Diabetes-Associated Variation in TCF7L2 Is Not Associated With Hepatic or Extrahepatic Insulin Resistance
Open accessAbstract
A common genetic variation in TCF7L2 is associated with type 2 diabetes. However, the mechanism by which this occurs remains elusive. In addition to affecting insulin secretion, genetic variation at the TCF7L2 locus may alter insulin action or directly modify hepatic glucose metabolism. We sought to determine whether the diabetes-associated variant in this locus (the T allele of rs7903146) increases fasting endogenous glucose production (EGP), and impairs insulin-induced suppression of EGP and insulin-stimulated glucose disappearance. To address this, we studied individuals who were either homozygous for the diabetes-associated allele (TT) at rs7903146 or were homozygous for the protective allele (CC). Subjects were matched for other anthropometric characteristics and were studied using a euglycemic clamp. EGP and glucose uptake were measured using the tracer dilution technique, and the relative contribution of gluconeogenesis to EGP was quantitated using deuterated water corrected for transaldolase exchange. We report that the diabetes-associated variation in TCF7L2 did not associate with fasting EGP, insulin-induced suppression of EGP, and insulin-induced stimulation of glucose uptake. There was no association with the contribution of gluconeogenesis and glycogenolysis to EGP. These data indicate that genetic variation at TCF7L2 does not predispose an individual to type 2 diabetes by altering either hepatic or extrahepatic insulin action.
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Somatostatin infusion inhibits endogenous glucagon and insulin secretion from pancreatic cells and ensures identical portal insulin concentrations on the two occasions.
“Concomitantly, an infusion of somatostatin (60 ng/kg/min) was started to inhibit endogenous glucagon and insulin secretion from pancreatic cells and therefore ensure identical portal insulin concentrations on the two occasions [25].”
From Modeling the effect of glucagon on endogenous glucose production in healthy individuals under meal-like conditions (2025) · cites this paper as [25]
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- Authors
- Varghese, R. T., Viegas, I., Barosa, C., Marques, C., Shah, M., Rizza, R. A., Jones, J. G., & Vella, A.
- Affiliations
- Mayo Clinic (US)
- Center for Neurosciences and Cell Biology, Department of Zoology, University of Coimbra, Coimbra, Portugal
- University of Coimbra (PT)
- Corresponding author
- Vella, Adrian
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2016-01-28
- Volume
- 65
- Issue
- 4
- Pages
- 887-892
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC4806663
- OpenAlex
- W2306955799
- Cited by
- 25
- References
- 21
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 1 · 2022: 3 · 2021: 2 · 2020: 3 · 2019: 4 · 2018: 1 · 2017: 4 · 2016: 4
- FWCI
- 3.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Diabetes (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5T32 DK007352-37, DK78646, DK82396, UL1 TR000135)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- TCF7L2, rs7903146, type 2 diabetes, insulin resistance, hepatic glucose production, endogenous glucose production, insulin-stimulated glucose uptake, gluconeogenesis, glycogenolysis, insulin secretion, genetic susceptibility, euglycemic clamp
- MeSH terms
- Adult, Diabetes Mellitus, Type 2, Female, Humans, Insulin Resistance, Liver, Male, Middle Aged, Glucose Clamp Technique, Case-Control Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genetic Association Studies, Transcription Factor 7-Like 2 Protein
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