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.
| Original language | English |
|---|---|
| Pages (from-to) | 679-685 |
| Number of pages | 7 |
| Journal | Diabetes |
| Volume | 59 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 1 2010 |
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ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism
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Progression to diabetes in relatives of type 1 diabetic patients : Mechanisms and mode of onset. / Ferrannini, Ele; Mari, Andrea; Nofrate, Valentina; Sosenko, Jay M; Skyler, Jay S.
In: Diabetes, Vol. 59, No. 3, 01.03.2010, p. 679-685.Research output: Contribution to journal › Article
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TY - JOUR
T1 - Progression to diabetes in relatives of type 1 diabetic patients
T2 - Mechanisms and mode of onset
AU - Ferrannini, Ele
AU - Mari, Andrea
AU - Nofrate, Valentina
AU - Sosenko, Jay M
AU - Skyler, Jay S
PY - 2010/3/1
Y1 - 2010/3/1
N2 - 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.
AB - 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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U2 - 10.2337/db09-1378
DO - 10.2337/db09-1378
M3 - Article
C2 - 20028949
AN - SCOPUS:77950356610
VL - 59
SP - 679
EP - 685
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 3
ER -