Progression to diabetes in relatives of type 1 diabetic patients: Mechanisms and mode of onset

Ele Ferrannini, Andrea Mari, Valentina Nofrate, Jay M Sosenko, Jay S Skyler

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)679-685
Number of pages7
JournalDiabetes
Volume59
Issue number3
DOIs
StatePublished - Mar 1 2010

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Glucose
Insulin Resistance
Insulin
Glucose Tolerance Test
C-Peptide
Islets of Langerhans
Hyperglycemia
Autoantibodies
Disease Progression
Fasting
Research Design

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 journalArticle

Ferrannini, Ele ; Mari, Andrea ; Nofrate, Valentina ; Sosenko, Jay M ; Skyler, Jay S. / Progression to diabetes in relatives of type 1 diabetic patients : Mechanisms and mode of onset. In: Diabetes. 2010 ; Vol. 59, No. 3. pp. 679-685.
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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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AU - Skyler, Jay S

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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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