Abstract
Beta (β)-cell senescence contributes to type 2 diabetes mellitus (T2DM). While exercise is vital for T2DM management and significantly affects cellular ageing markers, its effect on β-cell senescence remains unexplored. Here, we show that short-term endurance exercise training (treadmill running, 1 h per day for 10 days) in two male and female mouse models of insulin resistance decreases β-cell senescence. In vivo and in vitro experiments revealed that this effect is mediated, at least in part, by training-induced increases in serum glucagon, leading to activation of 5′-AMP-activated protein kinase (AMPK) signalling in β-cells. AMPK activation resulted in the nuclear translocation of NRF2 and decreased expression of senescence markers and effectors. Remarkably, human islets from male and female donors with T2DM treated with serum collected after a 10-week endurance exercise training programme showed a significant decrease in the levels of senescence markers. These findings indicate that exercise training decreases senescence in pancreatic islets, offering promising therapeutic implications for T2DM.
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Data availability
Bulk RNAseq data are deposited to the Gene Expression Omnibus with accession no. GSE227516. Source data are provided with this paper.
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Acknowledgements
This study was supported by institutional start-up funds to C.A.-M., National Institutes of Health (NIH) grants 1R01DK132535 to C.A.-M. and P30 DK036836 to Joslin Diabetes Center (Cores), Thomas J. Beatson Jr. Foundation grant 2020-010 and the Richard and Susan Smith Family Foundation Award to C.A.-M. Support was also provided by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil (CAPES)-Finance Code 001 (to P.C.), the 2021 STEP-UP (Short-term Research Experience for Underrepresented Persons) programme supported by award number 1R25DK113652 from the NIH-National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (to J.K.), NIDDK grant K23-DK114550 and BADERC P&F grant (to R.J.W.M.), NIH grant R01DK099511 and R01 DK112283 (to L.J.G.) and American Diabetes Association grant #1-17-PMF-009 (to A.B.A.-W.). G.A.R. was supported by a Wellcome Trust Investigator Award (212625/Z/18/Z), MRC Programme grant (MR/R022259/1), Diabetes UK Project grant (BDA16/0005485), CRCHUM start-up funds, an Innovation Canada John R. Evans Leader Award, JDRF, CIHR, NIH-NIDDK multi-PI project grant (R01DK135268) and CIHR-JDRF Team grant (CIHR-IRSC:0682002550; JDRF 4-SRA-2023-1182-S-N). Human pancreatic islets and/or other resources were provided by the NIDDK-funded IIDP (RRID:SCR _014387) at City of Hope, NIH grant #2UC4DK098085.
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P.C., K.I., F.H., J.K., A.B.A.-W. and R.J.W.M. conducted the experiments. P.C., M.F.H., L.J.G., G.A.R. and C.A.-M. designed the study. P.C. and C.A.-M. wrote the manuscript. All authors reviewed and edited the paper.
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G.A.R. has received grant funding from and is a consultant for Sun Pharmaceutical Industries Ltd. C.A.-M. has served as a consultant for eGenesis and Novo Nordisk. The other authors declare no competing interests.
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Extended data
Extended Data Fig. 1 Distance run per day.
Extended Data Figure 1 refers to Fig. 1. Distance (kilometers) run per day for young 6-weeks-old C57BL/6 females (a, n=5-11/group) and for retired breeders, male 6–9 months-old (b, n=5-10/group) in the wheel-running group (trained). Each line represents an individual mouse.
Extended Data Fig. 2 Body composition parameters.
Extended Data Figure 2 refers to Figs. 1 and 3. (a) Body weight in grams of female trained mice (6 weeks of age, n=5-11/group) from control and trained (wheel) groups. Relates to Fig. 1a and b. (b) Body weight in grams of sedentary and trained (treadmill) at the end of the protocol for 12 -weeks-old (n=10 animals/group, males), relates to Fig. 1d–h; (c) Representative pictures from DEXA Fat and lean mass were measured by dual-energy X-ray absorptiometry (DEXA) (d-g). (h) Body weight in grams of sedentary and trained (treadmill) animals sedentary and control with insulin resistance induced by S961 (males, n=5/group, 6–9 months-old), relates to Fig. 1i-l; (i) Body weight in grams of sedentary and trained (treadmill) animals sedentary and control (males, n=5/group, 6–9 months-old); relates to Fig. 3a–c.N= 5 animals/group, males, 6–9 months old. Two sided-test and Welch’s correction. Mean ± SD. *P<0.05.
Extended Data Fig. 3 Glucose and insulin tolerance tests.
Extended Data Figure 3 refer to Fig. 1d–h. AUC for ITT (a) in 12-weeks-old C57BL/6 males after treadmill exercise protocol; n=10/group (a), serum levels from S961 treated mice, n=4-5/group (b), AUC and blood glucose levels for IPGTT (c, e) and ITT (d, f) for trained and sedentary 6–9 months-old animals (n=5/group) from reversibility prevention (c and d) and reversibility groups (e and f). N=4-10/group. Two sided-test and Welch’s correction. Mean ± SD. ***P<0.001.
Extended Data Fig. 4 Glucose, IL6 and insulin response.
Extended Data Figure 4 refers to Figs. 4 and 5. Glucose levels (a) and concentration of IL-6 (b) after exercise-protocol (6–9-month-old C57BL/6 male mice; n=10/group in A and n=5/group in B). (c) insulin from glucose stimulated insulin secretion performed in islets from male mice (C57BL6, 3–6 months-old, cultured in presence of glucagon and trained serum. N=5 animals/group. Two sided-test and Welch’s correction. Mean ± SD. *P<0.05, **P<0.01, ****P<0.0001.
Extended Data Fig. 5 AMPK activation and P21CIP1 levels in islets treated with human from exercise participants without T2D.
Extended Data Figure 5 refers to Fig. 8. Experiment conducted in individuals without T2D. The results showed increased AMPK phosphorylation (A and B) but without changes in senescence marker P21CIP1 (A and C). Samples from individuals ranging from 22 to 57 years old, male, n=6/group. Two sided-test and Welch’s correction. Mean ± SD. *P<0.05.
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Carapeto, P., Iwasaki, K., Hela, F. et al. Exercise activates AMPK in mouse and human pancreatic islets to decrease senescence. Nat Metab 6, 1976–1990 (2024). https://doi.org/10.1038/s42255-024-01130-8
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DOI: https://doi.org/10.1038/s42255-024-01130-8
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