Impaired beta cell glucose sensitivity rather than inadequate compensation for insulin resistance is the dominant defect in glucose intolerance
Open accessAbstract
Aims/hypothesis It is commonly thought that hyperglycaemia results from insufficient compensation of insulin secretion for insulin resistance. To verify this hypothesis, we assessed beta cell function and insulin sensitivity (IS) in a large cohort of volunteers with normal glucose tolerance (NGT) or impaired glucose regulation (IGR), i.e. impaired glucose tolerance or impaired fasting glucose. Methods In men and women with NGT (n=1,123) or IGR(n=156) (age 44 +/- 8 years, BMI 25+/-4 kg/m2, mean +/- SD)we measured: (1) IS by clamp; (2) insulin secretion rates(ISR) and beta cell glucose sensitivity (=slope of the insulin secretion/plasma glucose dose-response) by C-peptide deconvolution and OGTT modelling; and (3) acute insulin response to intravenous glucose. Results After controlling for centre, sex, age and BMI, fasting and total ISR were inversely related to IS in both groups,whereas beta cell glucose sensitivity was not. Acute insulin response was reciprocally related to IS in both groups, but the relationships were incompatible with inadequate compensation and significance was lost after controlling for fasting ISR. InIGR vs NGT, IS was impaired (92 [75] vs 133 [86] micromol min(-1)[kg fat-free mass](-1) [nmol/l](-1), median [interquartile range],p<0.0001) as was beta cell glucose sensitivity (69 [46] vs 119[83] pmol min(-1) m(-2) [nmol/l](-1), p<0.0001), whereas fasting and total ISR were increased (35% and 25%, respectively, p<0.0001). In fully adjusted models, beta cell glucose sensitivity was the strongest determinant of OGTT glucose levels. Conclusions/interpretation Insulin resistance normally upregulates the secretory tone, with no evidence of defective compensation in IGR. In contrast, beta cell glucose sensitivity is independent of insulin resistance, but a key determinant of glucose tolerance. This suggests that hyperglycaemia results from an intrinsic beta cell defect rather than from inadequate compensation for insulin resistance.
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The slope of the relationship between glucose and insulin secretion (β-CGS) is a major controller of postprandial glucose levels.
“The slope of the relationship between glucose and insulin secretion (ie, β -CGS) is a major controller of postprandial glu cose levels (23, 24).”
From Effects of Tirzepatide vs Semaglutide on β-Cell Function, Insulin Sensitivity, and Glucose Control During a Meal Test (2024) · cites this paper as [23]
The Methods define β-cell glucose sensitivity as the slope of the insulin-secretion response to glucose. The Results and Discussion identify it as the largest contributor to glucose levels during an oral glucose tolerance test, but the paper assesses a glucose load rather than a meal and does not establish that the slope controls postprandial glucose levels generally. (LLM, conf=0.84)
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Cites
Ferrannini, E., Gastaldelli, A., Miyazaki, Y., Matsuda, M., Mari, A., & DeFronzo, R. A. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-1133 · Cited by 540 · cited 2× · see citing works
“In a recent study involving a relatively large number of patients with type 2 diabetes [9], we were unable to confirm the hyperbolic compensation paradigm as the sole mechanism responsible for the emergence of dysglycaemia.”
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Research works printed but not linked: 2
- Kahn SE, Porte D Jr (2003) The pathophysiology and genetics of type 2 diabetes mellitus. In: Porte D Jr, Sherwin R, Baron A (eds) Ellenberg and Rifkin's diabetes mellitus, 6th edn. McGraw-Hill, New York, pp 331-365
- DeFronzo RA, Mandarino L, Ferrannini E (2004) Metabolic and molecular pathogenesis of type 2 diabetes mellitus. In: DeFronzo RA, Ferrannini E, Keen H, Zimmet P (eds) International textbook of diabetes mellitus, 3rd edn. Wiley, Chichester
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on behalf of the RISC Investigators, Ferrannini, E., Natali, A., Muscelli, E., Nilsson, P. M., Golay, A., Laakso, M., Beck-Nielsen, H., & Mari, A. (2011) · Diabetologia · doi:10.1007/s00125-011-2112-x · Cited by 80 · see citing works
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Mather, K. J., Mari, A., Heise, T., DeVries, J. H., Hua, M., Urva, S., Coskun, T., Haupt, A., Heine, R. J., Pratt, E., et al. (2024) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgae319 · Cited by 32 · see citing works
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- Authors
- The RISC Investigators, Mari, A., Tura, A., Natali, A., Laville, M., Laakso, M., Gabriel, R., Beck-Nielsen, H., & Ferrannini, E.
- Affiliations
- National Research Council (IT)
- University of Pisa (IT)
- Lyon 1 Université (FR)
- University of Eastern Finland (FI)
- Hospital Universitario La Paz (ES)
- Corresponding author
- Mari, A.
- Venue
- Diabetologia
- Published
- 2010-01-09
- Volume
- 53
- Issue
- 4
- Pages
- 749-756
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2028113047
- Cited by
- 120
- References
- 1
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 7 · 2023: 3 · 2022: 10 · 2021: 3 · 2020: 5 · 2019: 4 · 2018: 4 · 2017: 12 · 2016: 3 · 2015: 10 · 2014: 13 · 2013: 7 · 2012: 9
- FWCI
- 11.83
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
- Funders
- AstraZeneca (QLG1-CT-2001-01252)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- beta-cell glucose sensitivity, insulin resistance, impaired glucose tolerance, impaired fasting glucose, insulin secretion rate, insulin sensitivity, acute insulin response, hyperglycemia
- MeSH terms
- Adult, Blood Glucose, C-Peptide, Fasting, Female, Glucose Tolerance Test, Humans, Hyperglycemia, Insulin Resistance, Male, Middle Aged, Glucose Intolerance, Patch-Clamp Techniques, Insulin-Secreting Cells
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