Resistance to the Beneficial Effects of Exercise in Type 2 Diabetes: Are Some Individuals Programmed to Fail?

Stephens, Natalie; Sparks, Lauren M.

doi:10.1210/jc.2014-2545

Cited by 90 publications

(87 citation statements)

References 107 publications

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“…For instance, individuals with IFG + IGT do not experience the same beneficial effects of exercise on 2 h glucose levels and insulin sensitivity as individuals with i-IGT [9]. In another study, approximately 15-20% of individuals with type 2 diabetes failed to improve their glucose homeostasis and insulin sensitivity with exercise training [31]. Large-scale clinical intervention studies including habitual monitoring of behaviour are needed to advance our ability to understand and identify responders vs nonresponders to exercise in order to optimise prevention and treatment strategies for type 2 diabetes.…”

Section: Discussionmentioning

confidence: 97%

Physical activity energy expenditure vs cardiorespiratory fitness level in impaired glucose metabolism

et al. 2015

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Aim/hypothesis Little is known about the relative roles of physical activity energy expenditure (PAEE) and cardiorespiratory fitness (CRF) as determinants of glucose regulation. The aim of this study was to examine the associations of PAEE and CRF with markers of glucose metabolism, and to test the hypothesis that CRF modifies the association between PAEE and glucose metabolism. Methods We analysed cross-sectional data from 755 adults from the Danish ADDITION-PRO study. On the basis of OGTT results, participants without known diabetes were classified as having normal glucose tolerance, isolated impaired fasting glycaemia (i-IFG), isolated impaired glucose tolerance (i-IGT), combined IFG + IGT or screen-detected diabetes mellitus. Markers of insulin sensitivity and beta cell function were determined. PAEE was measured using a combined heart rate and movement sensor. CRF (maximal oxygen uptake) was estimated using a submaximal 8 min step test. The associations were examined by linear regression analysis. Results were adjusted for relevant confounders. Results PAEE and CRF were reduced in individuals with i-IGT, combined IFG + IGT and screen-detected diabetes mellitus, but were not significantly different in individuals with i-IFG compared with those with normal glucose tolerance. When adjusting CRF for PAEE and vice versa, PAEE and CRF were both associated with lower fasting and 2 h insulin and higher peripheral insulin sensitivity. CRF was additionally associated with lower fasting and 2 h glucose and higher insulin sensitivity and beta cell function. There was no interaction between CRF and PAEE for any markers of glucose metabolism. Conclusions/interpretation Only CRF, not PAEE, appears to be independently associated with plasma glucose levels and beta cell function, suggesting that CRF may be particularly important for glycaemic control.

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Section: Discussionmentioning

confidence: 97%

Physical activity energy expenditure vs cardiorespiratory fitness level in impaired glucose metabolism

et al. 2015

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“…As many as 20% of individuals with type 2 diabetes do not respond favourably to exercise training in terms of glycaemic control and muscle mitochondrial function [32,52]. Non-response to exercise, however, is not unique to diseased or untrained populations, emphasising the importance of selecting a response variable profiles can be generated to distinguish the responders and non-responders at baseline and visualised via hierarchical clustering in a heatmap.…”

Section: Discussionmentioning

confidence: 99%

Exercise training response heterogeneity: physiological and molecular insights

2017

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The overall beneficial effects of exercise are well studied, but why some people do not respond favourably to exercise is less understood. The National Institutes of Health Common Fund has recently launched the large-scale discovery project 'Molecular Transducers of Physical Activity in Humans' to examine the physiological and molecular (i.e. genetic, epigenetic, lipidomic, metabolomic, proteomic, etc.) responses to exercise training. A nationwide, multicentre clinical trial such as this one also provides a unique opportunity to robustly investigate the non-response to exercise in thousands of individuals that have undergone supervised aerobic-and resistance-based exercise training interventions. The term 'non-responder' is used here to address the lack of a response (to an exercise intervention) in an outcome specified a priori. Cardiorespiratory fitness (V O 2peak ) as an exercise response variable was recently reviewed; thus, this review focuses on metabolic aspects of the non-response to exercise training. Integrated -omics platforms are discussed as an approach to disentangle the complicated relationships between endogenous and exogenous factors that drive the lack of a response to exercise in some individuals. Harnessing the power of combined -omics platforms with deep clinical phenotyping of human study participants will advance the field of exercise metabolism and shift the paradigm, allowing exercise interventions to be targeted at those most likely to benefit and identifying novel approaches to treat those who do not. What is a non-response?From a statistical perspective, a non-response is the lack of a difference between a control and a treatment condition with respect to a specific variable. A physiological non-response, however, is likely driven by genetic code and the mechanisms by which it is transcribed, translated and post-translationally modified. Drug resistance is an archetype of non-response that links physiology with genetics. For example, some individuals are 'rapid' or 'slow' metabolisers of a prescribed drug based solely on their genetic predispositions, and simple DNA tests can now identify these at-risk populations (reviewed in [1]). Combination drug therapy for initial non-response, acquired resistance or adverse response is usually the next course of action; therefore, tailoring treatment to the genetic code is a viable strategy for some diseases and conditions. Response heterogeneity is not unique to pharmaceutical therapies; lifestyle interventions, such as dietary weight loss and exercise, have also been linked to physiological, genetic and epigenetic factors. Differences in energy efficiency are important physiological regulators of body weight and Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00125-017-4461-6) contains a slide of the figure for download, which is available to authorised users. * Lauren M. Sparks

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“…However, evidence is accumulating that differences exist in the individual response to exercise training. On average, approximately 15-20% of people failed to improve their glucose tolerance and insulin sensitivity after exercise training interventions (7); this nonresponse is not restricted to a specific type of exercise (endurance or resistance training or combinations), although differences are reported (8)(9)(10)(11).…”

Section: Tgf-b Contributes To Impaired Exercise Response By Suppressimentioning

confidence: 99%

TGF-β Contributes to Impaired Exercise Response by Suppression of Mitochondrial Key Regulators in Skeletal Muscle

et al. 2016

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A substantial number of people at risk of developing type 2 diabetes could not improve insulin sensitivity by physical training intervention. We studied the mechanisms of this impaired exercise response in 20 middle-aged individuals at high risk of developing type 2 diabetes who performed 8 weeks of controlled cycling and walking training at 80% individual Vo2 peak. Participants identified as nonresponders in insulin sensitivity (based on the Matsuda index) did not differ in preintervention parameters compared with high responders. The failure to increase insulin sensitivity after training correlates with impaired upregulation of mitochondrial fuel oxidation genes in skeletal muscle, and with the suppression of the upstream regulators PGC1α and AMPKα2. The muscle transcriptomes of the nonresponders are further characterized by the activation of transforming growth factor (TGF)-β and TGF-β target genes, which is associated with increases in inflammatory and macrophage markers. TGF-β1 as inhibitor of mitochondrial regulators and insulin signaling is validated in human skeletal muscle cells. Activated TGF-β1 signaling downregulates the abundance of PGC1α, AMPKα2, the mitochondrial transcription factor TFAM, and mitochondrial enzymes. Thus, the data suggest that increased TGF-β activity in skeletal muscle can attenuate the improvement of mitochondrial fuel oxidation after training and contribute to the failure to increase insulin sensitivity.

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Resistance to the Beneficial Effects of Exercise in Type 2 Diabetes: Are Some Individuals Programmed to Fail?

Cited by 90 publications

References 107 publications

Physical activity energy expenditure vs cardiorespiratory fitness level in impaired glucose metabolism

Physical activity energy expenditure vs cardiorespiratory fitness level in impaired glucose metabolism

Exercise training response heterogeneity: physiological and molecular insights

TGF-β Contributes to Impaired Exercise Response by Suppression of Mitochondrial Key Regulators in Skeletal Muscle

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