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      What Have Slow Progressors Taught Us About T1D—Mind the Gap!

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      Author(s): ,
      Publication date (Electronic):
      Journal: Current Diabetes Reports
      Publisher: Springer US
      Keywords: Type 1 diabetes (T1D), Slow progression, Adult onset, Islet autoantibodies

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          Abstract

          Purpose of Review

          Progression rate from islet autoimmunity to clinical diabetes is unpredictable. In this review, we focus on an intriguing group of slow progressors who have high-risk islet autoantibody profiles but some remain diabetes free for decades.

          Recent Findings

          Birth cohort studies show that islet autoimmunity presents early in life and approximately 70% of individuals with multiple islet autoantibodies develop clinical symptoms of diabetes within 10 years. Some “at risk” individuals however progress very slowly. Recent genetic studies confirm that approximately half of type 1 diabetes (T1D) is diagnosed in adulthood. This creates a conundrum; slow progressors cannot account for the number of cases diagnosed in the adult population.

          Summary

          There is a large “gap” in our understanding of the pathogenesis of adult onset T1D and a need for longitudinal studies to determine whether there are “at risk” adults in the general population; some of whom are rapid and some slow adult progressors.

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          Most cited references36

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          The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes.

          Janet M Wenzlau, Kirstine Juhl, Liping Yu … (2007)
          Type 1 diabetes (T1D) results from progressive loss of pancreatic islet mass through autoimmunity targeted at a diverse, yet limited, series of molecules that are expressed in the pancreatic beta cell. Identification of these molecular targets provides insight into the pathogenic process, diagnostic assays, and potential therapeutic agents. Autoantigen candidates were identified from microarray expression profiling of human and rodent pancreas and islet cells and screened with radioimmunoprecipitation assays using new-onset T1D and prediabetic sera. A high-ranking candidate, the zinc transporter ZnT8 (Slc30A8), was targeted by autoantibodies in 60-80% of new-onset T1D compared with <2% of controls and <3% type 2 diabetic and in up to 30% of patients with other autoimmune disorders with a T1D association. ZnT8 antibodies (ZnTA) were found in 26% of T1D subjects classified as autoantibody-negative on the basis of existing markers [glutamate decarboxylase (GADA), protein tyrosine phosphatase IA2 (IA2A), antibodies to insulin (IAA), and islet cytoplasmic autoantibodies (ICA)]. Individuals followed from birth to T1D showed ZnT8A as early as 2 years of age and increasing levels and prevalence persisting to disease onset. ZnT8A generally emerged later than GADA and IAA in prediabetes, although not in a strict order. The combined measurement of ZnT8A, GADA, IA2A, and IAA raised autoimmunity detection rates to 98% at disease onset, a level that approaches that needed to detect prediabetes in a general pediatric population. The combination of bioinformatics and molecular engineering used here will potentially generate other diabetes autoimmunity markers and is also broadly applicable to other autoimmune disorders.
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            Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase.

            S Baekkeskov, H J Aanstoot, S Christgau … (1990)
            The pancreatic islet beta-cell autoantigen of relative molecular mass 64,000 (64K), which is a major target of autoantibodies associated with the development of insulin-dependent diabetes mellitus (IDDM) has been identified as glutamic acid decarboxylase, the biosynthesizing enzyme of the inhibitory neurotransmitter GABA (gamma-aminobutyric acid). Pancreatic beta cells and a subpopulation of central nervous system neurons express high levels of this enzyme. Autoantibodies against glutamic acid decarboxylase with a higher titre and increased epitope recognition compared with those usually associated with IDDM are found in stiff-man syndrome, a rare neurological disorder characterized by a high coincidence with IDDM.
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              A Type 1 Diabetes Genetic Risk Score Can Aid Discrimination Between Type 1 and Type 2 Diabetes in Young Adults.

              Richard Oram, Kashyap Patel, Anita Hill … (2016)
              With rising obesity, it is becoming increasingly difficult to distinguish between type 1 diabetes (T1D) and type 2 diabetes (T2D) in young adults. There has been substantial recent progress in identifying the contribution of common genetic variants to T1D and T2D. We aimed to determine whether a score generated from common genetic variants could be used to discriminate between T1D and T2D and also to predict severe insulin deficiency in young adults with diabetes.
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                Author and article information

                Contributors
                Kathleen M. Gillespie: +44(0) 117 414 7899 , k.m.gillespie@bristol.ac.uk
                Anna E. Long: Anna.Long@bristol.ac.uk
                Journal
                Journal ID (nlm-ta): Curr Diab Rep
                Journal ID (iso-abbrev): Curr. Diab. Rep
                Title: Current Diabetes Reports
                Publisher: Springer US (New York )
                ISSN (Print): 1534-4827
                ISSN (Electronic): 1539-0829
                Publication date (Electronic): 10 September 2019
                Publication date PMC-release: 10 September 2019
                Publication date (Print): 2019
                Volume: 19
                Issue: 10
                Electronic Location Identifier: 99
                Affiliations
                Diabetes and Metabolism, Bristol Medical School, University of Bristol, Level 2, Learning and Research, Southmead Hospital, Bristol, BS10 5NB UK
                Article
                Publisher ID: 1219
                DOI: 10.1007/s11892-019-1219-1
                PMC ID: 6733826
                PubMed ID: 31501992
                SO-VID: 0da8bdd4-fdfc-42ca-8aac-f3a6cae957f0
                Copyright © © The Author(s) 2019
                License:

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                Funding
                Funded by: University of Bristol
                Categories
                Subject: Pathogenesis of Type 1 Diabetes (A Pugliese and SJ Richardson, Section Editors)
                Custom metadata
                issue-copyright-statement © Springer Science+Business Media, LLC, part of Springer Nature 2019

                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: type 1 diabetes (t1d),slow progression,adult onset,islet autoantibodies
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes
                Keywords: type 1 diabetes (t1d), slow progression, adult onset, islet autoantibodies

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