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

  1. for the DPT-1 Study Group*
  1. 1Department of Medicine, University of Pisa School of Medicine, Pisa, Italy;
  2. 2C.N.R. Institute of Biomedical Engineering, Padua, Italy;
  3. 3Division of Endocrinology, University of Miami, Miami, Florida.
  1. Corresponding author: Ele Ferrannini, ferranni{at}ifc.cnr.it.

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.

Footnotes

  • *A full listing of the members of the DPT-1 Study Group can be found in the online appendix of N Engl J Med 2002;346:1685–1691.

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Received September 16, 2009.
    • Accepted December 11, 2009.
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  1. Diabetes vol. 59 no. 3 679-685
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