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. 2023 Aug;66(8):1472-1480.
doi: 10.1007/s00125-023-05923-6. Epub 2023 Jun 6.

Genetic evidence that high BMI in childhood has a protective effect on intermediate diabetes traits, including measures of insulin sensitivity and secretion, after accounting for BMI in adulthood

Gareth Hawkes  1 , Robin N Beaumont  1 , Jessica Tyrrell  1 , Grace M Power  2 , Andrew Wood  1 , Markku Laakso  3 , Lilian Fernandes Silva  3 , Michael Boehnke  4 , Xianyong Yin  4 , Tom G Richardson  2 , George Davey Smith  2 , Timothy M Frayling  5
Affiliations

Genetic evidence that high BMI in childhood has a protective effect on intermediate diabetes traits, including measures of insulin sensitivity and secretion, after accounting for BMI in adulthood

Gareth Hawkes et al. Diabetologia. 2023 Aug.

Abstract

Aims/hypothesis: Determining how high BMI at different time points influences the risk of developing type 2 diabetes and affects insulin secretion and insulin sensitivity is critical.

Methods: By estimating childhood BMI in 441,761 individuals in the UK Biobank, we identified which genetic variants had larger effects on adulthood BMI than on childhood BMI, and vice versa. All genome-wide significant genetic variants were then used to separate the independent genetic effects of high childhood BMI from those of high adulthood BMI on the risk of type 2 diabetes and insulin-related phenotypes using Mendelian randomisation. We performed two-sample MR using external studies of type 2 diabetes, and oral and intravenous measures of insulin secretion and sensitivity.

Results: We found that a childhood BMI that was one standard deviation (1.97 kg/m2) higher than the mean, corrected for the independent genetic liability to adulthood BMI, was associated with a protective effect for seven measures of insulin sensitivity and secretion, including increased insulin sensitivity index (β=0.15; 95% CI 0.067, 0.225; p=2.79×10-4) and reduced fasting glucose levels (β=-0.053; 95% CI -0.089, -0.017; p=4.31×10-3). However, there was little to no evidence of a direct protective effect on type 2 diabetes (OR 0.94; 95% CI 0.85, 1.04; p=0.228) independently of genetic liability to adulthood BMI.

Conclusions/interpretation: Our results provide evidence of the protective effect of higher childhood BMI on insulin secretion and sensitivity, which are crucial intermediate diabetes traits. However, we stress that our results should not currently lead to any change in public health or clinical practice, given the uncertainty regarding the biological pathway of these effects and the limitations of this type of study.

Keywords: Adulthood; BMI; Childhood; Diabetes; Genetics; Mendelian randomisation.

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Figures

Fig. 1
Fig. 1
Directed acyclic graph illustrating assumed causal relationship between childhood and adulthood BMI. Solid red and blue arrows indicate causality, unidirectional blue dashed arrows represent non-causal effects, and the double-ended blue dashed arrows indicate a covariance structure
Fig. 2
Fig. 2
Univariable MR meta-analysis results (red lines and symbols) and MVMR meta-analysis results (blue lines and symbols) for (a) childhood BMI and (b) adulthood BMI vs oral glucose tolerance test traits: AUC; corrected insulin response (CIR); ratio of insulin and glucose AUCs (AUC ratio); insulin after 30 min adjusted for BMI [Ins 30 (BMI adj)]; insulin after 30 min (Ins 30); insulin change after 30 min (incremental Ins 30); and insulin sensitivity index (ISI). Filled symbols indicate p<0.05
Fig. 3
Fig. 3
Univariable MR results (red lines and symbols) and MVMR results (blue lines and symbols) for the association between (a) childhood BMI and (b) adulthood BMI and FI and FG levels. Filled symbols indicate p<0.05
Fig. 4
Fig. 4
Univariable MR results (turquoise lines and symbols) and MVMR results (red/blue lines and symbols) for the association between childhood BMI and adulthood BMI and type 2 diabetes as measured in the present meta-analysis (diamonds), the study by Mahajan et al [16] (squares) and the FinnGen study [17] (circles). Filled symbols indicate p<0.05
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References

    1. Hannon TS, Rao G, Arslanian SA. Childhood obesity and type 2 diabetes mellitus. Pediatrics. 2005;116(2):473–480. doi: 10.1542/peds.20042536. - DOI - PubMed
    1. Bjerregaard LG, Jensen BW, Angquist L, Osler M, Sørensen TIA, Baker JL. Change in overweight from childhood to early adulthood and risk of type 2 diabetes. N Engl J Med. 2018;378(14):1302–1312. doi: 10.1056/nejmoa1713231. - DOI - PubMed
    1. Davey Smith G, Ebrahim S. ‘Mendelian randomization’: can genetic epidemiology contribute to understanding environmental determinants of disease? Int J Epidemiol. 2003;32(1):1–22. doi: 10.1093/ije/dyg070. - DOI - PubMed
    1. Richardson TG, Sanderson E, Elsworth B, Tilling K, Davey Smith G. Use of genetic variation to separate the effects of early and later life adiposity on disease risk: Mendelian randomisation study. BMJ. 2020;369:1–12. doi: 10.1136/bmj.m1203. - DOI - PMC - PubMed
    1. Power C, Elliott J. Cohort profile: 1958 British birth cohort (National Child Development Study) Int J Epidemiol. 2006;35(1):34–41. doi: 10.1093/ije/dyi183. - DOI - PubMed

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