CONTEXT:Maternal (vs paternal) type 1 diabetes is associated with a relative reduction in type 1 diabetes risk in offspring during early life. OBJECTIVE:To determine whether this effect extends into later life. To clarify the importance of intrauterine exposure to maternal type 1 diabetes, and baseline genetic susceptibility in this context. METHODS:We compared the proportion of individuals with type 1 diabetes diagnosed aged 0 to 88 years of age with affected mothers and fathers across 5 observational studies (n = 11 475), and used random-effects meta-analyses to generate overall effect estimates. We examined this by age at diagnosis, and timing of parental diagnosis relative to offspring birth. We compared the type 1 diabetes genetic risk score (T1D-GRS2) of individuals with affected mothers and fathers. RESULTS:Almost half as many individuals with type 1 diabetes had an affected mother vs father (odds ratio [OR], 0.55; 95% CI, 0.48-0.64; P < .0001). A lower proportion of individuals with affected mothers than fathers was apparent even among individuals diagnosed as adults (>18 years) (OR, 0.63; 95% CI, 0.43-0.91; P = .01). The lower proportion of individuals with maternal vs paternal type 1 diabetes was only observed if maternal diagnosis preceded offspring birth (OR, 0.51; 95% CI, 0.37-0.70; P < .001 vs OR 0.97; 95% CI, 0.69-1.38; P = .87 after birth). T1D-GRS2 was similar between individuals with affected mothers and fathers (P = .25). CONCLUSION:Our analyses suggest intrauterine exposure to maternal type 1 diabetes is associated with long-lasting relative protection against offspring type 1 diabetes, which is independent of genetic susceptibility as measured by T1D-GRS2.

INTRODUCTION:Insulin autoantibodies (IAA) are key predictors of type 1 diabetes, particularly in young children. Micro-radiobinding assays (RBA) are the gold standard for IAA measurement but have limitations. We assessed whether a luciferase immunoprecipitation system (LIPS) assay improved diabetes risk assessment. METHODS:To validate LIPS compared with RBA, samples from people with new-onset type 1 diabetes (n = 150) and first-degree relatives (FDRs) (n = 619), of whom 91 had developed diabetes during follow-up, were used. This cross-sectional observational data was analysed using the area under the receiver operator characteristic curve and cox-proportional hazard models. RESULTS:In new-onset diabetes, RBA and LIPS showed 88% agreement in IAA status. Positive IAA LIPS was more common in 89 FDRs with high-moderate affinity IAA (61%) compared with 22 FDRs with low-affinity IAA (18%) (p < 0.001). In FDRs positive for multiple other islet autoantibodies, 20-year diabetes risk was 80% for those positive compared with 30% for those negative for IAA by LIPS (p = 0.013). IAA LIPS added to diabetes risk independently of status/level of IAA by RBA, other autoantibodies and sampling age (p < 0.001). CONCLUSION:The IAA LIPS low-blood-volume, high-throughput technique identifies more individuals with the highest risk of diabetes. The ability to identify high-affinity IAA makes LIPS an ideal method for future clinical trials and population screening strategies to predict the risk of diabetes.

Autoantibodies to zinc transporter 8 (ZnT8A) are important diagnostic and predictive markers for type 1 diabetes (T1D). Current methods to detect ZnT8A use C-terminal ZnT8 (aa268-369). Previous research identified three major ZnT8A epitopes (R325, W325, and a four-residue conformational epitope [R332/E333/K336/K340]), but the human-specific cysteine region has not been investigated. We sought to examine ZnT8A binding to three C-terminal cysteines and confirm previously known ZnT8A epitopes. Assay buffer constituent (Tween-20) and site-directed mutagenesis of radiolabelled ZnT8 antigen were utilized to compare ZnT8A binding in R325-ZnT8 and W325-ZnT8 monomeric radiobinding assays (RBAs). Truncated ZnT8 (D360X) and cysteine-to-serine mutations (C361S, C364S, and C368S) were compared with wild-type R325-ZnT8/W325-ZnT8 RBAs in 71 newly diagnosed T1D cases. Samples were indexed to controls and the median reduction in binding (MRB, %) was compared using Wilcoxon signed-ranked tests. Unbiased hierarchical clustering analysis was used to review effects of all ZnT8 mutations. A higher Tween-20 concentration reduced ZnT8A binding (P < 0.0001). All cysteine region mutations reduced 325-agnostic ZnT8A binding towards wild-type R325-ZnT8 (MRB range -37.0 to -66.4%, P < 0.0001) and W325-ZnT8 (MRB range -32.1 to -43.8%, P < 0.0001). Mutating the cysteine region nearly abolished binding (>75%) in 7.7-36.8% of R325-ZnT8/W325-ZnT8 positive ZnT8A, and in 10.5-13.2% of subjects studied, reduced binding below that of major ZnT8A epitopes. The cysteine region of C-terminal ZnT8 constitutes an independent epitope for ZnT8A, but mature ZnT8A responses in newly diagnosed T1D are heterogeneous. Epitope spreading of ZnT8A during the natural history of preclinical T1D remains unclear and requires further investigation in larger studies.

Aim: This study aimed to evaluate characteristics of autoimmunity in individuals who have a type 2 diagnosis and are relatives of children with type 1 diabetes. Methods: Pre-diagnosis samples (median 17 months before onset) from relatives who were later diagnosed with type 2 diabetes were measured for autoantibodies to glutamate decarboxylase 65 (GADA), islet antigen-2 (IA-2A), zinc transporter 8 (ZnT8A) and insulin (IAA) as well as the type 1 diabetes genetic risk score (GRS2). Associations between islet autoantibodies, insulin treatment and GRS2 were analysed using Fisher's exact and t-tests. Results: Among 226 relatives (64% men; mean age at sampling 41 years; mean age 54 years at diagnosis), 32 (14%) were islet autoantibody-positive for at least one autoantibody more than a decade before diagnosis. Approximately half of these (n = 15) were treated with insulin. GADA-positivity was higher in insulin-treated relatives than in non-insulin-treated relatives (12/18 [67%] vs. 6/18 [33%], p < 0.001). IAA-positivity was observed in 13/32 (41%) of relatives with autoantibodies. GRS2 scores were increased in autoantibody-positive relatives (p = 0.032), but there was no clear evidence for a difference according to treatment (p = 0.072). Conclusion: This study highlights the importance of measuring islet autoantibodies, including IAA, in relatives of people with type 1 diabetes to avoid misdiagnosis.

Objective: C-peptide and islet autoantibodies are key type 1 diabetes biomarkers, typically requiring venous sampling, which limit their utility. We assessed transdermal capillary blood (TCB) collection as a practical alternative. Research Design and methods: Ninety-one individuals (71 type 1 diabetes, 20 controls; type 1 diabetes: aged median 14.8 years[interquartile range 9.1-17.1]; diabetes duration 4.0 years[1.5-7.7]; controls 42.2 years[38.0-52.1]) underwent contemporaneous venous and TCB sampling for measurement of plasma C-peptide. Type 1 diabetes participants also provided venous serum and plasma, and TCB plasma for measurement of autoantibodies to glutamate decarboxylase, islet antigen-2, and zinc transporter 8. The ability of TCB plasma to detect significant endogenous insulin secretion (venous C-peptide ≥200pmol/L) was compared along with agreement in levels using Bland-Altman. Venous serum was compared with venous and TCB plasma for detection of autoantibodies using established thresholds. Acceptability was assessed by age-appropriate questionnaire. Results: Transdermal sampling took a mean of 2.35minutes (SD 1.49). Median sample volume was 50 µl(IQR 40-50) with 3/91(3.3%) failures, and 13/88(14.7%) <35 µL). TCB C-peptide showed good agreement to venous plasma (mean venous ln(C-peptide) – TCB ln(C-peptide) = 0.008, 95% CI(-0.23, 0.29), with 100%(36/36) sensitivity/100%(50/50) specificity to detect venous C-peptide ≥ 200pmol/L. Where venous serum in multiple autoantibody positive TCB plasma agreed in 22/32 (sensitivity 69%), comparative specificity was 35/36 (97%). TCB was preferred to venous sampling (type 1 diabetes: 63% vs 7%; 30% undecided). Conclusions: Transdermal capillary testing for C-peptide is a sensitive, specific, and acceptable alternative to venous sampling, TCB sampling for islet autoantibodies needs further assessment.

Abstract We investigated whether characterisation of full-length (f-)GADA responses could identify early insulin requirement in adult-onset diabetes. In 179 f-GADA positive participants diagnosed with type 2 diabetes, we assessed associations of truncated (t-)GADA positivity, f-GADA IgG subclasses, and f-GADA affinity with early insulin requirement (<5 years), type 1 diabetes genetic risk score (T1D GRS), and C-peptide. t-GADA positivity was lower in f-GADA positive without early insulin in comparison to f-GADA positive type 2 diabetes requiring insulin within 5 years, and type 1 diabetes (75% vs. 91% and 95% respectively, p<0.0001). t-GADA positivity (in those f-GADA positive) identified a group with a higher type 1 diabetes genetic susceptibility (mean T1D GRS 0.248 vs. 0.225, p=0.003), lower C-peptide (1156 pmol/L vs. 4289 pmol/L, p=1x10-7), and increased IA-2A positivity (23% vs. 6%, p=0.03). In survival analysis, t-GADA positivity was associated with early insulin requirement compared with those only positive for f-GADA, independently from age of diagnosis, f-GADA titre and duration of diabetes [adjusted HR 5.7 (95% CI 1.4, 23.5), p=0.017]. The testing of t-GADA in f-GADA positive individuals with type 2 diabetes identifies those who have genetic and clinical characteristics comparable to type 1 diabetes and stratifies those at higher risk of early insulin requirement. Article Highlights · Progression to insulin therapy is highly variable in adult-onset GADA positive diabetes. · We further characterised GADA in adult-onset diabetes and assessed whether these are associated with early insulin requirement. · Truncated GADA positivity was associated with a type 1 diabetes like phenotype and stratified risk of early insulin requirement. Those GADA positive who were negative for truncated GADA had the characteristics and progression of classic type 2 diabetes. Assessing full-length GADA IgG subclass and affinity did not further stratify risk of progression. · t-GADA assessment remains underutilised in clinical practice, but could assist correct therapy allocation in adult-onset diabetes.

In very rare cases of monoclonal gammopathy, insulin-binding paraprotein can cause disabling hypoglycaemia. We report a 67-year-old man re-evaluated for hyperinsulinaemic hypoglycaemia that persisted despite distal pancreatectomy. He had no medical history of diabetes mellitus or autoimmune disease but was being monitored for an IgG kappa monoclonal gammopathy of undetermined significance. On glucose tolerance testing, hyperglycaemia occurred at 60 min (glucose 216 mg/dL) and hypoglycaemia at 300 min (52 mg/dL) concurrent with an apparent plasma insulin concentration of 52 850 pmol/L on immunoassay. Laboratory investigation revealed an IgG2 kappa with very high binding capacity but low affinity (Kd 1.43 x 10-6 mol/L) for insulin. The monoclonal gammopathy was restaged as smouldering myeloma not warranting plasma cell-directed therapy from a haematological standpoint. Plasma exchange reduced paraprotein levels and improved fasting capillary glucose concentrations. Lenalidomide was used to treat disabling hypoglycaemia, successfully depleting paraprotein and leading to resolution of symptoms.

Journal Article Corrected proof Scientific Business Abstracts Get access Keith Siew, Keith Siew University College London, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Vaksha Patel, Vaksha Patel University College London, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Jasminka Zimmermann, Jasminka Zimmermann University College London, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Michael Vaughan, Michael Vaughan University of Cork, Eire Search for other works by this author on: Oxford Academic PubMed Google Scholar Christopher Cheshire, Christopher Cheshire Crick Institute, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Angela Kubik, Angela Kubik NASA Ames Research Centre, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Rebecca Finch, Rebecca Finch University of Staffordshire, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Zhongwang Li, Zhongwang Li University College London, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Selin Altinok, Selin Altinok University North Carolina, Chapel Hill, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Willian De Silvera, Willian De Silvera University of Staffordshire, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar ... Show more Samuel Rodriques, Samuel Rodriques Crick Institute, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Elizabeth Blaber, Elizabeth Blaber NASA Ames Research Centre, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Jonathan Schisler, Jonathan Schisler University North Carolina, Chapel Hill, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Jonathan Galazka, Jonathan Galazka NASA Ames Research Centre, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Muratani Masafumi, Muratani Masafumi University of Tsukuba, Japan Search for other works by this author on: Oxford Academic PubMed Google Scholar Afshin Beheshti, Afshin Beheshti NASA Ames Research Centre, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Stephen Walsh, Stephen Walsh University College London, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Michael Lean, Michael Lean University of Glasgow, Glasgow, Scotland Search for other works by this author on: Oxford Academic PubMed Google Scholar Roy Taylor, Roy Taylor University of Glasgow, Glasgow, Scotland Search for other works by this author on: Oxford Academic PubMed Google Scholar Naveed Sattar, Naveed Sattar University of Glasgow, Glasgow, Scotland Search for other works by this author on: Oxford Academic PubMed Google Scholar Alasdair Mcintosh, Alasdair Mcintosh University of Glasgow, Glasgow, Scotland Search for other works by this author on: Oxford Academic PubMed Google Scholar Wilma Leslie, Wilma Leslie University of Glasgow, Glasgow, Scotland Search for other works by this author on: Oxford Academic PubMed Google Scholar Louise McCombie, Louise McCombie University of Glasgow, Glasgow, Scotland Search for other works by this author on: Oxford Academic PubMed Google Scholar Naomi Brosnahan, Naomi Brosnahan University of Glasgow, Glasgow, Scotland Search for other works by this author on: Oxford Academic PubMed Google Scholar George Thom, George Thom University of Glasgow, Glasgow, Scotland Search for other works by this author on: Oxford Academic PubMed Google Scholar Alison Barnes, Alison Barnes University of Glasgow, Glasgow, Scotland Search for other works by this author on: Oxford Academic PubMed Google Scholar Keaton Irvine, Keaton Irvine University of Glasgow, Glasgow, Scotland Search for other works by this author on: Oxford Academic PubMed Google Scholar Sarah Cook, Sarah Cook School of Public Health & National Heart and Lung InstituteImperial College London, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Sara Hatem, Sara Hatem Usher Institute, University of Edinburgh, Edinburgh, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Sean Scully, Sean Scully Swansea University Medical School, Swansea, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Hywel T Evans, Hywel T Evans Swansea University Medical School, Swansea, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Ian Farr, Ian Farr Swansea University Medical School, Swansea, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Chris Orton, Chris Orton Swansea University Medical School, Swansea, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar David V Ford, David V Ford Swansea University Medical School, Swansea, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Aziz Sheikh, Aziz Sheikh Usher Institute, University of Edinburgh, Edinburgh, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Jennifer K Quint, Jennifer K Quint School of Public Health & National Heart and Lung InstituteImperial College London, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar David Ferenbach, David Ferenbach University of Edinburgh, Edinburgh, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Lowri Allen, Lowri Allen Diabetes Research Group, Cardiff University, Cardiff, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Georgina Mortimer, Georgina Mortimer Diabetes and Metabolism, Bristol Medical School, University of Bristol, Bristol, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Rana Fareed, Rana Fareed Diabetes and Metabolism, Bristol Medical School, University of Bristol, Bristol, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Claire Williams, Claire Williams Diabetes and Metabolism, Bristol Medical School, University of Bristol, Bristol, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Steve Bain, Steve Bain Biomedical Sciences, Swansea University, Swansea, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Colin Dayan, Colin Dayan Diabetes Research Group, Cardiff University, Cardiff, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Diane Fraser, Diane Fraser Institute of Biomedical and Clinical Science, University of Exeter, Exeter, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar William Hagopian, William Hagopian Pacific North West Research Institute, Seattle, United States of America Search for other works by this author on: Oxford Academic PubMed Google Scholar Richard Oram, Richard Oram Institute of Biomedical and Clinical Science, University of Exeter, Exeter, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Kathleen Gillespie, Kathleen Gillespie Diabetes and Metabolism, Bristol Medical School, University of Bristol, Bristol, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Omid Sadeghi-Alavijeh, Omid Sadeghi-Alavijeh University College London, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Melanie Chan, Melanie Chan University College London, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Shabbir Moochhala, Shabbir Moochhala University College London, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Sarah Howles, Sarah Howles University of Oxford, Oxford, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Daniel Gale, Daniel Gale University College London, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Detlef Böckenhauer, Detlef Böckenhauer University College London, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Rachel Jennings, Rachel Jennings Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United KingdomEndocrinology department, Manchester University NHS Foundation Trust, Manchester, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Syed Murtuza Baker, Syed Murtuza Baker Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Peyman Zarrineh, Peyman Zarrineh Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Ali Al-Banaki, Ali Al-Banaki Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Aoibheann Mullan, Aoibheann Mullan Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Maria Alexandra Goncalves, Maria Alexandra Goncalves Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Neil Hanley, Neil Hanley Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United KingdomEndocrinology department, Manchester University NHS Foundation Trust, Manchester, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Caroline Watson, Caroline Watson University of Cambridge, Cambridge, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Sophia Apostolidou, Sophia Apostolidou MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Usha Menon, Usha Menon MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Jamie Blundell, Jamie Blundell University of Cambridge, Cambridge, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Claire Shovlin, Claire Shovlin National Heart and Lung Institute, Imperial College London, London, United KingdomNIHR Imperial Biomedical Research Centre, London, UKImperial College Healthcare NHS Trust, London, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Maria Bernabeu-Herrero, Maria Bernabeu-Herrero National Heart and Lung Institute, Imperial College London, London, United KingdomNIHR Imperial Biomedical Research Centre, London, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Kinshuk Jain, Kinshuk Jain National Heart and Lung Institute, Imperial College London, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Michaela Aldred, Michaela Aldred Indiana University School of Medicine, Indianapolis, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Adrianna Bielowka, Adrianna Bielowka National Heart and Lung Institute, Imperial College London, London, United KingdomNIHR Imperial Biomedical Research Centre, London, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Ian Mackay, Ian Mackay Charing Cross and Royal Brompton Hospitals, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Patricia Chaves Guerrero, Patricia Chaves Guerrero National Heart and Lung Institute, Imperial College London, London, United KingdomNIHR Imperial Biomedical Research Centre, London, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Stefan Marciniak, Stefan Marciniak University of Cambridge, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Michela Noseda, Michela Noseda National Heart and Lung Institute, Imperial College London, London, United KingdomNIHR Imperial Biomedical Research Centre, London, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Dilipkumar Patel, Dilipkumar Patel National Heart and Lung Institute, Imperial College London, London, United KingdomNIHR Imperial Biomedical Research Centre, London, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Antonia Ho, Antonia Ho MRC-university of Glasgow Centre For Virus Research, Glasgow, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Richard Orton, Richard Orton MRC-university of Glasgow Centre For Virus Research, Glasgow, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Rachel Tayler, Rachel Tayler Royal Hospital for Children, Glasgow, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Patawee Asamaphan, Patawee Asamaphan MRC-university of Glasgow Centre For Virus Research, Glasgow, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Vanessa Herder, Vanessa Herder MRC-university of Glasgow Centre For Virus Research, Glasgow, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Chris Davis, Chris Davis MRC-university of Glasgow Centre For Virus Research, Glasgow, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Lily Tong, Lily Tong MRC-university of Glasgow Centre For Virus Research, Glasgow, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Katherine Smollett, Katherine Smollett MRC-university of Glasgow Centre For Virus Research, Glasgow, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Louisa Pollock, Louisa Pollock Royal Hospital for Children, Glasgow, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Clair Evans, Clair Evans Queen Elizabeth University Hospital, Glasgow, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Jim McMenamin, Jim McMenamin Public Health Scotland, Glasgow, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Kirsty Roy, Kirsty Roy Public Health Scotland, Glasgow, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Kimberly Marsh, Kimberly Marsh Public Health Scotland, Glasgow, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Titus Divala, Titus Divala Public Health Scotland, Glasgow, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Matt Holden, Matt Holden Public Health Scotland, Glasgow, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Michael Lockhart, Michael Lockhart Public Health Scotland, Glasgow, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Samantha Shepherd, Samantha Shepherd West of Scotland Specialist Virology Centre, Glasgow, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Celia Jackson, Celia Jackson West of Scotland Specialist Virology Centre, Glasgow, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Rory Gunson, Rory Gunson West of Scotland Specialist Virology Centre, Glasgow, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Alasdair MacLean, Alasdair MacLean West of Scotland Specialist Virology Centre, Glasgow, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Paul Henderson, Paul Henderson Department of Child Life and Health, University of Edinburgh, Edinburgh, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Meera Chand, Meera Chand UK Health Security Agency, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Michael Levin, Michael Levin Department of Infectious Disease, Imperial College London, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Massimo Palmarini, Massimo Palmarini MRC-university of Glasgow Centre For Virus Research, Glasgow, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar David Robertson, David Robertson MRC-university of Glasgow Centre For Virus Research, Glasgow, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Ana da Silva Filipe, Ana da Silva Filipe MRC-university of Glasgow Centre For Virus Research, Glasgow, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Brian Willett, Brian Willett MRC-university of Glasgow Centre For Virus Research, Glasgow, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Judith Breuer, Judith Breuer University College London, London, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Malcolm Semple, Malcolm Semple Pandemic Institute, University of Liverpool, Liverpool, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar David Turner, David Turner Scottish National Blood Transfusion Service, Edinburgh Royal Infirmary, Edinburgh, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Kenneth Baillie, Kenneth Baillie Centre for Inflammation Research and Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Emma Thomson, Emma Thomson MRC-university of Glasgow Centre For Virus Research, Glasgow, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Elsie Horne, Elsie Horne University of Bristol, Bristol, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar William Hulme, William Hulme University of Oxford, Oxford, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Ruth Keogh, Ruth Keogh London School of Hygiene and Tropical Medicine, London, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Tom Palmer, Tom Palmer University of Oxford, Oxford, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Elizabeth Williamson, Elizabeth Williamson London School of Hygiene and Tropical Medicine, London, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Edward Parker, Edward Parker London School of Hygiene and Tropical Medicine, London, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Venexia Walker, Venexia Walker University of Bristol, Bristol, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar The OpenSAFELYCollaborative, The OpenSAFELYCollaborative Search for other works by this author on: Oxford Academic PubMed Google Scholar Ben Goldacre, Ben Goldacre University of Oxford, Oxford, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Miguel Hernán, Miguel Hernán Harvard, Boston, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Jonathan Sterne, Jonathan Sterne University of Bristol, Bristol, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Jeremy Schofield, Jeremy Schofield University of Liverpool, Liverpool, United KingdomLiverpool University Hospital Foundation Trust, Liverpool, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Simon Abrams, Simon Abrams University of Liverpool, Liverpool, United KingdomLiverpool University Hospital Foundation Trust, Liverpool, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Yasir Alhamdi, Yasir Alhamdi University of Liverpool, Liverpool, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Keirah Bartlett, Keirah Bartlett Liverpool School of Tropical Medicine, Liverpool, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Steve Hall, Steve Hall Liverpool School of Tropical Medicine, Liverpool, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Guozheng Wang, Guozheng Wang University of Liverpool, Liverpool, United KingdomLiverpool University Hospital Foundation Trust, Liverpool, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Nicholas Casewell, Nicholas Casewell Liverpool School of Tropical Medicine, Liverpool, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Cheng-Hock Toh, Cheng-Hock Toh University of Liverpool, Liverpool, United KingdomLiverpool University Hospital Foundation Trust, Liverpool, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Ashkan Dashtban, Ashkan Dashtban University College London Search for other works by this author on: Oxford Academic PubMed Google Scholar Mehrdad Mizani, Mehrdad Mizani University College London Search for other works by this author on: Oxford Academic PubMed Google Scholar Laura Pasea, Laura Pasea University College London Search for other works by this author on: Oxford Academic PubMed Google Scholar Spiros Denaxas, Spiros Denaxas University College London Search for other works by this author on: Oxford Academic PubMed Google Scholar Richard Corbett, Richard Corbett Imperial College Healthcare NHS Trust Search for other works by this author on: Oxford Academic PubMed Google Scholar Jilbilly Mamza, Jilbilly Mamza Astra Zeneca Search for other works by this author on: Oxford Academic PubMed Google Scholar He Gao, He Gao Astra Zeneca Search for other works by this author on: Oxford Academic PubMed Google Scholar Tamsin Morris, Tamsin Morris Astra Zeneca Search for other works by this author on: Oxford Academic PubMed Google Scholar Harry Hemingway, Harry Hemingway University College London Search for other works by this author on: Oxford Academic PubMed Google Scholar Amitava Banerjee, Amitava Banerjee University College London Search for other works by this author on: Oxford Academic PubMed Google Scholar Zahra Raisi-Estabragh, Zahra Raisi-Estabragh William Harvey Research Institute, NIHR Barts Biomedical Research Centre, Queen Mary University of London, Charterhouse SquareBarts Heart Centre, St Bartholomew’s Hospital, Barts Health NHS Trust Search for other works by this author on: Oxford Academic PubMed Google Scholar Maddalena Ardissino, Maddalena Ardissino National Heart and Lung Institute, Imperial College LondonHeart and Lung Research Institute, University of Cambridge Search for other works by this author on: Oxford Academic PubMed Google Scholar Andrew Bard, Andrew Bard William Harvey Research Institute, NIHR Barts Biomedical Research Centre, Queen Mary University of London, Charterhouse Square Search for other works by this author on: Oxford Academic PubMed Google Scholar Liliana Szabo, Liliana Szabo William Harvey Research Institute, NIHR Barts Biomedical Research Centre, Queen Mary University of London, Charterhouse SquareSemmelweis University, Heart and Vascular Center Search for other works by this author on: Oxford Academic PubMed Google Scholar Ahmed Salih, Ahmed Salih William Harvey Research Institute, NIHR Barts Biomedical Research Centre, Queen Mary University of London, Charterhouse Square Search for other works by this author on: Oxford Academic PubMed Google Scholar Celeste McCracken, Celeste McCracken Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust Search for other works by this author on: Oxford Academic PubMed Google Scholar Esmeralda Ruiz, Esmeralda Ruiz Departament de Matemàtiques i Informàtica, Universitat de Barcelona, Artificial Intelligence in Medicine Lab (BCN-AIM) Search for other works by this author on: Oxford Academic PubMed Google Scholar Andre Altman, Andre Altman Department of Medical Physics and Biomedical Engineering, Centre for Medical Image Computing (CMIC) Search for other works by this author on: Oxford Academic PubMed Google Scholar Charalambos Antoniades, Charalambos Antoniades Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust Search for other works by this author on: Oxford Academic PubMed Google Scholar Stefan Neubauer, Stefan Neubauer Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust Search for other works by this author on: Oxford Academic PubMed Google Scholar Karim Lekadir, Karim Lekadir Departament de Matemàtiques i Informàtica, Universitat de Barcelona, Artificial Intelligence in Medicine Lab (BCN-AIM) Search for other works by this author on: Oxford Academic PubMed Google Scholar Steffen Petersen, Steffen Petersen William Harvey Research Institute, NIHR Barts Biomedical Research Centre, Queen Mary University of London, Charterhouse SquareBarts Heart Centre, St Bartholomew’s Hospital, Barts Health NHS TrustHealth Data ResearchAlan Turing Institute Search for other works by this author on: Oxford Academic PubMed Google Scholar Jennifer Lees, Jennifer Lees University of Glasgow, Scotland Search for other works by this author on: Oxford Academic PubMed Google Scholar Jamie Crowther, Jamie Crowther University of Glasgow, Scotland Search for other works by this author on: Oxford Academic PubMed Google Scholar Peter Hanlon, Peter Hanlon University of Glasgow, Scotland Search for other works by this author on: Oxford Academic PubMed Google Scholar Elaine Butterly, Elaine Butterly University of Glasgow, Scotland Search for other works by this author on: Oxford Academic PubMed Google Scholar Sarah Wild, Sarah Wild University of Glasgow, Scotland Search for other works by this author on: Oxford Academic PubMed Google Scholar Frances Mair, Frances Mair University of Glasgow, Scotland Search for other works by this author on: Oxford Academic PubMed Google Scholar Bruce Guthrie, Bruce Guthrie University of Glasgow, Scotland Search for other works by this author on: Oxford Academic PubMed Google Scholar Katie Gillies, Katie Gillies University of Glasgow, Scotland Search for other works by this author on: Oxford Academic PubMed Google Scholar Sophie Dias, Sophie Dias University of Glasgow, Scotland Search for other works by this author on: Oxford Academic PubMed Google Scholar Nicky Welton, Nicky Welton University of Glasgow, Scotland Search for other works by this author on: Oxford Academic PubMed Google Scholar David McAllister, David McAllister University of Glasgow, Scotland Search for other works by this author on: Oxford Academic PubMed Google Scholar Freddy Frost, Freddy Frost University of LiverpoolAdult CF Centre Liverpool Heart & Chest Hospital NHS Foundation TrustLiverpool Centre for Cardiovascular Sciences Search for other works by this author on: Oxford Academic PubMed Google Scholar Dilip Nazareth, Dilip Nazareth University of LiverpoolAdult CF Centre Liverpool Heart & Chest Hospital NHS Foundation Trust Search for other works by this author on: Oxford Academic PubMed Google Scholar Dennis Wat, Dennis Wat University of LiverpoolAdult CF Centre Liverpool Heart & Chest Hospital NHS Foundation Trust Search for other works by this author on: Oxford Academic PubMed Google Scholar Martin Walshaw, Martin Walshaw University of LiverpoolAdult CF Centre Liverpool Heart & Chest Hospital NHS Foundation Trust Search for other works by this author on: Oxford Academic PubMed Google Scholar Gregory Lip, Gregory Lip University of LiverpoolLiverpool Centre for Cardiovascular SciencesDepartment of Cardiology, Liverpool Heart & Chest Hospital NHS Foundation Trust Search for other works by this author on: Oxford Academic PubMed Google Scholar Tin Orešković, Tin Orešković Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, Big Data Institute, University of Oxford, Oxford, OX3 7LF Search for other works by this author on: Oxford Academic PubMed Google Scholar Derrick Bennett, Derrick Bennett Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, Big Data Institute, University of Oxford, Oxford, OX3 7LFMedical Research Council Population Health Research, Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF Search for other works by this author on: Oxford Academic PubMed Google Scholar Ben Lacey, Ben Lacey Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, Big Data Institute, University of Oxford, Oxford, OX3 7LF Search for other works by this author on: Oxford Academic PubMed Google Scholar Sarah Lewington, Sarah Lewington Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, Big Data Institute, University of Oxford, Oxford, OX3 7LFMedical Research Council Population Health Research, Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF Search for other works by this author on: Oxford Academic PubMed Google Scholar Sofia Massa, Sofia Massa Oxford Clinical Trials Research Unit, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, OX3 7LD Search for other works by this author on: Oxford Academic PubMed Google Scholar Philip Bath, Philip Bath University of Nottingham, Nottingham, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Joanna Wardlaw, Joanna Wardlaw University of Edinburgh, Edinburgh, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Gashirai Mbizvo, Gashirai Mbizvo From the The University of Liverpool, Liverpool, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Christian Schnier, Christian Schnier The University of Edinburgh, Edinburgh, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Colin Simpson, Colin Simpson Victoria University of Wellington Search for other works by this author on: Oxford Academic PubMed Google Scholar Richard Chin, Richard Chin The University of Edinburgh, Edinburgh, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Susan Duncan, Susan Duncan The University of Edinburgh, Edinburgh, United Kingdom Search for other works by this author on: Oxford Academic PubMed Google Scholar Greta K Wood, Greta K Wood Institute of Infection Veterinary And Ecological Sciences, University of Liverpool, Liverpool, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar K Tharmaratnam, K Tharmaratnam Department of Health Data Science, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar B Sargent, B Sargent Institute of Infection Veterinary And Ecological Sciences, University of Liverpool, Liverpool, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Z Ahmad, Z Ahmad Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar S Pendered, S Pendered Institute of Infection Veterinary And Ecological Sciences, University of Liverpool, Liverpool, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Hc Rogers, Hc Rogers Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar D van Wamelen, D van Wamelen Department of Neuroimaging, Institute of Psychiatry Psychology and Neuroscience, King’s College London, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar C Dunai, C Dunai Institute of Infection Veterinary And Ecological Sciences, University of Liverpool, Liverpool, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar N Martin, N Martin Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar D K Menon, D K Menon Division of Anaesthesia, University of Cambridge, Cambridge, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar J P Taylor, J P Taylor Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar A David, A David Institute of Mental Health, Division of Psychiatry, University College London, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar J P Aggleton, J P Aggleton School of Psychology, Cardiff University, Cardiff, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar A Carson, A Carson Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar N Harrison, N Harrison Cardiff University Brain Research Imaging Centre, Cardiff University, Cardiff, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar T Jackson, T Jackson Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar T Nicholson, T Nicholson Institute of Psychiatry Psychology & Neuroscience, King’s College London, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar G Breen, G Breen Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar A Hampshire, A Hampshire Department of Brain Sciences, Faculty of Medicine, Imperial College London, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar B D Michael, B D Michael Institute of Infection Veterinary And Ecological Sciences, University of Liverpool, Liverpool, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar S M Paddick, S M Paddick Faculty of Medical Science, University of Newcastle, Newcastle, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar C Leek C Leek Institute of Population Health, University of Liverpool, Liverpool, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar QJM: An International Journal of Medicine, hcad072, https://doi.org/10.1093/qjmed/hcad072 Published: 07 July 2023

Objective We investigated whether further characterisation of full-length (f-) GADA responses could identify early insulin requirement in adult-onset diabetes. Research Design and Methods In 179 f-GADA positive participants diagnosed with type 2 diabetes, we assessed the association of truncated (t-)GADA positivity, f-GADA IgG subclasses, and f-GADA IgG affinity with early insulin requirement (<5 years), type 1 diabetes genetic risk score (T1D GRS), and C-peptide. These characteristics were compared to f-GADA positive type 1 diabetes (n=141) and f-GADA negative type 2 diabetes (n=6420) cohorts. Results t-GADA positivity was lower in f-GADA positive without early insulin in comparison to f-GADA positive type 2 diabetes requiring insulin within 5 years, and type 1 diabetes (75% vs. 91% and 95% respectively, p<0.0001). t-GADA positivity (in those f-GADA positive) identified a group with a higher type 1 diabetes genetic susceptibility (mean T1D GRS 0.248 vs. 0.225, p=0.003), lower C-peptide (1156 pmol/L vs. 4289 pmol/L, p=1x10-7), and increased IA-2A positivity (23% vs. 6%, p=0.03). In survival analysis, t-GADA positivity was associated with early insulin requirement compared with those only positive for f-GADA, independently from age of diagnosis, f-GADA titre and duration of diabetes [adjusted HR 5.7 (95% CI 1.4, 23.5), p=0.017]. Early insulin requirement was not associated with an IgG1-restricted f-GADA response (p=0.81) or a high affinity f-GADA response (p=0.89). Conclusions The testing of t-GADA in f-GADA positive individuals with type 2 diabetes identifies those who have genetic and clinical characteristics comparable to type 1 diabetes and stratifies those at higher risk of early insulin requirement.

Background: Zinc transporter 8 autoantibodies (ZnT8A) are thought to appear close to type 1 diabetes (T1D) onset and can identify high-risk multiple (>= 2) autoantibody positive individuals. Radiobinding assays (RBA) are widely used for ZnT8A measurement but have limited sustainability. We sought to develop a novel, high-performance, non-radioactive luciferase immunoprecipitation system (LIPS) assay to replace RBA. Methods: A custom dual C-terminal ZnT8 (aa268-369; R325/W325) heterodimeric antigen, tagged with a Nanoluciferase (TM) (Nluc-ZnT8) reporter, and LIPS assay was developed. Assay performance was evaluated by testing sera from new onset T1D (n = 573), healthy schoolchildren (n = 521), and selected first-degree relatives (FDRs) from the Bart's Oxford family study (n = 617; 164 progressed to diabetes). Results: In new-onset T1D, ZnT8A levels by LIPS strongly correlated with RBA (Spearman's r = 0.89; P < 0.0001), and positivity was highly concordant (94.3%). At a high specificity (95%), LIPS and RBA had comparable assay performance [LIPS pROC-AUC(95) 0.032 (95% CI: 0.029-0.036); RBA pROC-AUC(95) 0.031 (95% CI: 0.028-0.034); P = 0.376]. Overall, FDRs found positive by LIPS or RBA had a comparable 20-year diabetes risk (52.6% and 59.7%, respectively), but LIPS positivity further stratified T1D risk in FDRs positive for at least one other islet autoantibody detected by RBA (P = 0.0346). Conclusion: This novel, high-performance, cheaper, quicker, higher throughput, low blood volume Nluc-ZnT8 LIPS assay is a safe, non-radioactive alternative to RBA with enhanced sensitivity and ability to discriminate T1D progressors. This method offers an advanced approach to current strategies to screen the general population for T1D risk for immunotherapy trials and to reduce rates of diabetic ketoacidosis at diagnosis.

Aims Some childhood type 1 diabetes cases are islet autoantibody negative at diagnosis. Potential explanations include misdiagnosis of genetic forms of diabetes or insufficient islet autoantibody testing. Many NHS laboratories offer combinations of three autoantibody markers. We sought to determine the benefit of testing for additional islet autoantibodies, including insulin (IAA) and tetraspanin 7 (TSPAN7A). Methods Radiobinding assays (RBAs) were used to test for four islet autoantibodies in children with newly diagnosed type 1 diabetes (n = 486; 54.1% male; median age 10.4 years [range 0.7-18.0]; median duration 1 day [range -183 to 14]). Islet autoantibody negative children were tested for TSPAN7A using a luminescence-based test. Where available, islet cell antibody (ICA) and human leucocyte antigen (HLA) data were considered. Results Using three autoantibody markers, 21/486 (4.3%) children were autoantibody negative. Testing for IAA classified a further 9/21 (42.9%) children as autoantibody positive. Of the remaining 12 (2.5%) autoantibody negative children, all were TPAN7A negative, seven were ICA negative and one was positive for the protective variant DQB1*0602. One was subsequently diagnosed with Maturity Onset of Diabetes in the Young, but follow-up was not available in all cases. Conclusions Using highly sensitive assays, testing for three autoantibodies fails to detect islet autoimmunity in approximately 1/20 children diagnosed with type 1 diabetes. Testing for IAA in children 10 years was the most effective strategy for detecting islet autoimmunity. The ability to test for all islet autoantibodies should inform clinical decisions and make screening for monogenic diabetes more cost-effective.

The presence of islet autoantibodies remains a reliable biomarker to identify individuals at high risk of developing type 1 diabetes. As such, these autoantibodies play a pivotal role in understanding the prodrome of diabetes and selecting individuals for both prevention and intervention clinical trials. Over the last few decades, studies have sought to investigate autoantibody prevalence after diabetes onset to better understand ongoing islet autoimmunity; however, many findings are contradictory, and little is known about factors that may influence autoantibody persistence. Generally, glutamate decarboxylase autoantibodies (GADAs) are the most prevalent autoantibodies after diagnosis, particularly in adults, whilst zinc transporter 8 autoantibodies (ZnT8A) prevalence declines more rapidly. However, when studies with islet autoantibody data at diagnosis are considered, it becomes clear that overall islet antigen‐2 autoantibodies (IA‐2A) tend to persist for longer than GADA or ZnT8A. In this review, we assess the major studies that have contributed to our understanding of autoantibody persistence after diabetes onset and what factors affect this. Islet autoantibodies may provide biomarkers for long‐term β‐cell function and insights into how to prevent ongoing islet autoimmunity but larger studies collecting samples at and decades after diabetes onset are required to leverage the information they could provide.

Zinc transporter 8 (ZnT8), a protein highly specific to pancreatic insulin-producing beta cells, is vital for the biosynthesis and secretion of insulin. ZnT8 autoantibodies (ZnT8A) are among the most recently discovered and least-characterised islet autoantibodies. In combination with autoantibodies to several other islet antigens, including insulin, ZnT8A help predict risk of future type 1 diabetes. Often, ZnT8A appear later in the pathogenic process leading to type 1 diabetes, suggesting that the antigen is recognised as part of the spreading, rather than the initial, autoimmune response. The development of autoantibodies to different forms of ZnT8 depends on the genotype of an individual for a polymorphic ZnT8 residue. This genetic variant is associated with susceptibility to type 2 but not type 1 diabetes. Levels of ZnT8A often fall rapidly after diagnosis while other islet autoantibodies can persist for many years. In this review, we consider the contribution made by ZnT8 to our understanding of type 1 diabetes over the past decade and what remains to be investigated in future research.

Context: Insulin autoimmune syndrome (IAS), spontaneous hyperinsulinemic hypoglycemia due to insulin-binding autoantibodies, may be difficult to distinguish from tumoral or other forms of hyperinsulinemic hypoglycemia, including surreptitious insulin administration. No standardized treatment regimen exists. Objectives: To evaluate an analytic approach to IAS and responses to different treatments. Design and Setting: Observational study in the UK Severe Insulin Resistance Service. Patients: Six patients with hyperinsulinemic hypoglycemia and detectable circulating anti-insulin antibody (IA). Main Outcome Measures: Glycemia, plasma insulin, and C-peptide concentrations by immunoassay or mass spectrometry (MS). Immunoreactive insulin was determined in the context of polyethylene glycol (PEG) precipitation and gel filtration chromatography (GFC). IA quantification using ELISA and RIA, and IA were further characterized using radioligand binding studies. Results: All patients were diagnosed with IAS (five IgG, one IgA) based on a high insulin/C-peptide ratio, low insulin recovery after PEG precipitation, and GFC evidence of antibody-bound insulin. Neither ELISA nor RIA result proved diagnostic for every case. MS provided a more robust quantification of insulin in the context of IA. One patient was managed conservatively, four were treated with diazoxide without sustained benefit, and four were treated with immunosuppression with highly variable responses. IA affinity did not appear to influence presentation or prognosis. Conclusions: IAS should be considered in patients with hyperinsulinemic hypoglycemia and a high insulin/C-peptide ratio. Low insulin recovery on PEG precipitation supports the presence of insulin-binding antibodies, with GFC providing definitive confirmation. Immunomodulatory therapy should be customized according to individual needs and clinical response.