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. 2020 Feb;63(2):266-277.
doi: 10.1007/s00125-019-05016-3. Epub 2019 Nov 11.

Autoimmunity plays a role in the onset of diabetes after 40 years of age

Olov Rolandsson  1 , Christiane S Hampe  2 , Stephen J Sharp  3 , Eva Ardanaz  4   5   6 , Heiner Boeing  7 , Guy Fagherazzi  8 , Francesca Romana Mancini  8 , Peter M Nilsson  9 , Kim Overvad  10   11 , Maria-Dolores Chirlaque  5   12 , Miren Dorronsoro  5   13   14 , Marc J Gunter  15 , Rudolf Kaaks  16 , Timothy J Key  17 , Kay-Tee Khaw  18 , Vittorio Krogh  19 , Tilman Kühn  16 , Domenico Palli  20 , Salvatore Panico  21 , Carlotta Sacerdote  22 , Maria-José Sánchez  5   23   24 , Gianluca Severi  25   26 , Annemieke M W Spijkerman  27 , Rosario Tumino  28   29 , Yvonne T van der Schouw  30 , Elio Riboli  31 , Nita G Forouhi  3 , Claudia Langenberg  3 , Nicholas J Wareham  3
Affiliations

Autoimmunity plays a role in the onset of diabetes after 40 years of age

Olov Rolandsson et al. Diabetologia. 2020 Feb.

Abstract

Aims/hypothesis: Type 1 and type 2 diabetes differ with respect to pathophysiological factors such as beta cell function, insulin resistance and phenotypic appearance, but there may be overlap between the two forms of diabetes. However, there are relatively few prospective studies that have characterised the relationship between autoimmunity and incident diabetes. We investigated associations of antibodies against the 65 kDa isoform of GAD (GAD65) with type 1 diabetes and type 2 diabetes genetic risk scores and incident diabetes in adults in European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct, a case-cohort study nested in the EPIC cohort.

Methods: GAD65 antibodies were analysed in EPIC participants (over 40 years of age and free of known diabetes at baseline) by radioligand binding assay in a random subcohort (n = 15,802) and in incident diabetes cases (n = 11,981). Type 1 diabetes and type 2 diabetes genetic risk scores were calculated. Associations between GAD65 antibodies and incident diabetes were estimated using Prentice-weighted Cox regression.

Results: GAD65 antibody positivity at baseline was associated with development of diabetes during a median follow-up time of 10.9 years (HR for GAD65 antibody positive vs negative 1.78; 95% CI 1.43, 2.20) after adjustment for sex, centre, physical activity, smoking status and education. The genetic risk score for type 1 diabetes but not type 2 diabetes was associated with GAD65 antibody positivity in both the subcohort (OR per SD genetic risk 1.24; 95% CI 1.03, 1.50) and incident cases (OR 1.97; 95% CI 1.72, 2.26) after adjusting for age and sex. The risk of incident diabetes in those in the top tertile of the type 1 diabetes genetic risk score who were also GAD65 antibody positive was 3.23 (95% CI 2.10, 4.97) compared with all other individuals, suggesting that 1.8% of incident diabetes in adults was attributable to this combination of risk factors.

Conclusions/interpretation: Our study indicates that incident diabetes in adults has an element of autoimmune aetiology. Thus, there might be a reason to re-evaluate the present subclassification of diabetes in adulthood.

Keywords: Autoantibody; Autoimmunity; Genetic risk score; Incident diabetes; Type 1 diabetes; Type 2 diabetes.

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Figures

Fig. 1
Fig. 1
Violin plots of risk scores according to GAD65 antibody status for (a) type 1 diabetes and (b) type 2 diabetes in the EPIC-InterAct subcohort and incident diabetes cases. n values in (a) are: 12,526 (subcohort, GAD65Ab−), 149 (subcohort, low GAD65Ab+), 104 (subcohort, high GAD65Ab+), 9442 (incident diabetes, GAD65Ab−), 139 (incident diabetes, low GAD65Ab+), and 196 (incident diabetes, high GAD65Ab+). n values in (b) are: 12,249 (subcohort, GAD65Ab−), 146 (subcohort, low GAD65Ab+), 99 (subcohort, high GAD65Ab+), 9126 (incident diabetes, GAD65Ab−) and 135 (incident diabetes, low GAD65Ab+), 192 (incident diabetes, high GAD65Ab+). ‘High’ GAD65Ab+ is defined as GAD65 antibody ≥167.5 U/ml and ‘low’ GAD65Ab+ is defined as GAD65 antibody <167.5 U/ml. GAD65Ab+, GAD65 antibody positive; GAD65Ab−, GAD65 antibody negative; T1D, type 1 diabetes; T2D, type 2 diabetes
Fig. 2
Fig. 2
HRs for incident diabetes comparing GAD65 antibody-positive with GAD65 antibody-negative groups, by country, in the EPIC-InterAct study (Model 2, n = 26,147)
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