β Cell dysfunction exists more than 5 years before type 1 diabetes diagnosis

Abstract

Background: The duration and patterns of β cell dysfunction during type 1 diabetes (T1D) development have not been fully defined.

Methods: Metabolic measures derived from oral glucose tolerance tests (OGTTs) were compared between autoantibody-positive (aAb+) individuals followed in the TrialNet Pathway to Prevention study who developed diabetes after 5 or more years or less than 5 years of longitudinal follow-up (Progressors≥5, n = 75; Progressors<5, n = 474) and 144 aAb-negative (aAb-) relatives.

Results: Mean age at study entry was 15.0 ± 12.6 years for Progressors≥5; 12.0 ± 9.1 for Progressors<5; and 16.3 ± 10.4 for aAb- relatives. At baseline, Progressors≥5 already exhibited significantly lower fasting C-peptide (P < 0.01), C-peptide AUC (P < 0.001), and early C-peptide responses (30- to 0-minute C-peptide; P < 0.001) compared with aAb- relatives, while 2-hour glucose (P = 0.03), glucose AUC (<0.001), and Index60 (<0.001) were all higher. Despite significant baseline impairment, metabolic measures in Progressors≥5 were relatively stable until 2 years prior to T1D diagnosis, when there was accelerated C-peptide decline and rising glycemia from 2 years until diabetes diagnosis. Remarkably, patterns of progression within 3 years of diagnosis were nearly identical between Progressors≥5 and Progressors<5.

Conclusion: These data provide insight into the chronicity of β cell dysfunction in T1D and indicate that β cell dysfunction may precede diabetes diagnosis by more than 5 years in a subset of aAb+ individuals. Even among individuals with varying lengths of aAb positivity, our findings indicate that patterns of metabolic decline are uniform within the last 3 years of progression to T1D.

Trial registration: Clinicaltrials.gov NCT00097292.

Funding: The Type 1 Diabetes TrialNet Study Group is a clinical trials network currently funded by the NIH through the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, and The Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Juvenile Diabetes Research Foundation.

Keywords: Beta cells; Diabetes; Endocrinology; Insulin; Metabolism.

Figure 1. Participant flow through the Type 1 Diabetes TrialNet Pathway to Prevention Study.

Figure 2. Longitudinal patterns of metabolic decline in Progressors≥5.

Shown are the mean values for the fasting C-peptide (A), early C-peptide response (B), C-peptide AUC (C), fasting glucose (D), 2-hour glucose (E), glucose AUC, (F) and Index60 (G) at baseline and then each year (±6 months) from 4 years to diagnosis for Progressors≥5. Also shown for reference are mean values of the aAb– individuals at baseline (red dotted line). Note that the aAb– control group (n = 144) was studied at a single time point, and the dotted line indicates the value obtained at this single time point. The number of Progressors≥5 with available data at each time point is indicated.