Interaction between plasma phospholipid odd-chain fatty acids and GAD65 autoantibodies on the incidence of adult-onset diabetes: the EPIC-InterAct case-cohort study

Abstract

Aims/hypothesis: Islet autoimmunity may progress to adult-onset diabetes. We investigated whether circulating odd-chain fatty acids (OCFA) 15:0 and 17:0, which are inversely associated with type 2 diabetes, interact with autoantibodies against GAD65 (GAD65Ab) on the incidence of adult-onset diabetes.

Methods: We used the European EPIC-InterAct case-cohort study including 11,124 incident adult-onset diabetes cases and a subcohort of 14,866 randomly selected individuals. Adjusted Prentice-weighted Cox regression estimated HRs and 95% CIs of diabetes in relation to 1 SD lower plasma phospholipid 15:0 and/or 17:0 concentrations or their main contributor, dairy intake, among GAD65Ab-negative and -positive individuals. Interactions between tertiles of OCFA and GAD65Ab status were estimated by proportion attributable to interaction (AP).

Results: Low concentrations of OCFA, particularly 17:0, were associated with a higher incidence of adult-onset diabetes in both GAD65Ab-negative (HR 1.55 [95% CI 1.48, 1.64]) and GAD65Ab-positive (HR 1.69 [95% CI 1.34, 2.13]) individuals. The combination of low 17:0 and high GAD65Ab positivity vs high 17:0 and GAD65Ab negativity conferred an HR of 7.51 (95% CI 4.83, 11.69), with evidence of additive interaction (AP 0.25 [95% CI 0.05, 0.45]). Low dairy intake was not associated with diabetes incidence in either GAD65Ab-negative (HR 0.98 [95% CI 0.94, 1.02]) or GAD65Ab-positive individuals (HR 0.97 [95% CI 0.79, 1.18]).

Conclusions/interpretation: Low plasma phospholipid 17:0 concentrations may promote the progression from GAD65Ab positivity to adult-onset diabetes.

Keywords: Diabetes; GAD65Ab; Heptadecanoic; Islet autoimmunity; OCFA; Pentadecanoic.

Fig. 1

HR (95% CI) of incident diabetes in relation to GAD65Ab positivity vs negativity and per 1 SD lower plasma phospholipid 15:0 and/or 17:0 concentrations or dairy product intake, stratified by GAD65Ab status (GAD65Ab negative [n cases=10,735, n non-cases=13,900], GAD65Ab positive [n cases=389, n non-cases=274] and GAD65Ab positive-high [n cases=223, n non-cases=104]. HRs were adjusted for age (underlying time scale), centre (stratified baseline hazard), sex, education level, smoking status, physical activity and BMI. HRs for fatty acids or intake of dairy products were additionally adjusted for total energy intake and intake of alcohol, fruits, vegetables, cereal and cereal products, fish and shellfish, and red and processed meat (g/day)

Fig. 2

HR (95% CI) of incident diabetes in relation to high GAD65Ab positivity (indicated by + −), the lowest tertile of concentrations of plasma phospholipid 15:0 plus 17:0 (a), 15:0 alone (b) or 17:0 alone (c) (indicated by − +), or the combination of high GAD65Ab positivity and the lowest tertile of plasma phospholipid 15:0 and/or 17:0 concentrations (indicated by + +). The reference group is the combination of GAD65Ab negativity and the highest tertile of plasma phospholipid 15:0 and/or 17:0 concentrations (indicated by − −). Analyses were adjusted for age (underlying time scale), centre (stratified baseline hazard), sex, education level, smoking status, physical activity, BMI, total energy intake and intake of alcohol, fruits, vegetables, cereal and cereal products, fish and shellfish, and red and processed meat (g/day)