The effect of age on longitudinal measures of beta cell function and insulin sensitivity during the progression of early stage type 1 diabetes

Abstract

Aim/hypothesis: The risk of progressing from autoantibody positivity to type 1 diabetes is inversely related to age. Separately, whether age influences patterns of C-peptide loss or changes in insulin sensitivity in autoantibody-positive individuals who progress to stage 3 type 1 diabetes is unclear.

Methods: Beta cell function and insulin sensitivity were determined by modelling of OGTTs performed in 658 autoantibody-positive participants followed longitudinally in the Diabetes Prevention Trial-Type 1 (DPT-1). In this secondary analysis of DPT-1 data, time trajectories of beta cell function and insulin sensitivity were analysed in participants who progressed to type 1 diabetes (progressors) to address the impact of age on patterns of metabolic progression to diabetes.

Results: Among the entire DPT-1 cohort, the highest discriminant age for type 1 diabetes risk was 14 years, with participants aged <14 years being twice as likely to progress to type 1 diabetes as those aged ≥14 years. At study entry, beta cell glucose sensitivity was impaired to a similar extent in progressors aged <14 years and progressors aged ≥14 years. From study entry to stage 3 type 1 diabetes onset, beta cell glucose sensitivity and insulin sensitivity declined in both progressor groups. However, there were no significant differences in the yearly rate of decline in either glucose sensitivity (-13.7 [21.2] vs -11.9 [21.5] pmol min^-1 m^-2 [mmol/l]^-1, median [IQR], p=0.52) or insulin sensitivity (-22 [37] vs -14 [40] ml min^-1 m^-2, median [IQR], p=0.07) between progressors aged <14 years and progressors aged ≥14 years.

Conclusions/interpretation: Our data indicate that during progression to stage 3 type 1 diabetes, rates of change in declining glucose and insulin sensitivity are not significantly different between progressors aged <14 years and progressors aged ≥14 years. These data suggest there is a predictable course of declining metabolic function during the progression to type 1 diabetes that is not influenced by age.

Keywords: Age; Beta cell glucose sensitivity; C-peptide; Type 1 diabetes.

Fig. 1

Diabetes-free survival function of study participants by the discriminant age of 14 years (p=2.0×10⁻⁷). Age <14 years, n=448; age ≥14 years, n=210; 295 prepubertal, 221 peripubertal and 142 adults

Fig. 2

Diabetes-free survival function by sex-specific quartiles of beta cell glucose sensitivity in participants aged <14 years (a) (n=448, p=3.4×10⁻¹⁵) or ≥14 years (b) (n=210, p=2.4×10⁻¹²). Colours indicate glucose sensitivity quartiles (red, green, blue and orange, from the lowest to the highest quartile). Each quartile includes 112 participants aged <14 years and 53 participants aged ≥14 years; progressors, n=227; non-progressors n=431

Fig. 3

Multivariate Cox proportional hazard model of diabetes progression in the entire cohort (n=658). Plots show HR and 95% CI. Insulin secretion represents total insulin output over the 2 h of the OGTT; AIR represents the AIR to i.v. injection of glucose

Fig. 4

Time course of plasma glucose levels, beta cell function variables and insulin sensitivity by outcome (progressors vs non-progressors). Time 0 is the time of diabetes diagnosis or study end. Numbers of participants are given at the bottom of the figure. NP, non-progressors; P, progressors

Fig. 5

Time course of plasma glucose levels, beta cell function variables and insulin sensitivity by baseline age in progressors aged <14 years (n=184) and ≥14 years (n=43). Within each age group, trajectories are first aligned to the age of diagnosis (as in Fig. 4). Then, trajectories are shifted by the median group-specific age at diagnosis (last time point is the median age at diagnosis in the group)

Fig. 6

Scattergram of glucose sensitivity against insulin sensitivity in progressors and non-progressors by age <14 or ≥14 years (progressors aged <14 years, n=184; progressors aged ≥14 years, n=43; non-progressors aged <14 years, n=264; non-progressors aged ≥14 years, n=167). Historical data from healthy control groups of participants aged ≥14 years (n=72; age 30 ± 2 years, BMI 24.2 ± 5.0 kg/m², mean ± SD) and younger individuals (n=68; age 9 ± 2 years, BMI 23.6 ± 1.1 kg/m², mean ± SD) are also plotted. Squares, baseline values; circles, follow-up values; dashed arrows connect non-progressors; solid arrows connect progressors. Plots are mean ± SEM