ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2022) 19 10.4 | DOI: 10.1530/ey.19.10.4

ESPEYB19 10. Type 1 Diabetes Mechanisms (1 abstracts)

10.4. Childhood body size directly increases type 1 diabetes risk based on a lifecourse Mendelian randomization approach

Richardson TG , Crouch DJM , Power GM , Morales-Berstein F , Hazelwood E , Fang S , Cho Y , Inshaw JRJ , Robertson CC , Sidore C , Cucca F , Rich SS , Todd JA & Davey Smith G

Nat Commun. 2022 Apr 28;13(1):2337.

Brief Summary: This Mendelian randomization study analysed genetic data from 454,023 individuals from the UK Biobank and 15,573 type 1 diabetes (T1D) cases from other cohorts and provides strong evidence that larger childhood body size increases T1D risk, independently from body size at birth and during adulthood.

Observational studies have suggested a contributing role of obesity to the increasing rates of T1D (1). Several hypotheses have been formulated to explain this association, such as the ‘accelerator hypothesis’, which proposes that increased insulin resistance and insulin demand, related to excess body fat, cause beta cell stress and fragility, apoptosis and early autoimmunity (2). In addition, diets high in fat and carbohydrate and low in fibre can affect the metabolic and immune functions of the gut microbiome, which in turns has been linked to T1D risk (2). However, observational studies are limited in explaining causality because of possible bias from unmeasured confounding factors and reverse causation. Mendelian randomization is an approach using instrumental variable analysis, where genetic variants are used as a non-confounded proxy for the exposure of interest.

This study provides strong support for a link between childhood adiposity and T1D risk. The study also addressed the relationship between childhood obesity and other immune-mediated conditions, such as asthma, eczema and hypothyroidism, to explore if there was a generalizable effect of childhood adiposity on the immune system. Childhood obesity increases risk of these other diseases, but this is likely related to being overweight for many years, given that the effect was attenuated after accounting for adulthood body size.

Although the underlying mechanisms for the association between adiposity and T1D are not fully clear, these data support the existence of a critical window in childhood to mitigate the influence of adiposity on T1D.

These findings, along with previous observational data, strongly emphasize the importance of preventive measures to reduce the related global epidemics of childhood obesity and T1D.

References: 1. Verbeeten KC, Elks CE, Daneman D, Ong KK. Association between childhood obesity and subsequent Type 1 diabetes: a systematic review and meta-analysis. Diabet Med 2011;28:10–8. 2. March CA, Becker DJ, Libman IM. Nutrition and Obesity in the Pathogenesis of Youth-Onset Type 1 Diabetes and Its Complications. Front Endocrinol (Lausanne) 2021;12:622–901.

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