The overall aim of this application is to better understand the mechanism(s) that lead to diabetes. Of the various common genetic variants associated with type 2 diabetes that in TCF7L2, has the strongest effect on disease predisposition and might provide insight into various diverse mechanisms that drive the progression of prediabetes to diabetes. The product of TCF7L2 is an important constituent of the wnt-signaling cascade that was originally shown to regulate proglucagon gene expression. However, it is apparent that TCF7L2 regulates multiple genes regulating metabolic processes, all of which may be important in the pathogenesis of diabetes. Beta-cell function has been quantified by the Disposition Index (DI) which expresses insulin secretion as a function of insulin action. However, the relationship between these 2 parameters has been assumed to be uniform across various states of glucose tolerance, and indeed different states of beta-cell reserve. Direct measurement of the secretory response in response to an acute decrease in insulin action validate or improve DI as a characterization of beta-cell function and the effect of diabetes-associated variation in TCF7L2 on this measurement. Moreover, incretin hormones (regulated by TCF7L2 have been suggested to be part of the compensatory response to acute decreases in insulin action. Hepatic insulin action is impaired early in the pathogenesis of prediabetes and is characterized by impaired suppression of gluconeogenesis. The contribution of diabetes-associated variation in TCF7L2 to these processes is unknown. Finally, insulin secretion and insulin action decline in parallel across the spectrum of prediabetes. The mechanism(s) underlying this observation are unknown. One potential explanation, supported by animal experiments, is that decreased interdigestive insulin pulsatility leads to decreased hepatic insulin action. The processes regulating the amplitude and frequency of insulin secretion are complex and have been shown to be abnormal in many states associated with increased predisposition to diabetes. A direct effect of diabetes-associated variation in TCF7L2 on insulin pulsatility and amplitude of secretion is unknown. The experimental design will also allow direct correlation of interdigestive insulin secretion with hepatic insulin action in humans. The proposed experiments will directly address how TCF7L2 alters glucose homeostasis and provide insights into the pathogenesis of prediabetes and progression to diabetes.

Public Health Relevance

Genome-wide association studies have identified multiple common genetic variants that predisposed to type 2 diabetes. Of these genetic variation in TCF7L2 has the strongest effect on diabetes risk. However, its direct effects on glucose metabolism and on progression to diabetes are poorly understood. Diabetes-associated variation in this locus provides an opportunity to improve our understanding of the processes driving the conversion of prediabetes to diabetes, refine clinical measurements of beta-cell function and improve our ability to target prevention strategies to predisposed individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK078646-08
Application #
8682806
Study Section
Clinical and Integrative Diabetes and Obesity Study Section (CIDO)
Program Officer
Laughlin, Maren R
Project Start
2007-08-01
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
8
Fiscal Year
2014
Total Cost
$488,753
Indirect Cost
$147,799
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Sharma, Anu; Varghese, Ron T; Shah, Meera et al. (2018) Impaired Insulin Action Is Associated With Increased Glucagon Concentrations in Nondiabetic Humans. J Clin Endocrinol Metab 103:314-319
Varghese, Ron T; Dalla Man, Chiara; Laurenti, Marcello C et al. (2018) Performance of individually measured vs population-based C-peptide kinetics to assess ?-cell function in the presence and absence of acute insulin resistance. Diabetes Obes Metab 20:549-555
Bogachus, Lindsey D; Bellin, Melena D; Vella, Adrian et al. (2018) Deficient Glucagon Response to Hypoglycemia During a Mixed Meal in Total Pancreatectomy/Islet Autotransplantation Recipients. J Clin Endocrinol Metab 103:1522-1529
Karanth, Santhosh; Adams, J D; Serrano, Maria de Los Angeles et al. (2018) A Hepatocyte FOXN3-? Cell Glucagon Axis Regulates Fasting Glucose. Cell Rep 24:312-319
Vella, Adrian; Matveyenko, Aleksey (2018) Walking a fine line between ?-cell secretion and proliferation. J Biol Chem 293:14190-14191
Sharma, Anu; Vella, Adrian (2017) Obstacles to Translating Genotype-Phenotype Correlates in Metabolic Disease. Physiology (Bethesda) 32:42-50
Vella, Adrian; Camilleri, Michael (2017) The Gastrointestinal Tract as an Integrator of Mechanical and Hormonal Response to Nutrient Ingestion. Diabetes 66:2729-2737
Bogachus, Lindsey D; Oseid, Elizabeth; Bellin, Melena et al. (2017) Deficient Endogenous Glucose Production During Exercise After Total Pancreatectomy/Islet Autotransplantation. J Clin Endocrinol Metab 102:3288-3295
Newhouse, Lauren P; Joyner, Michael J; Curry, Timothy B et al. (2017) Three hours of intermittent hypoxia increases circulating glucose levels in healthy adults. Physiol Rep 5:
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

Showing the most recent 10 out of 67 publications