Lean mass, grip strength and risk of type 2 diabetes: a bi-directional Mendelian randomisation study
Muscle mass and strength may protect against type 2 diabetes as a sink for glucose disposal. In randomised controlled trials, resistance training improves glucose metabolism in people with the metabolic syndrome. Whether increasing muscle mass and strength protects against diabetes in the general population is unknown. We assessed the effect of markers of muscle mass and strength on diabetes and glycaemic traits using bi-directional Mendelian randomisation.
Inverse variance weighting estimates were obtained by applying genetic variants that predict male lean mass, female lean mass and grip strength, obtained from the UK Biobank GWAS, to the largest available case–control study of diabetes (DIAbetes Genetics Replication And Meta-analysis [DIAGRAM]; n = 74,124 cases and 824,006 controls) and to a study of glycaemic traits (Meta-Analyses of Glucose and Insulin-related traits Consortium [MAGIC]). Conversely, we also applied genetic variants that predict diabetes, HbA1c, fasting glucose, fasting insulin and HOMA-B to UK Biobank summary statistics for genetic association with lean mass and grip strength. As sensitivity analyses we used weighted median, Mendelian randomisation (MR)-Egger and Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO) and removed pleiotropic SNPs.
Grip strength was not significantly associated with diabetes using inverse variance weighting (OR 0.72 per SD increase in grip strength, 95% CI 0.51, 1.01, p = 0.06) and including pleiotropic SNPs but was significantly associated with diabetes using MR-PRESSO (OR 0.77, 95% CI 0.62, 0.95, p = 0.02) after removing pleiotropic SNPs. Female lean mass was significantly associated with diabetes (OR 0.91, 95% CI 0.84, 0.99, p = 0.02) while male lean mass was not significant but directionally similar (OR 0.94, 95% CI 0.88, 1.01, p = 0.09). Conversely, diabetes was inversely and significantly associated with male lean mass (β −0.02 SD change in lean mass, 95% CI −0.04, −0.00, p = 0.04) and grip strength (β −0.01, 95% CI −0.02, −0.00, p = 0.01).
Increased muscle mass and strength may be related to lower diabetes risk. Diabetes may also be associated with grip strength and lean mass. Muscle strength could warrant further investigation as a possible target of intervention for diabetes prevention.
KeywordsBody composition Diabetes mellitus Grip strength Hand strength Lean mass Mendelian randomisation Muscle Type 2 diabetes
DIAbetes Genetics Replication And Meta-analysis
Genome-wide association study
Instrument Strength Independent of Direct Effect
Meta-Analyses of Glucose and Insulin-related traits Consortium
Mendelian Randomization Pleiotropy RESidual Sum and Outlier
Data on diabetes have been contributed by DIAGRAM investigators and have been downloaded from http://www.diagram-consortium.org. Data on glycaemic traits have been contributed by MAGIC investigators and have been downloaded from www.magicinvestigators.org.
CHCY conducted the literature review and the analysis and drafted the manuscript. SLAY, CMS and SSMF conceptualised ideas and designed the study. SLAY and CMS directed the analytical strategy and supervised the study from conception to completion. SLAY, CMS and SSMF revised drafts of the manuscript. All the authors contributed to the interpretation of the data, critically revising the paper and approval of the final version. CHCY is the guarantor of this work.
This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
- 1.Yoon KH, Lee JH, Kim JW et al (2006) Epidemic obesity and type 2 diabetes in Asia. Lancet (London, England) 368(9548):1681–1688. https://doi.org/10.1016/s0140-6736(06)69703-1
- 2.Wang T, Huang T, Li Y et al (2016) Low birthweight and risk of type 2 diabetes: a Mendelian randomisation study. Diabetologia 59(9):1920–1927. https://doi.org/10.1007/s00125-016-4019-z
- 3.Bann D, Wills A, Cooper R et al (2014) Birth weight and growth from infancy to late adolescence in relation to fat and lean mass in early old age: findings from the MRC National Survey of Health and Development. Int J Obes 38(1):69–75. https://doi.org/10.1038/ijo.2013.115
- 6.Strasser B, Siebert U, Schobersberger W (2010) Resistance training in the treatment of the metabolic syndrome: a systematic review and meta-analysis of the effect of resistance training on metabolic clustering in patients with abnormal glucose metabolism. Sports Med (Auckland, NZ) 40(5):397–415. https://doi.org/10.2165/11531380-000000000-00000 CrossRefGoogle Scholar
- 12.The Neale Lab (2018) GWAS results. Available from http://www.nealelab.is/uk-biobank/, accessed 28 Oct 2018
- 14.UK Biobank (2011) Grip strength measurement. Available from http://biobank.ctsu.ox.ac.uk/crystal/docs/Gripstrength.pdf, accessed 28 Oct 2018
- 15.Howrigan D (2017) Details and considerations of the UK Biobank GWAS. Available from http://www.nealelab.is/blog/2017/9/11/details-and-considerations-of-the-uk-biobank-gwas, accessed 28 Oct 2018
- 17.Visser M, Fuerst T, Lang T, Salamone L, Harris TB (1999) Validity of fan-beam dual-energy X-ray absorptiometry for measuring fat-free mass and leg muscle mass. Health, Aging, and Body Composition Study—Dual-Energy X-ray Absorptiometry and Body Composition Working Group. J Appl Physiol 87(4):1513–1520. https://doi.org/10.1152/jappl.1918.104.22.1683
- 21.Wheeler E, Leong A, Liu C-T et al (2017) Impact of common genetic determinants of hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations: a transethnic genome-wide meta-analysis. PLoS Med 14(9):e1002383. https://doi.org/10.1371/journal.pmed.1002383 CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28(7):412–419. https://doi.org/10.1007/BF00280883 CrossRefPubMedPubMedCentralGoogle Scholar
- 27.Bowden J, Del Greco MF, Minelli C, Davey Smith G, Sheehan NA, Thompson JR (2016) Assessing the suitability of summary data for two-sample Mendelian randomization analyses using MR-Egger regression: the role of the I 2 statistic. Int J Epidemiol 45(6):1961–1974. https://doi.org/10.1093/ije/dyw220 CrossRefPubMedPubMedCentralGoogle Scholar
- 33.Robinson C, Tomek S, Schumacker R (2013) Tests of moderation effects: difference in simple slopes versus the interaction term. Multiple Linear Regression Viewpoints 39:16–25Google Scholar
- 35.R Core Team (2016) R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, AustriaGoogle Scholar
- 38.Gomez-Ambrosi J, Silva C, Galofre JC et al (2011) Body adiposity and type 2 diabetes: increased risk with a high body fat percentage even having a normal BMI. Obesity 19(7):1439–1444. https://doi.org/10.1038/oby.2011.36
- 40.Kalyani RR, Corriere M, Ferrucci L (2014) Age-related and disease-related muscle loss: the effect of diabetes, obesity, and other diseases. Lancet Diabetes Endocrinol 2(10):819–829. https://doi.org/10.1016/s2213-8587(14)70034-8
- 41.Kalyani RR, Saudek CD, Brancati FL, Selvin E (2010) Association of diabetes, comorbidities, and A1C with functional disability in older adults: results from the National Health and Nutrition Examination Survey (NHANES), 1999-2006. Diabetes Care 33(5):1055–1060. https://doi.org/10.2337/dc09-1597 CrossRefPubMedPubMedCentralGoogle Scholar
- 43.Geirsdottir OG, Arnarson A, Briem K, Ramel A, Jonsson PV, Thorsdottir I (2012) Effect of 12-week resistance exercise program on body composition, muscle strength, physical function, and glucose metabolism in healthy, insulin-resistant, and diabetic elderly Icelanders. J Gerontol A Biol Sci Med Sci 67(11):1259–1265. https://doi.org/10.1093/gerona/gls096 CrossRefPubMedGoogle Scholar
- 48.Schooling CM (2018) Selection bias in population-representative studies? A commentary on Deaton and Cartwright. Soc Sci Med. https://doi.org/10.1016/j.socscimed.2018.04.047