The Longitudinal Effect of Diabetes-Associated Variation in TCF7L2 on Islet Function in Humans
Open accessAbstract
The T allele at rs7903146 in TCF7L2 increases the rate of conversion from prediabetes to type 2 diabetes. This has been associated with impaired β-cell function and with defective suppression of α-cell secretion by glucose. However, the temporal relationship of these abnormalities is uncertain. To study the longitudinal changes in islet function, we recruited 128 subjects, with 67 homozygous for the diabetes-associated allele (TT) at rs7903146 and 61 homozygous for the protective allele. Subjects were studied on two occasions, 3 years apart, using an oral 75-g glucose challenge. The oral minimal model was used to quantitate β-cell function; the glucagon secretion rate was estimated from deconvolution of glucagon concentrations. Glucose tolerance worsened in subjects with the TT genotype. This was accompanied by impaired postchallenge glucagon suppression but appropriate β-cell responsivity to rising glucose concentrations. These data suggest that α-cell abnormalities associated with the TT genotype (rs7903146) occur early and may precede β-cell dysfunction in people as they develop glucose intolerance and type 2 diabetes. Article Highlights:
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An insulin-centric view of glucose regulation may lead to inaccurate assessment of insulin sensitivity because abnormal glucagon concentrations cause hyperglycemia that may be erroneously attributed to lower insulin action.
“This insulin-centric vision of the glucose regulatory system may also lead to an inaccurate assessment of insulin sensitivity [9], since abnormal glucagon concentrations cause hyperglycemia, which may be erroneously attributed to a lower ability of insulin to exert its hypoglycemic effect.”
From Modeling the effect of glucagon on endogenous glucose production in healthy individuals under meal-like conditions (2025) · cites this paper as [9]
Cites
Færch, K., Vistisen, D., Pacini, G., Torekov, S. S., Johansen, N. B., Witte, D. R., Jonsson, A., Pedersen, O., Hansen, T., Lauritzen, T., et al. (2016) · Diabetes · doi:10.2337/db16-0240 · Cited by 217 · see citing works
Cobelli, C., Dalla Man, C., Toffolo, G., Basu, R., Vella, A., & Rizza, R. (2014) · Diabetes · doi:10.2337/db13-1198 · Cited by 216 · see citing works
Self-citationVarghese, R. T., Viegas, I., Barosa, C., Marques, C., Shah, M., Rizza, R. A., Jones, J. G., & Vella, A. (2016) · Diabetes · doi:10.2337/db15-1593 · Cited by 25 · see citing works
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Faggionato, E., Tonello, A., Laurenti, M. C., Vella, A., & Dalla Man, C. (2025) · American Journal of Physiology - Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00172.2025
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- Authors
- Zeini, M., Laurenti, M. C., Egan, A. M., Muthusamy, K., Ramar, A., Vella, E., Bailey, K. R., Cobelli, C., Dalla Man, C., & Vella, A.
- Affiliations
- Mayo Clinic (US)
- University of Padua (IT)
- 4Department of Information Engineering, University of Padova, Padova, Italy
- Corresponding author
- Vella, Adrian
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2024-06-13
- Volume
- 73
- Issue
- 9
- Pages
- 1440-1446
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC11333375
- OpenAlex
- W4399604727
- Cited by
- 10
- References
- 3
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 1
- FWCI
- 4.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK TR000135, DK116231, DK126206, DK78646)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- TCF7L2, rs7903146, type 2 diabetes, islet function, beta-cell function, glucagon suppression, glucose tolerance, prediabetes, genetic susceptibility, oral glucose tolerance test, oral minimal model
- MeSH terms
- Adult, Alleles, Blood Glucose, Diabetes Mellitus, Type 2, Female, Genotype, Glucagon, Glucose Tolerance Test, Humans, Islets of Langerhans, Longitudinal Studies, Male, Middle Aged, Glucose Intolerance, Glucagon-Secreting Cells, Insulin-Secreting Cells, Transcription Factor 7-Like 2 Protein
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