Cited by 1,940Pancreatic function and diabetesDiabetes, Cardiovascular Risks, and LipoproteinsDiabetes Treatment and Management

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The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus

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Weyer, Christian, Bogardus, Clifton, Mott, David M., Pratley, Richard E.·1999·Journal of Clinical Investigation

DOI 10.1172/jci7231PMC PMC408438

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Abstract

The pathogenesis of type 2 diabetes involves abnormalities in insulin action, insulin secretion, and endogenous glucose output (EGO). However, the sequence with which these abnormalities develop and their relative contributions to the deterioration in glucose tolerance remain unclear in the absence of a detailed longitudinal study. We measured insulin action, insulin secretion, and EGO longitudinally in 17 Pima Indians, in whom glucose tolerance deteriorated from normal (NGT) to impaired (IGT) to diabetic over 5.1 +/- 1.4 years. Transition from NGT to IGT was associated with an increase in body weight, a decline in insulin-stimulated glucose disposal, and a decline in the acute insulin secretory response (AIR) to intravenous glucose, but no change in EGO. Progression from IGT to diabetes was accompanied by a further increase in body weight, further decreases in insulin-stimulated glucose disposal and AIR, and an increase in basal EGO. Thirty-one subjects who retained NGT over a similar period also gained weight, but their AIR increased with decreasing insulin-stimulated glucose disposal. Thus, defects in insulin secretion and insulin action occur early in the pathogenesis of diabetes. Intervention to prevent diabetes should target both abnormalities.

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Authors: Weyer, C., Bogardus, C., Mott, D. M., & Pratley, R. E.
Affiliations: National Institutes of Health (US)
Corresponding author: Weyer, Christian
ORCID: Bogardus, Clifton
Pratley, Richard E.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 1999-09-15
Volume: 104
Issue: 6
Pages: 787-794
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci7231
PMC: PMC408438
OpenAlex: W2077149049
Cited by: 1,940
References: 68
Citations by year: 2026: 24 · 2025: 53 · 2024: 53 · 2023: 74 · 2022: 63 · 2021: 80 · 2020: 64 · 2019: 64 · 2018: 61 · 2017: 72 · 2016: 88 · 2015: 81 · 2014: 91 · 2013: 85 · 2012: 83
FWCI: 44.54
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › 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: type 2 diabetes, insulin resistance, insulin secretion, impaired glucose tolerance, Pima Indians, insulin-stimulated glucose disposal, weight gain, diabetes prevention, pathogenesis
MeSH terms: Insulin Secretion, Adult, Anthropometry, Diabetes Mellitus, Type 2, Female, Glucose, Glucose Tolerance Test, Humans, Insulin, Insulin Resistance, Male, Obesity, Sex Factors

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The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus

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