Progression to diabetes in relatives of type 1 diabetic patients: mechanisms and mode of onset - PubMed (original) (raw)

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

Ele Ferrannini et al. Diabetes. 2010 Mar.

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 beta-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. 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.

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Figures

FIG. 1.

FIG. 1.

Dose-response curve of insulin secretion rates vs. plasma glucose levels during the OGTT in 280 subjects with normal glucose tolerance according to whether (progressors) or not (nonprogressors) they developed diabetes. Data are means ± SEM. The mean slope of the dose response is β-cell glucose sensitivity. Full lines, baseline data; dotted lines, data at follow-up.

FIG. 2.

FIG. 2.

Kaplan-Meier plots of diabetes-free survival in 280 subjects with normal glucose tolerance at baseline according to tertile of baseline β-cell glucose sensitivity (log-rank χ2 = 25.5, P < 0.0001, and 13.2, P = 0.0003, in female [_A_] and male [_B_] subjects, respectively). The risk ratio of subjects in the bottom tertile of β-cell glucose sensitivity (dotted line) is 2.40 (95% CI 1.76–3.30), P < 0.0001 vs. the top tertile, adjusted for sex, age, and BMI.

FIG. 3.

FIG. 3.

Example of a monophasic (A) (subject YW3599) and a biphasic (B) (subject HR2920) time course of 2-h plasma glucose concentrations; note the change in slope at transition time in the biphasic time pattern.

FIG. 4.

FIG. 4.

Half-yearly averages of 2-h plasma glucose concentrations (left panel) and individual fits of their time series (right panel) in nonprogressors and progressors. The thick lines are the mean of the individual fitting functions.

FIG. 5.

FIG. 5.

Time course of 2-h plasma glucose concentrations, glucose sensitivity, fasting insulin secretion, and insulin sensitivity in the progressor group. Time series are synchronized on the transition time of 2-h plasma glucose levels.

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