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

• Published in: Diabetes (New York, N.Y.) Vol. 59; no. 3; pp. 679 - 685
• Main Authors: FERRANNINI, Ele, MARI, Andrea, NOFRATE, Valentina, SOSENKO, Jay M, SKYLER, Jay S
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.03.2010
• Subjects: Adolescent; Biological and medical sciences; Blood Glucose - metabolism; C-Peptide - metabolism; Child; Child, Preschool; Diabetes; Diabetes Mellitus, Type 1 - epidemiology; Diabetes Mellitus, Type 1 - immunology; Diabetes Mellitus, Type 1 - physiopathology; Diabetes. Impaired glucose tolerance; Disease Progression; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Follow-Up Studies; Genetic aspects; Glucose; Glucose Intolerance - epidemiology; Glucose Intolerance - immunology; Glucose Intolerance - physiopathology; Glucose Tolerance Test; Health aspects; Homeostasis; Humans; Hyperglycemia; Hyperglycemia - epidemiology; Hyperglycemia - immunology; Hyperglycemia - physiopathology; Insulin - metabolism; Insulin resistance; Insulin Resistance - physiology; Insulin Secretion; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - physiology; Kaplan-Meier Estimate; Male; Medical sciences; Metabolism; Models, Biological; Original; Pancreatic beta cells; Peptides; Plasma; Predictive Value of Tests; Research design; Risk Factors; Type 1 diabetes; United States; Endocrinopathy; Human; Immunopathology; Autoimmune disease; Type 1 diabetes
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db09-1378

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 beta-cell function contribute to the progression to the disease. 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. Beta-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. In progressors, baseline insulin sensitivity, fasting insulin secretion, and total postglucose insulin output were similar to those of nonprogressors, whereas beta-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 (approximately 13 mmol x l(-1) x 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. In high-risk relatives, beta-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 beta-cell glucose sensitivity.