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Dual effects of insulin resistance on mortality and function in non-diabetic older adults: findings from the Toledo Study of Healthy Aging

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Abstract

Insulin signalling declines with increasing age and impacts skeletal muscle function and longevity in animal models. Our aim was to assess the relationships between insulin resistance (IR) and frailty and mortality in a unique community-dwelling cohort of older people. 991 non-diabetic subjects from the Toledo Study of Healthy Ageing (TSHA) cohort were included. IR was estimated by the homeostasis model assessment index (HOMA-IR) at baseline while frailty was determined by frailty phenotype (FP) and Frailty Trait Scale (FTS) at baseline and after 5-year follow-up. Deaths were also determined. Multivariate regression models were used to analyze the effects of HOMA-IR on outcomes. Age, gender, BMI, education level, cardio- and cerebro-vascular disease, glomerular filtration rate, and disability were included as potential confounding variables in progressive adjustment models. IR determined as increasing log HOMA-IR was inversely associated with risk of mortality. The association remained significant for all adjustment models (HR: 0.64–0.69). When we analyzed survival curves, the higher the HOMA-IR tertile, the lower the mortality rate (highest vs lowest tertile, p = 0.0082). In contrast, IR increased the risk of incident frailty determined by FP (OR 1.81 [1.14–2.87]) as well as deterioration of frailty status determined by worsening in FTS score (OR 1.28 [1.01–1.63]) at 5-year follow-up. In non-diabetic older subjects, IR significantly increases the risk for frailty and functional decline but decreased the risk of death at 5-year follow-up. This finding raises the need of assessing the effect of biomarkers on different outcomes before establishing their role as biomarkers of aging.

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Acknowledgements

We appreciate the altruistic contribution of the participants from the Toledo Study for Healthy Aging cohort.

Funding

This work has received funding from the European Union’s Seventh Framework Programme (FP7/2007–2013) under grant agreement number 305483 and was supported by grants from the Ministry of Economy and Competitiveness and co-financed by FEDER funds (Instituto de Salud Carlos III, PI20/00977 and CIBERFES (CB16/10/00464), Spanish Government.

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Authors and Affiliations

  1. Servicio de Geriatría, Hospital Universitario de Getafe, Getafe, Spain

    Leocadio Rodríguez-Mañas

  2. Fundación de Investigación Biomédica del Hospital Universitario de Getafe, Getafe, Spain

    Leocadio Rodríguez-Mañas, José A. Carnicero & Mariam El Assar

  3. Centro de Investigación Biomédica en Red de Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid, Spain

    Leocadio Rodríguez-Mañas, Javier Angulo, José A. Carnicero & Mariam El Assar

  4. Division of Geriatric Medicine, Hospital Universitario de Getafe, Ctra de Toledo km 12,500, 28905, Getafe, Spain

    Leocadio Rodríguez-Mañas

  5. Servicio de Histología-Investigación, Unidad de Investigación Traslacional en Cardiología (IRYCIS-UFV), Hospital Universitario Ramón y Cajal, Madrid, Spain

    Javier Angulo

  6. Hospital Virgen del Valle, Complejo Hospitalario de Toledo, Toledo, Spain

    Francisco J. García-García

  7. Foundation for Diabetes Research in Older People (fDROP) and King’s College London, London, UK

    Alan J. Sinclair

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Contributions

LRM, JA, JAC, MEA, FRA and AJS participated in conceptualization and design of the study; LRM, JA, JAC, MEA, FRA and AJS performed data acquisition analysis and interpretation; LRM, JA, JAC, MEA, and AJS wrote the original draft of the manuscript; all authors reviewed, edited, and approved the final version of the manuscript.

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Correspondence to Leocadio Rodríguez-Mañas.

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The study protocols were approved by the Clinical Research Ethics Committee of the Complejo Hospitalario de Toledo (Toledo Study for Healthy Aging cohort). All participants gave written informed consent to participate.

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The authors declare no competing interests.

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Rodríguez-Mañas, L., Angulo, J., Carnicero, J.A. et al. Dual effects of insulin resistance on mortality and function in non-diabetic older adults: findings from the Toledo Study of Healthy Aging. GeroScience 44, 1095–1108 (2022). https://doi.org/10.1007/s11357-021-00384-4

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