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Separate Impact of Obesity and Glucose Tolerance on the Incretin Effect in Normal Subjects and Type 2 Diabetic Patients
Open accessAbstract
OBJECTIVE—To quantitate the separate impact of obesity and hyperlycemia on the incretin effect (i.e., the gain in β-cell function after oral glucose versus intravenous glucose). RESEARCH DESIGN AND METHODS—Isoglycemic oral (75 g) and intravenous glucose administration was performed in 51 subjects (24 with normal glucose tolerance [NGT], 17 with impaired glucose tolerance [IGT], and 10 with type 2 diabetes) with a wide range of BMI (20–61 kg/m2). C-peptide deconvolution was used to reconstruct insulin secretion rates, and β-cell glucose sensitivity (slope of the insulin secretion/glucose concentration dose-response curve) was determined by mathematical modeling. The incretin effect was defined as the oral-to-intravenous ratio of responses. In 8 subjects with NGT and 10 with diabetes, oral glucose appearance was measured by the double-tracer technique. RESULTS—The incretin effect on total insulin secretion and β-cell glucose sensitivity and the GLP-1 response to oral glucose were significantly reduced in diabetes compared with NGT or IGT (P ≤ 0.05). The results were similar when subjects were stratified by BMI tertile (P ≤ 0.05). In the whole dataset, each manifestation of the incretin effect was inversely related to both glucose tolerance (2-h plasma glucose levels) and BMI (partial r = 0.27–0.59, P ≤ 0.05) in an independent, additive manner. Oral glucose appearance did not differ between diabetes and NGT and was positively related to the GLP-1 response (r = 0.53, P < 0.01). Glucagon suppression during the oral glucose tolerance test was blunted in diabetic patients. CONCLUSIONS—Potentiation of insulin secretion, glucose sensing, glucagon-like peptide-1 release, and glucagon suppression are physiological manifestations of the incretin effect. Glucose tolerance and obesity impair the incretin effect independently of one another.
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“Also, we only tested young and healthy adults and did not confirm our results in obese subjects or patients with impaired glucose metabolism (18, 37).”
From Assessment of the incretin effect in healthy subjects: concordance between clamp and OGTT methods (2023) · cites this paper as [37]
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The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus* (2002) · Diabetes Care · doi:10.2337/diacare.25.2007.s5 · Cited by 10,325
Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus
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β-Cell Deficit and Increased β-Cell Apoptosis in Humans With Type 2 Diabetes
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Self-citationReduced incretin effect in Type 2 (non-insulin dependent) diabetes
Nauck, M., Stöckmann, F., Ebert, R., & Creutzfeldt, W. (1986) · Diabetologia · doi:10.1007/bf02427280 · Cited by 1,307
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Self-citationPlasma Insulin Responses to Oral and Intravenous Glucose: Studies in Normal and Diabetic Subjects*
Perley, M. J., & Kipnis, D. M. (1967) · Journal of Clinical Investigation · doi:10.1172/jci105685 · Cited by 917
Tissue and Plasma Concentrations of Amidated and Glycine-Extended Glucagon-Like Peptide I in Humans
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Self-citationFerrannini, E., Natali, A., Bell, P., Cavallo-Perin, P., Lalic, N., & Mingrone, G. (1997) · Journal of Clinical Investigation · doi:10.1172/jci119628 · Cited by 898
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Astiarraga, B., Rodríguez-Castellano, A., Ceperuelo‐Mallafré, V., Marsal-Beltran, A., Osuna‐Prieto, F. J., Vilanova, N., Gracia-Sancho, J., Quer, J. C., Ana, M., Balteiro, A. P., et al. (2026) · Journal of Physiology and Biochemistry · doi:10.1007/s13105-026-01141-x
Adaptive changes of human islets to an obesogenic environment in the mouse
Gargani, S. (2013) · theses.fr (ABES) · doi:10.70675/cebf7176z1bb8z414bzb159ze850f327d2d5
Α-gustducine intestinale : implication dans l'obésité et le diabète de type 2
Gléau, L. L. (2021) · theses.fr (ABES) · doi:10.70675/dc436e75zb6d2z4bb4zb9a1z17b025f205a6
Tudosie, A. C., Marin, L.-M., Popa, S. G., & Golli, A. L. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27083628 · Cited by 1
Vignera, S. L., Fioriglio, C., & Condorelli, R. A. (2026) · Diagnostics · doi:10.3390/diagnostics16131979
Han, Y., Shon, J., & Park, Y. J. (2026) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2026.2728313
Metadata
- Authors
- Muscelli, E., Mari, A., Casolaro, A., Camastra, S., Seghieri, G., Gastaldelli, A., Holst, J. J., & Ferrannini, E.
- Affiliations
- University of Pisa (IT)
- National Research Council (IT)
- Division of Internal Medicine, Spedali Riuniti, Pistoia, Italy
- University of Copenhagen (DK)
- Corresponding author
- Ferrannini, Ele
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2008-05-01
- Volume
- 57
- Issue
- 5
- Pages
- 1340-1348
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2145818242
- Cited by
- 409
- References
- 50
- Citations by year
- 2026: 9 · 2025: 4 · 2024: 17 · 2023: 19 · 2022: 23 · 2021: 21 · 2020: 17 · 2019: 22 · 2018: 20 · 2017: 27 · 2016: 22 · 2015: 35 · 2014: 35 · 2013: 34 · 2012: 20
- FWCI
- 18.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- incretin effect, obesity, glucose tolerance, type 2 diabetes, impaired glucose tolerance, beta-cell function, beta-cell glucose sensitivity, glucagon-like peptide-1, glucagon suppression, insulin secretion, body mass index, hyperglycemia
- MeSH terms
- Insulin Secretion, Adult, Blood Glucose, Diabetes Mellitus, Type 2, Female, Glucose Tolerance Test, Humans, Hypoglycemic Agents, Insulin, Male, Middle Aged, Obesity, Reference Values, Body Mass Index, Insulin-Secreting Cells
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