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, Robin N Beaumont, Jessica Tyrrell, Grace Marion Power, Andrew R Wood, Markku Laakso, Lilian Fernandes Silva, Michael Boehnke, Xianyong Yin, Tom G Richardson, George Davey Smith, Tim M Frayling*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

3 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1472-1480
Number of pages9
JournalDiabetologia
Volume66
Issue number8
Early online date6 Jun 2023
DOIs
Publication statusPublished - 1 Aug 2023

Bibliographical note

Funding Information:
We wish to acknowledge the participants and investigators of the FinnGen, METSIM, 1958NCDS and UK Biobank studies. This manuscript is part of the Stratification of Obesity Phenotypes to Optimise Future Obesity Therapy (SOPHIA) project ( www.imisophia.eu ). The SOPHIA project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement number 875534. This joint undertaking receives support from the European Union’s Horizon 2020 research and innovation programme, the European Federation of Pharmaceutical Industries and Associations, the T1D Exchange, JDRF and Obesity Action Coalition. The research utilised data from the UK Biobank resource carried out under UK Biobank application number 9072. UK Biobank protocols were approved by the National Research Ethics Service Committee. The authors would like to thank the Exeter Sequencing service for carrying out the RNA sequencing. The authors would also like to acknowledge use of the University of Exeter High-Performance Computing Facility for carrying out this work. This study was supported by the National Institute for Health and Care Research Exeter Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Neither the Innovative Medicine Initiative nor the European Union, the European Federation of Pharmaceutical Industries and Associations or any associated partners are responsible for any use that may be made of the information contained therein.

Funding Information:
GH has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement number 875534. JT is supported by an Academy of Medical Sciences Springboard award, which is supported by the Academy of Medical Sciences, the Wellcome Trust, the global Challenges Research Fund, the UK Government Department of Business, Energy and Industrial Strategy, the British Heart Foundation and Diabetes UK (SBF004\1079). TGR and GDS work within the MRC Integrative Epidemiology Unit at the University of Bristol supported by the Medical Research Council (MC UU 00011/1). The equipment utilised is funded by the Wellcome Trust Institutional Strategic Support Fund (WT097835 MF), a Wellcome Trust Multi-User Equipment Award (WT101650 MA) and a Biotechnology and Biological Science Research Council LoLa award (BB/K003240/1). The high-performance computing was funded by a Medical Research Council Clinical Research Infrastructure award (MR/M008924/1). TMF is supported by MRC awards MR/WO14548/1 and MR/T002239/1. MB, XY and ML are supported by NIH grant DK062370.

Publisher Copyright:
© 2023, The Author(s).

Structured keywords

  • Bristol Population Health Science Institute

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