Active Voice: Common Mechanistic Link Between Age and Exercise Associations with Glucose Regulation
By Shuen Yee Lee, BSc (Hons) and Chin Leong Lim, Ph.D.

Shuen Yee Lee Chin Leong Lim
People with Type 2 diabetes (T2DM) have greater risk of serious health problems and have substantially higher health care expenditures. The T2DM prevalence is projected to double globally to 366 million by 2030. It is well established that habitual moderate- or higher-intensity exercise is effective for preventing and reversing glucose dysregulation. However, there is no consensus on the mechanisms that mediate the positive effects of regular exercise training on glucose regulation.

Age and sedentary lifestyle are independent risk factors for pre-diabetes and T2DM. Fibroblast growth factor 21 (FGF21) is an endocrine hormone produced mainly by the liver and is associated with improvements in glucose regulation through insulin sensitization and the moderation of gluconeogenesis. The glucoregulatory effects of FGF21 were suggested to be mediated by adiponectin in animal models and patients with chronic disease. Aging and exercise independently increase circulating FGF21 concentration, implying the potential role of FGF21 as a mediator of exercise and age-related impairment in glucose regulation.

Our study, published in the February 2020 issue of Medicine & Science in Sports & Exercise, investigated FGF21 as a potential mediator of the associations between aging and exercise with glucose regulation in healthy adults. Eighty (80) healthy men and women were recruited based on their age and five-year exercise history. They were assigned equally across four groups: younger (ages 1836) sedentary and active; and older (ages 4580) sedentary and active. Within each age group, the subjects were matched for sex and age in five-year intervals. The participants underwent an oral glucose tolerance test with blood samples collected every 30 minutes for measurement of circulating glucose, insulin, FGF21 and adiponectin concentrations.

Our study showed that aging was associated with higher glucose and FGF21 concentrations following glucose challenge, independent of exercise habits and adiponectin concentration. This implies a compensatory FGF21 response to the poorer glucose tolerance with age. In contrast, active individuals had lower insulin and FGF21 concentrations following glucose challenge, independent of age. These responses suggest that active individuals require less FGF21 and insulin than sedentary individuals to normalize glucose concentration during glucose loading. Thus, implying that in healthy individuals, aging alone may induce poorer glucose tolerance, which can be countered by the effects of exercise in promoting insulin sensitivity. FGF21 may act as the central mediator between these opposing effects of aging and exercise to normalize glucose regulation. Unlike people with chronic disease, FGF21 mediates glucose regulation in healthy individuals without involving the adiponectin pathway.

Our study supported the potential role of FGF21 as a target pathway for protecting glucose regulation against the detrimental effects of aging. Habitual exercise should be promoted for preventing T2DM in both young and older individuals and to counter the projected increase in the prevalence of T2DM globally in the next decade. Future studies can shed more light on the downstream mechanisms of FGF21 and its interaction with other mechanistic pathways that influence metabolic health, e.g., gut microbiomes and inflammatory response.

About the authors:
Shuen Yee Lee is a Ph.D. candidate in Lee Kong Chian School of Medicine at Nanyang Technological University in Singapore. Her research interests focus on the roles of FGF21 in mediating the associated effects of exercise and age-associated chronic diseases. Connect with Ms. Lee at

Chin Leong Lim, Ph.D., is an associate professor of exercise physiology at Lee Kong Chian School of Medicine at Nanyang Technological University. His research focuses on the therapeutic properties of exercise on age-related declines in metabolic and musculoskeletal health. He is currently investigating the effects of a 20-week, community-based Tai Chi program in promoting metabolic and musculoskeletal health and muscular functions in the elderly population. Dr. Lim is an ACSM member. Connect with Dr. Lim at

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