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

Weyer, Christian; Bogardus, Clifton; Mott, David M.; Pratley, Richard E.

doi:10.1172/jci7231

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

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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Insulin resistance, relative insulin deficiency, and glucagon dysregulation underlie the pathophysiology of type 2 diabetes.
“Insulin resistance and concurrent relative insulin deficiency and glucagon dysregulation underlie T2D pathophysiology.33–35”
From American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. (2022) · cites this paper as [34]
The Introduction and Discussion identify impaired insulin action and insulin secretory dysfunction as contributors to type 2 diabetes, supporting the insulin-resistance and relative-insulin-deficiency portions of the claim. The paper discusses increased endogenous glucose output but does not attribute it to glucagon dysregulation; searches for glucagon-related terms found no supporting passage. The supplied passages have section labels but no page numbers. (LLM, conf=0.90)
Experimental — accuracy not yet measured
A longitudinal study in Pima Indians demonstrated impaired beta-cell function in those destined to progress to Type 2 diabetes.
“These findings derived from cross-sectional data are supported by a longitudinal study in Pima Indians that has also shown the importance of accounting for the hyperbolic relationship between insulin sensitivity and insulin secretion and demonstrated the presence of impaired beta-cell function in those destined to progress to Type 2 diabetes [95].”
From The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes (2003) · cites this paper as [95]
In Pima Indians with NGT at baseline followed for an average of 5 years, 17 (35%) progressed from NGT to IGT and then to diabetes.
“Seventeen (35%) of these subjects progressed from NGT to IGT and then to diabetes during follow up.”
From The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes (2003) · cites this paper as [95]
The hyperbolic relationship between insulin sensitivity and insulin secretion in healthy subjects has been confirmed in large cohorts of Danish and Pima Indian subjects.
“Our finding of a hyperbolic relationship between insulin sensitivity and insulin secretion in healthy subjects has been confirmed in large cohorts of Danish [94] and Pima Indian subjects [95].”
From The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes (2003) · cites this paper as [95]
During follow up in Pima Indians, insulin secretion declined progressively by 78% while insulin sensitivity decreased by only 14%.
“During follow up, insulin secretion declined progressively by 78% while insulin sensitivity decreased by only 14%.”
From The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes (2003) · cites this paper as [95]

Based on the UKPDS and the longitudinal assessment in Pima Indians, the major reason for the decline in glucose tolerance seems to be a progressive loss of beta-cell function.
“Based on the UKPDS [18] and the longitudinal assessment in Pima Indians [95], the major reason for the decline in glucose tolerance seems to be a progressive loss of beta-cell function.”
From The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes (2003) · cites this paper as [95]
Progressive deterioration of β-cell function accounts for the natural history from impaired glucose tolerance to type 2 diabetes.
“Further progressive deterioration of β-cell function accounts for the evolving natural history of the disease from impaired glucose tolerance to type 2 diabetes10,11.”
From Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future (2014) · cites this paper as [10]
The results may help explain the association between N3 lack and T2DM, as a loss in first-phase insulin secretion is both an early marker of T2DM and part of its pathogenesis.
“Our results may help explain the aforementioned association between N3 lack and T2DM, as a loss in first-phase insulin secretion is both an early marker of T2DM and part of its pathogenesis (20).”
From Sleep architecture and glucose and insulin homeostasis in obese adolescents (2011) · cites this paper as [20]
IGT and T2DM ensue when beta cell function fails to compensate.
“IGT and T2DM ensue when beta cell function fails to compensate.”
From The Vasculature in Prediabetes (2018) · cites this paper as [16]
Insulin resistance precedes the development of hyperglycemia and T2DM and results in compensatory hyperinsulinemia.
“Insulin resistance precedes the development of hyperglycemia and T2DM and results in compensatory hyperinsulinemia.”
From The Vasculature in Prediabetes (2018) · cites this paper as [16]

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Self-citation
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Youth Type 2 Diabetes
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Chronic Palmitate Exposure Inhibits Insulin Secretion by Dissociation of Ca2+ Channels from Secretory Granules
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The Vasculature in Prediabetes
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“Our results may help explain the aforementioned association between N3 lack and T2DM, as a loss in first-phase insulin secretion is both an early marker of T2DM and part of its pathogenesis (20).”
Effect of donor age on function of isolated human islets
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Primary Defects in β-Cell Function Further Exacerbated by Worsening of Insulin Resistance Mark the Development of Impaired Glucose Tolerance in Obese Adolescents
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Novel views on new-onset diabetes after transplantation: development, prevention and treatment
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Effects of aldosterone on insulin sensitivity and secretion
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Prevention of Diabetes With Pioglitazone in ACT NOW
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Effects of Exenatide Plus Rosiglitazone on β-Cell Function and Insulin Sensitivity in Subjects With Type 2 Diabetes on Metformin
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Glucose-Lowering Drugs to Reduce Cardiovascular Risk in Type 2 Diabetes
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Self-citation
Emerging treatments for post-transplantation diabetes mellitus
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Actos Now for the prevention of diabetes (ACT NOW) study
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Postchallenge Hyperglycemia in a National Sample of U.S. Adults With Type 2 Diabetes
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Androgen Excess in Pancreatic β Cells and Neurons Predisposes Female Mice to Type 2 Diabetes
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Importance of Obtaining Independent Measures of Insulin Secretion and Insulin Sensitivity During the Same Test
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Parallel manifestation of insulin resistance and beta cell decompensation is compatible with a common defect in type 2 diabetes
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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: 67
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 › 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: 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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