Mechanisms of Progression to Diabetes in Relatives of Type 1 Diabetic Patients.

Relatives of type 1 diabetic patients are at enhanced risk of developing diabetes (DM). We investigated the mechanisms by which risk progresses to disease. In 144 islet-cell autoantibody-positive, non-diabetic relatives from the close observation (control) group of the DPT-1 Parenteral Insulin Trial (73 female, age=12 [10] years (median [interquartile range]), BMI=18.3 [6.1] kg⋅m[sup -2], 42 IGT and 102 NGT). A frequently-sampled OGTT was performed at baseline and again 2.5 [2.8] years later, when 61 subjects (33 female/28 male, 28 from IGT, 33 from NGT) had developed DM. β-cell glucose sensitivity (β-GS, slope of the insulin-secretion/plasma glucose dose-response function) and insulin sensitivity (IS) were obtained by mathematical modelling of glucose/C-peptide responses to OGTT. Relatives progressing to DM had worse β-GS at follow up (18 [21] vs 62 [50] pmol⋅min[sub -1]⋅m[sub -2], p<0.0001 [Mann Whitney]) as well as at baseline (41 [30] vs 75 [68] pmol⋅min[sup -1]⋅m[sup -2]⋅mM[sup -1], p<0.0001). In contrast, IS was only marginally lower in progressors than non-progressors both at baseline (418 [79] vs 427 [61 ] ml⋅min[sup -1]⋅m[sup -2], p=0.77) and follow up (386 [66] vs 405 [64] ml⋅min[sup -1]⋅m[sup -2], p=0.12). By Kaplan-Meier modelling, DM-free survival was significantly (log-rank p<0.0001) worse in the bottom β-GS tertile (30 [21] pmol⋅min[sup -1]⋅m[sup -2]⋅mM[sup -1]) as compared to the middle (56 [13]) or top tertile (117 [53]). By proportional hazards analysis, incident DM was predicted (as relative risk, RR and [95% confidence interval] per 1 SD of the predictor) by baseline β-GS (RR=0.42 [0.32-0.56]), age (RR=0.27 [0.14-0.52]), female gender (RR=3.08 [1.73-5.45]), baseline IS (RR=0.66 [0.49-0.90]) and baseline BMI (RR=1.64 [0.98-2.73]), in that order of strength (χ²=36.9, 15.3, 14.8, 6.8 and 3.6, respectively). In this multivariate model, baseline glucose tolerance, fasting and 2-hour plasma glucose levels were not significant predictors. We conclude that, in high-risk relatives of type 1 patients progression to DM is mainly predicted by impaired β-cell glucose sensitivity, with younger age, female sex, reduced insulin sensitivity and higher BMI making additional contributions to DM risk. ADA-Funded Research [ABSTRACT FROM AUTHOR]