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Cited by 141Diabetes and associated disordersPancreatic function and diabetesDiabetes Management and Research

Progression to Diabetes in Relatives of Type 1 Diabetic Patients: Mechanisms and Mode of Onset

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Ferrannini, Ele, Mari, Andrea, Nofrate, Valentina, Sosenko, Jay M., Skyler, Jay S., for the DPT-1 Study Group·2010·Diabetes
DOI 10.2337/db09-1378PMC PMC2828663
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Abstract

OBJECTIVE: Relatives of type 1 diabetic patients are at enhanced risk of developing diabetes. We investigated the mode of onset of hyperglycemia and how insulin sensitivity and β-cell function contribute to the progression to the disease. RESEARCH DESIGN AND METHODS: In 328 islet cell autoantibody–positive, nondiabetic relatives from the observational arms of the Diabetes Prevention Trial-1 Study (median age 11 years [interquartile range 8], sequential OGTTs (2,143 in total) were performed at baseline, every 6 months, and 2.7 years [2.7] later, when 115 subjects became diabetic. β-Cell glucose sensitivity (slope of the insulin-secretion/plasma glucose dose-response function) and insulin sensitivity were obtained by mathematical modeling of the OGTT glucose/C-peptide responses. RESULTS: In progressors, baseline insulin sensitivity, fasting insulin secretion, and total postglucose insulin output were similar to those of nonprogressors, whereas β-cell glucose sensitivity was impaired (median 48 pmol/min per m2 per mmol/l [interquartile range 36] vs. 87 pmol/min per m2 per mmol/l [67]; P < 0.0001) and predicted incident diabetes (P < 0.0001) independently of sex, age, BMI, and clinical risk. In progressors, 2-h glucose levels changed little until 0.78 years before diagnosis, when they started to rise rapidly (∼13 mmol · l−1 · year−1); glucose sensitivity began to decline significantly (P < 0.0001) earlier (1.45 years before diagnosis) than the plasma glucose surge. During this anticipation phase, both insulin secretion and insulin sensitivity were essentially stable. CONCLUSIONS: In high-risk relatives, β-cell glucose sensitivity is impaired and is a strong predictor of diabetes progression. The time trajectories of plasma glucose are frequently biphasic, with a slow linear increase followed by a rapid surge, and are anticipated by a further deterioration of β-cell glucose sensitivity.

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  • Metabolic changes in the natural history of type 1 diabetes are marked by decreased early C-peptide response at least 2 years before onset, increased glucose fluctuations as an individual approaches onset, and an overall linear rise, with a last-minute surge, in plasma glucose in the months before onset.

    “Metabolic changes in the natural history of type 1 diabetes are marked by decreased early C-peptide response at least 2 years before onset,80 increased glucose fluctuations as an individual approaches onset,81 and an overall linear rise, with a last-minute surge, in plasma glucose in”

    From Type 1 diabetes (2014) · cites this paper as [82]

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Authors
Ferrannini, E., Mari, A., Nofrate, V., Sosenko, J. M., Skyler, J. S., & for the DPT-1 Study Group
Affiliations
  • University of Pisa (IT)
  • C.N.R. Institute of Biomedical Engineering, Padua, Italy;
  • University of Miami (US)
Corresponding author
Ferrannini, Ele
ORCID
Venue
Diabetes
Publisher
American Diabetes Association
Published
2009-12-22
Volume
59
Issue
3
Pages
679-685
ISSN
  • 0012-1797 (ISSN-L)
  • 1939-327X
DOI
10.2337/db09-1378
PMC
PMC2828663
OpenAlex
W2145193656
Cited by
140
References
39
Citations by year
2026: 4 · 2025: 7 · 2024: 7 · 2023: 7 · 2022: 9 · 2021: 12 · 2020: 5 · 2019: 9 · 2018: 14 · 2017: 10 · 2016: 10 · 2015: 12 · 2014: 8 · 2013: 8 · 2012: 10
FWCI
3.51
Type
journal article
Language
en
Open access
Licence
Locations
  • Diabetes (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
Funders
  • National Institutes of Health
  • National Institute of Allergy and Infectious Diseases
  • National Institute of Diabetes and Digestive and Kidney Diseases
  • Division of Diabetes, Endocrinology, and Metabolic Diseases
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, diabetes progression, islet autoantibodies, beta-cell glucose sensitivity, insulin sensitivity, insulin secretion, prediabetes, risk prediction
MeSH terms
Insulin Secretion, Adolescent, Blood Glucose, C-Peptide, Child, Child, Preschool, Diabetes Mellitus, Type 1, Female, Follow-Up Studies, Glucose Tolerance Test, Humans, Hyperglycemia, Insulin, Insulin Resistance, Male, Models, Biological, Predictive Value of Tests, Risk Factors, Glucose Intolerance, Disease Progression, Insulin-Secreting Cells, Kaplan-Meier Estimate

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