The measurement of autoantibodies to insulin informs diagnosis of diabetes in a childhood population negative for other autoantibodies

Claire L Williams; Rachel J Aitken; Isabel V Wilson; Georgina L M Mortimer; Anna E Long; Alistair J K Williams; Kathleen M Gillespie

doi:10.1111/dme.14979

The measurement of autoantibodies to insulin informs diagnosis of diabetes in a childhood population negative for other autoantibodies

Claire L Williams^*, Rachel J Aitken, Isabel V Wilson, Georgina L M Mortimer, Anna E Long, Alistair J K Williams, Kathleen M Gillespie

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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Abstract

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 -183-14.0)]. Islet autoantibody negative children were tested for TSPAN7A using a luminescence-based test. Where available, islet cell antibody (ICA) and human leukocyte 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 <5 years and GADA in those >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.

Original language	English
Article number	e14979
Number of pages	10
Journal	Diabetic Medicine
Volume	39
Issue number	12
Early online date	17 Oct 2022
DOIs	https://doi.org/10.1111/dme.14979
Publication status	Published - 15 Nov 2022

Bibliographical note

Funding Information:
The authors thank the diabetes teams and the families participating in the BOX study, without whom this work would not be possible. Some of the data were presented as an abstract at the Diabetes UK Professional Conference 2022. The BOX Study Group is comprised of Drs Chitrabhanu Ballav, Atanu Dutta, and Michelle Russell-Taylor, Bucks Healthcare Trust, UK; Dr Rachel Besser, Oxford University Hospitals Trust UK, UK; Drs James Bursell and Shanthi Chandran, Milton Keynes University Hospital, UK, Dr Sejal Patel, Wexham Park Hospital, UK; Drs Anne Smith and Manohara Kenchaiah, Northampton General Hospital, UK; Dr Gomathi Margabanthu, Kettering General Hospital, UK; Drs Foteini Kavvoura and Chandan Yaliwal, Royal Berkshire Hospital, UK. We are grateful to Diabetes UK for providing financial support to KMG for The Bart's Oxford study (14/0004869 and 20/0006300), jointly funding AEL with JDRF via an RD Lawrence Fellowship (18/0005778 and 3-APF-2018-591-A-N), funding a PhD studentship and postdoctoral awards for CLW (16/0005556 and 21/0006332), and funding towards accredited use of cost-effective islet autoantibody tests (20/0006300).

Funding Information:
The authors thank the diabetes teams and the families participating in the BOX study, without whom this work would not be possible. Some of the data were presented as an abstract at the Diabetes UK Professional Conference 2022. The BOX Study Group is comprised of Drs Chitrabhanu Ballav, Atanu Dutta, and Michelle Russell‐Taylor, Bucks Healthcare Trust, UK; Dr Rachel Besser, Oxford University Hospitals Trust UK, UK; Drs James Bursell and Shanthi Chandran, Milton Keynes University Hospital, UK, Dr Sejal Patel, Wexham Park Hospital, UK; Drs Anne Smith and Manohara Kenchaiah, Northampton General Hospital, UK; Dr Gomathi Margabanthu, Kettering General Hospital, UK; Drs Foteini Kavvoura and Chandan Yaliwal, Royal Berkshire Hospital, UK. We are grateful to Diabetes UK for providing financial support to KMG for The Bart's Oxford study (14/0004869 and 20/0006300), jointly funding AEL with JDRF via an RD Lawrence Fellowship (18/0005778 and 3‐APF‐2018‐591‐A‐N), funding a PhD studentship and postdoctoral awards for CLW (16/0005556 and 21/0006332), and funding towards accredited use of cost‐effective islet autoantibody tests (20/0006300).

Publisher Copyright:
© 2022 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

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10.1111/dme.14979Licence: CC BY

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Measurement of autoantibodies to insulin informs diagnosis of diabetes in a childhood population negative for other autoantibodies
Williams, C. L., 29 Mar 2022, Diabetic Medicine. p. 0742-3071 S1
Research output: Chapter in Book/Report/Conference proceeding › Conference Contribution (Conference Proceeding)

Diabetes UK Basic Science Poster Award 2022 (Runner's Up)
Williams, C. L. (Recipient), 1 Apr 2022
Prize: Prizes, Medals, Awards and Grants

Diabetes UK Professional Conference 2022
Williams, C. L. (Participant)
28 Mar 2022 → 1 Apr 2022
Activity: Participating in or organising an event types › Participation in conference

Cite this

@article{6d90b289f0b14991a9e95767f9e77cdb,

title = "The measurement of autoantibodies to insulin informs diagnosis of diabetes in a childhood population negative for other autoantibodies",

abstract = "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 -183-14.0)]. Islet autoantibody negative children were tested for TSPAN7A using a luminescence-based test. Where available, islet cell antibody (ICA) and human leukocyte 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 <5 years and GADA in those >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.",

author = "Williams, \{Claire L\} and Aitken, \{Rachel J\} and Wilson, \{Isabel V\} and Mortimer, \{Georgina L M\} and Long, \{Anna E\} and Williams, \{Alistair J K\} and Gillespie, \{Kathleen M\}",

note = "Funding Information: The authors thank the diabetes teams and the families participating in the BOX study, without whom this work would not be possible. Some of the data were presented as an abstract at the Diabetes UK Professional Conference 2022. The BOX Study Group is comprised of Drs Chitrabhanu Ballav, Atanu Dutta, and Michelle Russell-Taylor, Bucks Healthcare Trust, UK; Dr Rachel Besser, Oxford University Hospitals Trust UK, UK; Drs James Bursell and Shanthi Chandran, Milton Keynes University Hospital, UK, Dr Sejal Patel, Wexham Park Hospital, UK; Drs Anne Smith and Manohara Kenchaiah, Northampton General Hospital, UK; Dr Gomathi Margabanthu, Kettering General Hospital, UK; Drs Foteini Kavvoura and Chandan Yaliwal, Royal Berkshire Hospital, UK. We are grateful to Diabetes UK for providing financial support to KMG for The Bart's Oxford study (14/0004869 and 20/0006300), jointly funding AEL with JDRF via an RD Lawrence Fellowship (18/0005778 and 3-APF-2018-591-A-N), funding a PhD studentship and postdoctoral awards for CLW (16/0005556 and 21/0006332), and funding towards accredited use of cost-effective islet autoantibody tests (20/0006300). Funding Information: The authors thank the diabetes teams and the families participating in the BOX study, without whom this work would not be possible. Some of the data were presented as an abstract at the Diabetes UK Professional Conference 2022. The BOX Study Group is comprised of Drs Chitrabhanu Ballav, Atanu Dutta, and Michelle Russell‐Taylor, Bucks Healthcare Trust, UK; Dr Rachel Besser, Oxford University Hospitals Trust UK, UK; Drs James Bursell and Shanthi Chandran, Milton Keynes University Hospital, UK, Dr Sejal Patel, Wexham Park Hospital, UK; Drs Anne Smith and Manohara Kenchaiah, Northampton General Hospital, UK; Dr Gomathi Margabanthu, Kettering General Hospital, UK; Drs Foteini Kavvoura and Chandan Yaliwal, Royal Berkshire Hospital, UK. We are grateful to Diabetes UK for providing financial support to KMG for The Bart's Oxford study (14/0004869 and 20/0006300), jointly funding AEL with JDRF via an RD Lawrence Fellowship (18/0005778 and 3‐APF‐2018‐591‐A‐N), funding a PhD studentship and postdoctoral awards for CLW (16/0005556 and 21/0006332), and funding towards accredited use of cost‐effective islet autoantibody tests (20/0006300). Publisher Copyright: {\textcopyright} 2022 The Authors. Diabetic Medicine published by John Wiley \& Sons Ltd on behalf of Diabetes UK.",

year = "2022",

month = nov,

day = "15",

doi = "10.1111/dme.14979",

language = "English",

volume = "39",

journal = "Diabetic Medicine",

issn = "0742-3071",

publisher = "Wiley-Blackwell",

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TY - JOUR

T1 - The measurement of autoantibodies to insulin informs diagnosis of diabetes in a childhood population negative for other autoantibodies

AU - Williams, Claire L

AU - Aitken, Rachel J

AU - Wilson, Isabel V

AU - Mortimer, Georgina L M

AU - Long, Anna E

AU - Williams, Alistair J K

AU - Gillespie, Kathleen M

N1 - Funding Information: The authors thank the diabetes teams and the families participating in the BOX study, without whom this work would not be possible. Some of the data were presented as an abstract at the Diabetes UK Professional Conference 2022. The BOX Study Group is comprised of Drs Chitrabhanu Ballav, Atanu Dutta, and Michelle Russell-Taylor, Bucks Healthcare Trust, UK; Dr Rachel Besser, Oxford University Hospitals Trust UK, UK; Drs James Bursell and Shanthi Chandran, Milton Keynes University Hospital, UK, Dr Sejal Patel, Wexham Park Hospital, UK; Drs Anne Smith and Manohara Kenchaiah, Northampton General Hospital, UK; Dr Gomathi Margabanthu, Kettering General Hospital, UK; Drs Foteini Kavvoura and Chandan Yaliwal, Royal Berkshire Hospital, UK. We are grateful to Diabetes UK for providing financial support to KMG for The Bart's Oxford study (14/0004869 and 20/0006300), jointly funding AEL with JDRF via an RD Lawrence Fellowship (18/0005778 and 3-APF-2018-591-A-N), funding a PhD studentship and postdoctoral awards for CLW (16/0005556 and 21/0006332), and funding towards accredited use of cost-effective islet autoantibody tests (20/0006300). Funding Information: The authors thank the diabetes teams and the families participating in the BOX study, without whom this work would not be possible. Some of the data were presented as an abstract at the Diabetes UK Professional Conference 2022. The BOX Study Group is comprised of Drs Chitrabhanu Ballav, Atanu Dutta, and Michelle Russell‐Taylor, Bucks Healthcare Trust, UK; Dr Rachel Besser, Oxford University Hospitals Trust UK, UK; Drs James Bursell and Shanthi Chandran, Milton Keynes University Hospital, UK, Dr Sejal Patel, Wexham Park Hospital, UK; Drs Anne Smith and Manohara Kenchaiah, Northampton General Hospital, UK; Dr Gomathi Margabanthu, Kettering General Hospital, UK; Drs Foteini Kavvoura and Chandan Yaliwal, Royal Berkshire Hospital, UK. We are grateful to Diabetes UK for providing financial support to KMG for The Bart's Oxford study (14/0004869 and 20/0006300), jointly funding AEL with JDRF via an RD Lawrence Fellowship (18/0005778 and 3‐APF‐2018‐591‐A‐N), funding a PhD studentship and postdoctoral awards for CLW (16/0005556 and 21/0006332), and funding towards accredited use of cost‐effective islet autoantibody tests (20/0006300). Publisher Copyright: © 2022 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.

PY - 2022/11/15

Y1 - 2022/11/15

N2 - 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 -183-14.0)]. Islet autoantibody negative children were tested for TSPAN7A using a luminescence-based test. Where available, islet cell antibody (ICA) and human leukocyte 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 <5 years and GADA in those >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.

AB - 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 -183-14.0)]. Islet autoantibody negative children were tested for TSPAN7A using a luminescence-based test. Where available, islet cell antibody (ICA) and human leukocyte 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 <5 years and GADA in those >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.

U2 - 10.1111/dme.14979

DO - 10.1111/dme.14979

M3 - Article (Academic Journal)

C2 - 36251483

SN - 0742-3071

VL - 39

JO - Diabetic Medicine

JF - Diabetic Medicine

IS - 12

M1 - e14979

ER -

The measurement of autoantibodies to insulin informs diagnosis of diabetes in a childhood population negative for other autoantibodies

Abstract

Bibliographical note

UN SDGs

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Research output

Measurement of autoantibodies to insulin informs diagnosis of diabetes in a childhood population negative for other autoantibodies

Prizes

Diabetes UK Basic Science Poster Award 2022 (Runner's Up)

Activities

Diabetes UK Professional Conference 2022

Cite this