1 Background
As the prevalence of type 2 diabetes and its precursor state of prediabetes increases [
1], risk reduction strategies to prevent the development of this chronic disease are critical. A recent systematic review and meta-analysis of observational research presented in adults suggested that a one standard deviation increase in muscular strength is associated with a 13% lower risk of type 2 diabetes [
2]. This finding is supported by a Mendelian randomization study that showed SNPs associated with higher grip strength, a proxy of muscular strength, to associate with lower odds of type 2 diabetes [
3]. However, the link between muscular strength and impaired glucose homeostasis, a risk factor for type 2 diabetes, is not limited to adults. Greater childhood muscular strength is associated with lower levels of insulin resistance and beta cell function in adulthood [
4,
5], while findings from a Swedish cohort of male military conscripts showed low muscular strength measured at age 18 years to associate with a 52% increased risk of type 2 diabetes 10–40 years later [
6]. These findings suggest childhood muscular strength, often measured as grip strength, could be a potential early life target for strategies aimed at preventing type 2 diabetes in adulthood. However, previous observational studies have been limited to two time point analyses or had muscular strength data available only at baseline. It is currently unknown how grip strength measured across the life course is associated with type 2 diabetes.
Examining how grip strength associates with prediabetes or type 2 diabetes using life course approaches could inform future prevention strategies [
7]. This association may be reflected by a critical period model, where grip strength at only one life stage is important for prediabetes or type 2 diabetes risk; a sensitive period model, where grip strength measured at one or more life stages has a greater effect on prediabetes or type 2 diabetes risk compared with grip strength at other life stages; or an accumulation model, where grip strength measured across the life course is equally important for the development of prediabetes or type 2 diabetes [
7]. The pattern by which life course grip strength is associated with type 2 diabetes could provide insight into when interventions aimed at preventing type 2 diabetes by targeting muscular strength levels could be most effectively implemented.
This study aimed to identify the life course model that best describes the association between grip strength measured in childhood, young adulthood and mid-adulthood and the risk of prediabetes or type 2 diabetes in mid-adulthood.
4 Discussion
This study is the first to identify the relative contribution of grip strength measured across the life course with prediabetes or type 2 diabetes in mid-adulthood. Our estimates suggest an approximately equal contribution from grip strength measured in childhood, young adulthood and mid-adulthood on prediabetes or type 2 diabetes risk and that greater cumulative grip strength across the life course was associated with a 34% reduction in the odds of developing prediabetes or type 2 diabetes in mid-adulthood. These findings are consistent with recent confirmation of a causal link between grip strength and type 2 diabetes from Mendelian randomization analysis [
3] by demonstrating the cumulative nature of the association across the life course. As such, our data support the importance of developing and maintaining higher levels of muscular strength beginning in childhood and continuing through mid-adulthood to maximize future cardiometabolic health benefits.
Despite this being the first study to apply a life course modelling framework to examine the association of grip strength with prediabetes or type 2 diabetes, previous work provides a strong rationale for a causal link. For example, a recent two-sample Mendelian randomization study [
3] that applied SNPs associated with grip strength obtained from the UK Biobank to data from two large meta-analysis consortia of type 2 diabetes and glycaemic traits (DIAGRAM and MAGIC) found a one SD increase in grip strength was associated with 23% lower odds of type 2 diabetes (OR 0.77, 95% CI 0.62, 0.95) [
3]. The association between measures of muscular strength and type 2 diabetes risk is also supported by observational data. Results from a systematic review and meta-analysis suggest that in adulthood, a one SD increase in muscular strength is associated with a 13% decreased risk of type 2 diabetes (RR 0.87, 95% CI 0.81, 0.94), independent of BMI or waist to hip ratio [
2]. The longitudinal association between child and adolescent muscular strength with adult type 2 diabetes and associated risk factors has also been described, independent of CRF and waist circumference. Higher levels of childhood muscular strength were associated with lower adult levels of insulin resistance and beta cell function, precursors of type 2 diabetes, among cohorts from Australia and Europe [
4,
5], while low levels of muscular strength among Swedish male military conscripts aged 18 years were associated with an increased risk of type 2 diabetes 10–40 years later, independent of CRF and BMI [
6].
Our findings expand current evidence by suggesting grip strength measured at three life stages were similarly associated with prediabetes or type 2 diabetes in mid-adulthood. Consequently, childhood, young adulthood and mid-adulthood are equally important life stages that can be targeted to help protect against the development of type 2 diabetes. That is, it is not grip strength at a single period in the life course or the tracking of grip strength from distal to proximal time points that explains the association with type 2 diabetes. These results suggest that greater cumulative grip strength across the life course is important in preventing prediabetes and type 2 diabetes. These findings support current national and global physical activity guidelines where both children and adults are encouraged to participate in muscle-strengthening activities [
17,
18]. Strategies aimed at promoting environments and factors leading to muscular strength gains in childhood and initiating and maintaining participation in muscle-strengthening activities into adulthood could help prevent the development of type 2 diabetes. Evidence suggests resistance training interventions administered in schools can increase childhood muscular fitness levels [
19]. Furthermore, the modifiable factors of lower adiposity and higher fat-free mass, CRF, flexibility, and speed capability could be targeted for strategies aimed at increasing childhood muscular strength [
20]. Of concern, childhood muscular fitness levels have declined over time [
21], and as muscular strength tracks between childhood and adulthood [
22], this decline could have long-term effects on future muscular strength. Therefore, implementing well-informed strategies aimed at improving muscular strength in childhood are required to help promote favourable muscular strength levels across the life course.
The mechanism explaining the association between grip strength and type 2 diabetes is unknown. Associations may be acting indirectly through adiposity levels. However, grip strength appears to associate with type 2 diabetes independent of adiposity levels. The direct association between grip strength and type 2 diabetes could be explained by resistance training-induced improvements in glucose homeostasis, whereby resistance training lowers HbA1c levels [
23,
24] and upregulates key proteins in the insulin signalling cascade [
25]. Given grip strength is a measure of overall muscular strength [
26] and resistance training increases muscular strength levels [
27,
28], the glucose homeostasis benefits of resistance training are likely to explain the observed association. However, whether the link between behaviours that increase muscular strength and type 2 diabetes explain the relaxed accumulation model highlighted in this study is unknown. Genetic factors or the persistence of higher levels of fat-free mass and protective innate muscle traits, such as mitochondrial density, intramuscular fat and skeletal muscle fibre type, across the life course could be responsible for the accumulative effect of muscle strength on type 2 diabetes risk. Although additional research is required to confirm the exact mechanisms, results from this study suggest protective effects begin in childhood and that greater cumulative grip strength across the life course is beneficial. These data reinforce the causal link between grip strength and type 2 diabetes highlighted by Mendelian randomization analysis [
3].
This study had limitations. Due to time and economic constraints at baseline, a subset of children had grip strength measured. For inclusion in our analysis dataset, those with grip strength measured at baseline had to attend and pass fitness exclusion questionnaires at both follow-ups. A substantial proportion did not fulfil all participation requirements, resulting in a relatively small sample size and case numbers for analysis. Nevertheless, our simulation study showed that we had > 80% power to detect the true life course model in a sample of this size given the prevalence of type 2 diabetes (see supplementary material). Whilst we cannot discount participation bias, it is reassuring that participants and non-participants were similar in baseline characteristics, and that for the two characteristics (socioeconomic status and smoking status) in which there were differences, the strength of the inverse relationship between baseline grip strength and prediabetes or type 2 diabetes for non-participants at follow-up was close to uniform in each category of socioeconomic status and smoking status. In all categories of socioeconomic status and for the large group of non-smokers, our estimate of the inverse relationship between baseline grip strength and risk of prediabetes or type 2 diabetes was stronger (further from the null) for non-participants than for participants. This raises the possibility that the protective effect of grip strength has been underestimated in this study (any bias is towards the null). Furthermore, given our low sample size, the posterior (Fig.
2) and prior distributions (Figure S1) overlapped and credible intervals were wide. We recommend that the research be replicated in other cohorts with larger sample sizes to see if findings are consistent. Furthermore, the newly developed BRLM approach does not currently allow inclusion of time varying covariates. In our study, it was important to attempt to remove the influence of CRF and waist circumference from the association between life course grip strength and prediabetes or type 2 diabetes. In the absence of a formal method incorporated within the BRLM, we included an average life course standardized value of CRF and waist circumference in the model. Although this approach is not ideal as it considers a cumulative effect averaged from one to three time points, this was the best approach available to us. Strengths of this study include the use of a national cohort including both sexes with a baseline age of 9–15 years and a follow-up period of over 30 years. Furthermore, measures of grip strength were available at three time points across the life course. This meant the BRLM could be used to address a research question that was, up to this point, unknown. Lastly, grip strength, a measure of overall muscular strength [
26], is a reliable and valid field-based measure [
29] and correlates with the one repetition maximum, a gold standard test to assess muscular strength [
30].