon-like peptide-1 (GLP-1), an incretin hormone that is a potent insulin secretagogue and defective secretion of GLP-1 has been associated with type 2 diabetes and impaired glucose tolerance. The ability to predict diabetes development will allow targeted prevention strategies. It has been shown that common genetic variation in TCF7L2 predisposes to diabetes. Understanding the effect of this gene on glucose metabolism and GLP-1 secretion will immeasurably increase our ability to target prevention strategies to predisposed individuals.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
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Laughlin, Maren R
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Mayo Clinic, Rochester
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Sharma, Anu; Vella, Adrian (2017) Obstacles to Translating Genotype-Phenotype Correlates in Metabolic Disease. Physiology (Bethesda) 32:42-50
Lu, Jin; Varghese, Ron T; Zhou, Lianzhen et al. (2017) Glucose tolerance and free fatty acid metabolism in adults with variations in TCF7L2 rs7903146. Metabolism 68:55-63
Vella, Adrian; Camilleri, Michael (2017) The Gastrointestinal Tract as an Integrator of Mechanical and Hormonal Response to Nutrient Ingestion. Diabetes 66:2729-2737
Cobelli, Claudio; Vella, Adrian (2017) Exocrine and Endocrine Interactions in Cystic Fibrosis: A Potential Key to Understanding Insulin Secretion in Health and Disease? Diabetes 66:20-22
Varghese, Ron T; Dalla Man, Chiara; Sharma, Anu et al. (2016) Mechanisms Underlying the Pathogenesis of Isolated Impaired Glucose Tolerance in Humans. J Clin Endocrinol Metab 101:4816-4824
Vella, Adrian; Jensen, Michael D; Nair, K Sreekumaran (2016) Eulogy for the Metabolic Clinical Investigator? Diabetes 65:2821-3
Varghese, Ron T; Viegas, Ivan; Barosa, Cristina et al. (2016) Diabetes-Associated Variation in TCF7L2 Is Not Associated With Hepatic or Extrahepatic Insulin Resistance. Diabetes 65:887-92
Piccinini, Francesca; Dalla Man, Chiara; Vella, Adrian et al. (2016) A Model for the Estimation of Hepatic Insulin Extraction After a Meal. IEEE Trans Biomed Eng 63:1925-1932
Dalla Man, Chiara; Micheletto, Francesco; Sathananthan, Matheni et al. (2016) Model-Based Quantification of Glucagon-Like Peptide-1-Induced Potentiation of Insulin Secretion in Response to a Mixed Meal Challenge. Diabetes Technol Ther 18:39-46
Shah, Meera; Varghese, Ron T; Miles, John M et al. (2016) TCF7L2 Genotype and ?-Cell Function in Humans Without Diabetes. Diabetes 65:371-80

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