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- Title
Progression to Diabetes in Relatives of Type 1 Diabetic Patients: Mechanisms and Mode of Onset.
- Authors
Ferrannini, Ele; Marl, Andrea; Nofrate, Valentina; Sosenko, Jay M.; Skyler, Jay S.
- 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 ⋅ 1[sup -1] ⋅ year[sup -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. Diabetes 59:679-685, 2010
- Subjects
DISEASE progression; DIABETES risk factors; RELATIVES; PEOPLE with diabetes; HYPERGLYCEMIA; ALLERGENICITY of insulin; PANCREATIC beta cells; BLOOD sugar
- Publication
Diabetes, 2010, Vol 59, Issue 3, p679
- ISSN
0012-1797
- Publication type
Academic Journal
- DOI
10.2337/db09-1378