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JCI Insight. 2018 Aug 9;3(15). pii: 120877. doi: 10.1172/jci.insight.120877. [Epub ahead of print]

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

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Departments of Medicine.
Cellular and Integrative Physiology.
Biochemistry and Molecular Biology.
Pediatrics, and the.
Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Roudebush VA Medical Center, Indianapolis, Indiana, USA.
Children's Hospital of Pittsburgh of UPMC, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Denver, Colorado, USA.
VA Puget Sound Health Care System and the University of Washington, Seattle, Washington, USA.
Health Informatics Institute, University of South Florida, Tampa, Florida, USA.
Department of Medicine and the Diabetes Research Institute, Leonard Miller School of Medicine, University of Miami, Miami, Florida, USA.



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


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.


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.


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.



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.


Beta cells; Diabetes; Endocrinology; Insulin; Metabolism

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