Progression to diabetes in relatives of type 1 diabetic patients: mechanisms and mode of onset.
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 beta-cell function contribute to the progression to the disease.


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. 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.


RESULTS
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.


CONCLUSIONS
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.
Ferrannini
Ele
E
Department of Medicine, University of Pisa School of Medicine, Pisa, Italy. ferranni@ifc.cnr.it
Mari
Andrea
A
Nofrate
Valentina
V
Sosenko
Jay M
JM
Skyler
Jay S
JS
D000293:Adolescent; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000453:epidemiology / Q000276:immunology* / Q000503:physiopathology*; D018450:Disease Progression; D005260:Female; D005500:Follow-Up Studies; D018149:Glucose Intolerance / Q000453:epidemiology / Q000276:immunology / Q000503:physiopathology; D005951:Glucose Tolerance Test; D006801:Humans; D006943:Hyperglycemia / Q000453:epidemiology / Q000276:immunology / Q000503:physiopathology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D053208:Kaplan-Meier Estimate; D008297:Male; D008954:Models, Biological; D011237:Predictive Value of Tests; D012307:Risk Factors
D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin