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Cited by 1,508Diabetes, Cardiovascular Risks, and LipoproteinsPancreatic function and diabetesDiabetes Management and Research

Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of pima indians

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Lillioja, Stephen, Mott, David M., Spraul, Maximilian, Ferraro, Robert, Foley, James E., Ravussin, Eric, Knowler, William C., Bennett, Peter H. +1 more·1993·New England Journal of Medicine
DOI 10.1056/nejm199312303292703
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Abstract

BACKGROUND: The relative roles of obesity, insulin resistance, insulin secretory dysfunction, and excess hepatic glucose production in the development of non-insulin-dependent diabetes mellitus (NIDDM) are controversial. We conducted a prospective study to determine which of these factors predicted the development of the disease in a group of Pima Indians. METHODS: A body-composition assessment, oral and intravenous glucose-tolerance tests, and a hyperinsulinemic--euglycemic clamp study were performed in 200 non-diabetic Pima Indians (87 women and 113 men; mean [+/- SD] age, 26 +/- 6 years). The subjects were followed yearly thereafter for an average of 5.3 years. RESULTS: Diabetes developed in 38 subjects during follow-up. Obesity, insulin resistance (independent of obesity), and low acute plasma insulin response to intravenous glucose (with the degree of obesity and insulin resistance taken into account) were predictors of NIDDM: The six-year cumulative incidence of NIDDM was 39 percent in persons with values below the median for both insulin action and acute insulin response, 27 percent in those with values below the median for insulin action but above that for acute insulin response, 13 percent in those with values above the median for insulin action and below that for acute insulin response, and 0 in those with values originally above the median for both characteristics. CONCLUSIONS: Insulin resistance is a major risk factor for the development of NIDDM: A low acute insulin response to glucose is an additional but weaker risk factor.

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Crossref · 10.1056/nejm199312303292703

Cites

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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 [35]

    The Discussion (p. 4) identifies insulin resistance and a low acute insulin response as factors leading to NIDDM, supporting the insulin-resistance and relative-insulin-deficiency parts of the claim. The paper does not address glucagon dysregulation (searched: “glucagon dysregulation” and “glucagon”), so that part is not supported by this source. (LLM, conf=0.89)

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  • Progressive β-cell failure is required and ultimately responsible for type 2 diabetes to become fully manifest.

    “However, progressive β-cell failure is required and ultimately responsible for type 2 diabetes to become fully manifest ( 1 , 34 , 35 , 37 , 38 ).”

    From Skeletal Muscle Insulin Resistance Is the Primary Defect in Type 2 Diabetes (2009) · cites this paper as [35]

    The Discussion (p. 4) describes an eventual decline in insulin secretion alongside rising glucose concentrations, supporting a role for β-cell dysfunction as diabetes develops. It also says the sequence of events is unknown and identifies insulin resistance as another etiologic factor; it does not establish that progressive β-cell failure is required or ultimately responsible for diabetes becoming manifest. (LLM, conf=0.87)

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  • Re-examination of data from some other studies of high-risk NGT subjects suggests that conclusions disputing the presence of beta-cell dysfunction are erroneous because no difference in insulin responses existed between groups despite insulin resistance, indicating impaired beta-cell adaptation.

    “Thus, re-examination of data from some other studies of high risk subjects with NGT would suggest that the conclusions in those papers disputing the presence of beta-cell dysfunction are erroneous because no difference in the insulin responses existed between groups despite the presence of insulin resistance, indicating impaired beta-cell adaptation [108, 109, 110, 111, 112, 113, 114].”

    From The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes (2003) · cites this paper as [113]

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Cites

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Research works printed but not linked: 5

  1. [14]14. Diabetes mellitus: report of a WHO Study Group. World Health Organ Tech Rep Ser 1985;727:9-17.
  2. [18]18. Siri WE. Body composition from fluid spaces and density: analysis of methods. In: Brožek J, Henschel A, eds. Techniques for measuring body composition: proceedings of a conference: Quartermaster Research and Engineering Center, Natick, Mass., January 22–23, 1959. Washington, D.C.: National Research Council, 1961:223-44.
  3. [17]17. Goldman RF, Bushkirk ER. Body volume measurement by underwater weighing: description of a method. In: Brožek J, Henschel A, eds. Techniques for measuring body composition: proceedings of a conference: Quartermaster Research and Engineering Center, Natick, Mass., January 22–23, 1959. Washington, D.C.: National Research Council, 1961:78-89.
  4. [22]22. Gottesman I, Mandarino L, Gerich J. Estimation and kinetic analysis of insulin-independent glucose uptake in human subjects. Am J Physiol 1983;244:E632-E635.
  5. [27]27. Shulman GI, Rothman DL, Jue T, Stein P, DeFronzo RA, Shulman RG. Quantitation of muscle glycogen synthesis in normal subjects and subjects wiaer nr nn u-r ne spectroscopy. N Engl J Med 1989;322:223-8.

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Authors
Lillioja, S., Mott, D. M., Spraul, M., Ferraro, R., Foley, J. E., Ravussin, E., Knowler, W. C., Bennett, P. H., & Bogardus, C.
Affiliations
National Institutes of Health (US)
ORCID
Venue
New England Journal of Medicine
Publisher
Massachusetts Medical Society
Published
1993-12-30
Volume
329
Issue
27
Pages
1988-1992
ISSN
  • 0028-4793 (ISSN-L)
  • 1533-4406
DOI
10.1056/nejm199312303292703
OpenAlex
W2334309509
Cited by
1,508
References
27
Citations by year
2026: 13 · 2025: 16 · 2024: 30 · 2023: 22 · 2022: 34 · 2021: 38 · 2020: 39 · 2019: 37 · 2018: 40 · 2017: 30 · 2016: 40 · 2015: 52 · 2014: 44 · 2013: 45 · 2012: 44
FWCI
30.07
Type
journal article
Language
en
Open access
Locations
  • New England Journal of Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Research Online (University of Wollongong) (submittedVersion)
  • Figshare (submittedVersion, cc-by)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
Keywords
insulin resistance, type 2 diabetes, Pima Indians, obesity, acute insulin response, hepatic glucose production, insulin action, diabetes risk factors, hyperinsulinemic-euglycemic clamp, glucose tolerance
MeSH terms
Insulin Secretion, Adult, Arizona, Body Composition, Diabetes Mellitus, Type 2, Female, Follow-Up Studies, Glucose, Glucose Tolerance Test, Humans, Indians, North American, Insulin, Insulin Resistance, Liver, Male, Obesity, Prospective Studies, Risk Factors, Proportional Hazards Models

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