Predictive value of intravenous glucose tolerance test insulin secretion less than or greater than the first percentile in islet cell antibody positive relatives of type 1 (insulin-dependent) diabetic patients
Open accessAbstract
We have followed-up 35 islet cell antibody-positive first degree relatives of patients with Type 1 (insulin-dependent) diabetes mellitus for an average of 1,300 days with sequential intravenous glucose tolerance tests. At the time of analysis and manuscript submission approximately half (18 of 35) had developed diabetes during follow-up. At initial intravenous glucose tolerance test, 11 had a 1 + 3 min insulin secretion below the first percentile of insulin secretion compared to 225 similarly studied normal control subjects. Six islet cell antibody positive relatives on follow-up developed an intravenous glucose tolerance test less than the first percentile. Fifteen out of 17 (88%) of these islet cell antibody positive relatives with secretion ever found to be below the first percentile are now overtly diabetic (positive predictive value = 88%) and insulin-treated, while only 3 of 18 (17%) without an intravenous glucose tolerance test demonstrating loss of first phase insulin secretion have progressed to diabetes (with approximately 1,300 days of follow-up for both groups relative risk or odds ratio with intravenous glucose tolerance test ever below vs never below the first percentile = 38, p less than 0.001). Intravenous glucose tolerance test response below the first percentile preceded diabetes by an average of 656 days. Even when first phase insulin secretion is below the first percentile, the absolute value of 1 + 3 min insulin above basal insulin correlates with the time to development of diabetes (r = 0.586, p less than 0.001). With our current duration of follow-up, the negative predictive value (intravenous glucose tolerance test never below the first percentile) is 83%, and overall accuracy 86%. Incidence rates of diabetes development amongst our islet cell antibody positive relatives with follow-up while intravenous glucose tolerance test is below the first percentile is 0.48 per year (15 conversions to diabetes amongst 17 relatives in 30.8 patient years of follow-up) vs 0.05 per year (three diabetic patients in 55.5 patient years) with intravenous glucose tolerance test greater than the first percentile.
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The importance of first-phase insulin secretion in the pathogenesis of hyperglycemia is well known in both type 1 diabetes and T2D.
“The importance of first-phase insulin secretion in the pathogenesis of hyperglycemia is well known in both type 1 diabetes and T2D (28,29).”
From Melatonin Impairs Glucose Tolerance, First-Phase Insulin Secretion, and Insulin Feedback Inhibition; Interaction With <i>MTNR1B</i> Diabetes Risk Variant (2026) · cites this paper as [28]
The Discussion reports that loss of first-phase insulin secretion preceded overt type 1 diabetes in the studied relatives and notes that it also occurs in type 2 diabetes. The paper does not establish its role in the pathogenesis of hyperglycemia in type 2 diabetes; its findings concern prediction of type 1 diabetes. (LLM, conf=0.84)
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Seltzer, H. S., Allen, E. W., Herron, A. L., & Brennan, M. T. (1967) · Journal of Clinical Investigation · doi:10.1172/jci105534 · Cited by 819 · cited 1× · see citing works
“It is also important to note that loss of 1st phase insulin secretion is not an abnormality specific to Type i diabetes but occurs with Type 2 diabetes [13] and following partial pancreatectomy [14].”
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Research works printed but not linked: 3
- Gale EAM, Bottazzo GF (1986) Can we predict Type I (insulin- dependent) diabetes? In: Krall L (ed) World book of diabetes in practice. Elsevier, The Netherlands, pp 25-29
- Bottazzo GF, Pujol-Borrell R, Gale EAM (1987) Autoimmunity and Type I diabetes: bringing the story up to date. In: Alberti K, Krall L (eds) The Diabetes Annual 3. Elsevier, The Netherlands, pp 15-38
- Boitard CH, Bonifacio E, Bottazzo GF, Gleichmann H, Mole- naar J (1988) Immunology and Diabetes Workshop: Report of the Third International (Stage3) Workshop on the Stan- dardization of Cytoplasmic Islet Cell Antibodies. Diabetologia 31:451.452
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Insel, R. A., Dunne, J. L., Atkinson, M. A., Chiang, J. L., Dabelea, D., Gottlieb, P. A., Greenbaum, C. J., Herold, K. C., Krischer, J. P., Lernmark, Å., et al. (2015) · Diabetes Care · doi:10.2337/dc15-1419 · Cited by 1,216 · see citing works
Differentiation of diabetes by pathophysiology, natural history, and prognosis
Skyler, J. S., Bakris, G. L., Bonifacio, E., Darsow, T., Eckel, R. H., Groop, L., Groop, P.-H., Handelsman, Y., Insel, R. A., Mathieu, C., et al. (2017) · Diabetes · doi:10.2337/db16-0806 · Cited by 823 · see citing works
Verge, C. F., Gianani, R., Kawasaki, E., Yu, L., Pietropaolo, M., Chase, H. P., Eisenbarth, G. S., & Jackson, R. A. (1996) · Diabetes · doi:10.2337/diab.45.7.926 · Cited by 827 · see citing works
Self-citationProgression to Diabetes in Relatives of Type 1 Diabetic Patients: Mechanisms and Mode of Onset
Ferrannini, E., Mari, A., Nofrate, V., Sosenko, J. M., Skyler, J. S., & for the DPT-1 Study Group (2010) · Diabetes · doi:10.2337/db09-1378 · Cited by 140 · see citing works
Sosenko, J. M., Skyler, J. S., Palmer, J. P., Krischer, J. P., Yu, L., Mahon, J., Beam, C. A., Boulware, D. C., Rafkin, L., Schatz, D., et al. (2013) · Diabetes Care · doi:10.2337/dc13-0425 · Cited by 123 · see citing works
Self-citationRisk assessment, prediction and prevention of type 1 diabetes
Harrison, L. C. (2001) · Pediatric Diabetes · doi:10.1034/j.1399-5448.2001.002002071.x · Cited by 48 · see citing works
Qian, J., Stefanovski, D., Andersen, P. A. K., Vujovic, N., Kelly, L., Lepson, J., Nguyen, H., Byrne, S., Wang, W., Mandrup-Poulsen, T., et al. (2026) · Diabetes Care · doi:10.2337/dc26-0164
- Authors
- Vardi, P., Crisa, L., Jackson, R. A., Dumont Herskowitz, R., Wolfsdorf, J. I., Einhorn, D., Linarelli, L., Dolinar, R., Wentworth, S., Brink, S. J., Starkman, H., Soeldner, J. S., & Eisenbarth, G. S.
- Affiliations
- Brigham and Women's Hospital (US)
- Morristown Medical Center (US)
- Venue
- Diabetologia
- Published
- 1991-02
- Volume
- 34
- Issue
- 2
- Pages
- 93-102
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2074845177
- Cited by
- 122
- References
- 1
- Citations by year
- 2026: 2 · 2025: 2 · 2023: 1 · 2022: 2 · 2021: 6 · 2020: 2 · 2019: 1 · 2018: 1 · 2016: 4 · 2015: 4 · 2014: 2 · 2013: 3 · 2012: 1
- FWCI
- 4.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Brigham and Women's Hospital
- Massachusetts Lions Eye Research Fund
- National Institutes of Health (5r01dk039233-05, 5r01dk033790-08, DK32083)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK32083, DK33790, DK39233, R01DK032083)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- type 1 diabetes, islet cell antibodies, first-degree relatives, first-phase insulin secretion, intravenous glucose tolerance test, diabetes prediction, predictive value
- MeSH terms
- Insulin Secretion, Administration, Oral, Adolescent, Adult, Aged, Autoantibodies, Child, Child, Preschool, Diabetes Mellitus, Type 1, Follow-Up Studies, Glucose, Glucose Tolerance Test, HLA-DR Antigens, Humans, Infusions, Intravenous, Insulin, Middle Aged, Prediabetic State, Prognosis, Biomarkers
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