Abstract
Introduction Aging increases the prevalence of glucose intolerance, but exercise improves glucose homeostasis. The fibroblast growth factor 21 (FGF21)-adiponectin axis helps regulate glucose metabolism. However, the role of FGF21 in mediating glucose metabolism with aging and exercise remains unknown. Purpose This study examined whether FGF21 responses to a glucose challenge are associated with habitual exercise, aging and glucose regulation. Methods Eighty age- A nd sex-matched healthy individuals were assigned to young sedentary and active (≤36 yr, n = 20 each group) and older sedentary and active (≥45 yr, n = 20 each group) groups. Fasted and postprandial blood glucose concentration and plasma concentration of insulin, FGF21, and adiponectin were determined during an oral glucose tolerance test (OGTT). Results During the OGTT, glucose concentrations were 9% higher (P = 0.008) and FGF21 concentrations were 58% higher (P = 0.014) in the older than the younger group, independent of activity status. Active participants had 40% lower insulin concentration and 53% lower FGF21 concentration than sedentary participants, independent of age (all P < 0.001). Adiponectin concentration during the OGTT did not differ by age (P = 0.448) or activity status (P = 0.611). Within the younger group, postprandial glucose, insulin and FGF21 concentrations during the OGTT were lower in active than in sedentary participants. In the older group, only postprandial insulin and FGF21 concentrations were lower in active participants. Conclusions FGF21, but not adiponectin, response during the OGTT is higher in older than younger adults and lower in active than sedentary individuals. Exercise-associated reduction in OGTT glucose concentrations was observed in younger but not older adults.
| Original language | English |
|---|---|
| Pages (from-to) | 370-380 |
| Number of pages | 11 |
| Journal | Medicine and Science in Sports and Exercise |
| Volume | 52 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 2020 Feb 1 |
| Externally published | Yes |
Keywords
- Adiponectin
- Healthy
- Insulin
- Oral Glucose Tolerance Test
ASJC Scopus subject areas
- Orthopedics and Sports Medicine
- Physical Therapy, Sports Therapy and Rehabilitation
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Fibroblast Growth Factor 21 Mediates the Associations between Exercise, Aging, and Glucose Regulation. / Lee, Shuen Yee; Burns, Stephen F.; Ng, Kenneth K.C.; Stensel, David J.; Zhong, Liang; Tan, Frankie H.Y.; Chia, Kar Ling; Fam, Kai Deng; Yap, Margaret M.C.; Yeo, Kwee Poo; Yap, Eric P.H.; Lim, Chin Leong.
In: Medicine and Science in Sports and Exercise, Vol. 52, No. 2, 01.02.2020, p. 370-380.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Fibroblast Growth Factor 21 Mediates the Associations between Exercise, Aging, and Glucose Regulation
AU - Lee, Shuen Yee
AU - Burns, Stephen F.
AU - Ng, Kenneth K.C.
AU - Stensel, David J.
AU - Zhong, Liang
AU - Tan, Frankie H.Y.
AU - Chia, Kar Ling
AU - Fam, Kai Deng
AU - Yap, Margaret M.C.
AU - Yeo, Kwee Poo
AU - Yap, Eric P.H.
AU - Lim, Chin Leong
N1 - Funding Information: The present study is the first to show the association between FGF21 and glucose regulation with aging and habitual exercise. However, neither age nor habitual exercise status were associated with adiponectin concentrations during the OGTT, suggesting that adiponectin is unlikely involved in the FGF21 glucoregulatory axis. These results also suggest that the mechanisms driving habitual exercise-related improvements in glucose tolerance may differ between younger and older groups. Compared with sedentary individuals, habitually active individuals had lower fasted and postprandial plasma FGF21 and insulin concentrations during the OGTT, implying that active individuals require a lower FGF21 response to normalize hyperglycemia. Although habitually active and sedentary groups had different plasma FGF21 and insulin concentrations during the OGTT, blood glucose and plasma adiponectin concentrations were similar. Our results concurred with a study on middle-age and elderly Japanese men, which found that fasted serum FGF21 concentration was negatively associated with cardiorespiratory fitness and peak oxygen uptake ( 14 ). Five weeks of endurance training in elderly men also reduced fasted serum FGF21 concentration ( 24 ). Habitually active individuals also have 25% to 47% lower fasted insulin concentration and approximately twofold increase in peripheral insulin action compared with sedentary individuals ( 25,26 ). Furthermore, exercise-induced improvements in insulin sensitivity and glucose clearance were reversed after 2 to 3 d of exercise cessation, suggesting that exercise improves insulin action and glycemia ( 26 ). Our results showed a 1.9-fold higher circulating basal plasma FGF21 concentration in sedentary than in habitually active individuals. Similarly, compared with healthy lean individuals, individuals with T2DM and obesity had approximately twofold higher circulating basal FGF21 concentrations ( 10 ). The higher circulating FGF21 concentrations in T2DM patients is indicative of basal FGF21 resistance due to diminished expression of FGF21 receptors or increased peripheral and hepatic insulin resistance ( 9 ). These findings could imply that habitual exercise is associated with lower basal FGF21 and insulin resistance. However, in contrast to our findings, acute and short-term exercise interventions resulted in a onefold to threefold increase in circulating FGF21 concentrations ( 12,13 ). Unlike acute and short-term exercises, long-term exercise training reduces visceral fat mass and increases muscle mass, which could lower FGF21 secretion ( 14,27 ). These results suggest FGF21- and insulin-dependent pathways can potentially contribute to better insulin sensitivity and glucose regulation with habitual exercise. The favorable glycemic and insulin-sensitizing effects of FGF21 was shown to be mediated through the effects of adiponectin ( 6–8 ). Adiponectin enhances insulin sensitivity, inhibits hepatic glucose production and maintains functional beta cell mass ( 28 ). However, we found that FGF21, but not adiponectin, was influenced independently by both habitual exercise and age, suggesting that habitual exercise and aging unlikely mediates glycemia via FGF21–adiponectin axis. Our results agree with observations in mice that adiponectin was not upregulated in response to both acute and chronic FGF21 administration, which improved insulin sensitivity in control and adiponectin null mice ( 29 ). In contrast to our results, adiponectin was found to be a downstream effector of FGF21, as FGF21 administration significantly increased circulating concentration of adiponectin by fourfold in animals and by 1.8-fold in humans ( 6–8 ). The disparity on the role of the FGF21–adiponectin axis ( 6–8,29 ) could be due to the differences in mouse lines, dose or source of FGF21. Studies supporting the activation of the FGF21–adiponectin axis administered supra-pharmacologic and supra-physiological doses of exogenous FGF21. Fibroblast growth factor 21 could also regulate glucose independently of adiponectin through direct signaling to the brain, interorgan crosstalk between the liver and brain, or by increasing energy expenditure and improving glucose uptake in brown adipose tissues ( 30,31 ). Other factors, such as proinflammatory cytokines and oxidative stress, could also regulate adiponectin independently of FGF21. Taken together, FGF21-dependent pathways and glucose regulation are likely associated with habitual exercise and aging in healthy humans, but the role of adiponectin as a downstream effector is not supported by our study. Our results also suggest that age-associated changes in glucose regulation could be affected by FGF21. Both blood glucose and plasma FGF21 concentrations during the OGTT were higher in older than in younger individuals. The negative association between fasted plasma FGF21 concentration and insulin sensitivity was also greater in the older than the younger groups, independent of activity status. It is likely that increased plasma FGF21 concentration compensated for the poorer glucose tolerance that occurs with age. In agreement with our results, a negative correlation between insulin sensitivity and serum FGF21 concentration was also found in older adults (>60 yr) with normal glucose tolerance, IGT, and diabetes ( 32 ). Our results also concurred with findings from community dwelling older adults (~63 yr) showing a positive association between basal circulating FGF21 concentration and abnormal glucose metabolism ( 32 ). Circulating FGF21 concentration was positively associated with age in individuals age 5 to 103 yr, independent of body fat and health status ( 33,34 ). In our study of healthy individuals, no positive correlation was found between fasted FGF21 concentration and age (ranging from 18 to 80 yr), regardless of activity status, BMI or WC, potentially due to differences in the statistical methods of analysis and profile of subjects. Unlike our study, earlier studies used a multiple linear regression model with age as a categorial independent variable, and included individuals younger than 18 yr ( 33 ) and individuals older than 90 to 100 yr with heterogenous health status ( 34 ). The small sample size and the exclusion of a 36- to 45-yr age group in our study could have also affected the linearity of the relationship between FGF21 concentration and age. Nonetheless, our findings collectively support previous literature that aging is linked to higher FGF21 concentrations and lower insulin sensitivity. Therefore, the age-associated increases in plasma FGF21 concentration during the OGTT in our study could alter insulin sensitivity and compensate for the concurrently higher glucose concentrations. We also found that plasma adiponectin and insulin concentrations during the OGTT were similar between younger and older adults, suggesting no association with age and that the age-associated effects of FGF21 on glucose tolerance are independent of both insulin and adiponectin. In agreement with our results, age-associated changes in insulin responses to both an oral dextrose tolerance test and a mixed-meal test were not observed in men age 47 to 90 yr ( 35 ). Younger and older participants also had similar fasted insulin concentration regardless of activity status ( 25 ). In contrast, other studies have shown that serum adiponectin concentration increases with age in both healthy individuals and T2DM patients and is negatively associated with insulin resistance ( 36,37 ). These differences could be attributed to the measurement of total adiponectin in the present study, compared with high-molecular weight adiponectin measured in other studies. Our findings are also limited to a clinically healthy population. It is plausible that FGF21-dependent pathways directly regulate age-associated increases in glucose concentrations during the OGTT, independent of adiponectin. We demonstrated for the first time that habitual exercise-associated improvements in glucose regulation may be driven by different mechanisms between younger and older groups. Within the younger group, circulating blood glucose and plasma insulin and FGF21 concentrations during the OGTT were lower in active than in sedentary individuals. In contrast, in the older group, circulating blood glucose concentration during the OGTT was independent of exercise habits, despite lower plasma FGF21 and insulin concentrations in active than in sedentary participants. Therefore, it is likely that the lower postprandial plasma insulin and FGF21 concentrations resulted in a corresponding decrease in glucose concentrations only in YA compared with YS. Exercise habits could have influenced glycemic response in the older group by increasing insulin-dependent peripheral glucose uptake and peripheral insulin sensitivity ( 38,39 ). The OA and OS individuals could also have similar endogenous glucose production or hepatic and adipose insulin sensitivity ( 38,39 ). In contrast, within the younger group, exercise lowered blood glucose concentration and increases glucose uptake directly through insulin-independent mechanisms, such as greater vascular muscle perfusion rate and glucose transporter upregulation ( 40 ). However, these subgroup results are preliminary and explorative due to the small sample size. Future studies involving a larger cohort are required to investigate the exercise-associated glucoregulatory mechanisms with age. Exercise measures were self-reported based on the type, intensity, frequency, and duration of regular exercise per week, and future studies using more objective measures of physical activity and exercise should be undertaken. As this is a cross-sectional study that cannot conclude causality in inferring that FGF21 or adiponectin are involved in age- and exercise-associated changes in glucose regulation, future studies should investigate FGF21 and adiponectin response to an acute exercise bout, in active and sedentary individuals. Moreover, we did not account for muscle mass in this present study, which is a key regulator of glucose uptake, and could be involved in glucoregulatory functions of FGF21. Collectively, our results support that habitual exercise-associated improvement in glucoregulatory mechanisms may differ between younger and older individuals. In conclusion, habitual exercise is associated with lower plasma FGF21 and insulin concentrations in both fasted and fed states during an oral glucose challenge. Aging is associated with higher blood glucose and plasma FGF21 concentrations in both fasted and fed states during the OGTT. Adiponectin unlikely modulates the downstream effects of FGF21 on glucose regulation. Nonetheless, these findings are preliminary and the precise mechanisms driving the difference in FGF21 and glucose regulation with age and exercise remains to be elucidated. This study is supported by the Ministry of Education Singapore Start-up Grant for Human and Metabolic disease (L0412270). David Stensel acknowledges support from the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health. The authors would like to thank all the participants for their contribution. Conflict of Interest: The authors declare no conflict of interest. The results of the present study do not constitute endorsement by ACSM. We declare that the results of the study are presented clearly, honestly and without fabrication, falsification, or inappropriate data manipulation. Publisher Copyright: © Lippincott Williams & Wilkins.
PY - 2020/2/1
Y1 - 2020/2/1
N2 - Introduction Aging increases the prevalence of glucose intolerance, but exercise improves glucose homeostasis. The fibroblast growth factor 21 (FGF21)-adiponectin axis helps regulate glucose metabolism. However, the role of FGF21 in mediating glucose metabolism with aging and exercise remains unknown. Purpose This study examined whether FGF21 responses to a glucose challenge are associated with habitual exercise, aging and glucose regulation. Methods Eighty age- A nd sex-matched healthy individuals were assigned to young sedentary and active (≤36 yr, n = 20 each group) and older sedentary and active (≥45 yr, n = 20 each group) groups. Fasted and postprandial blood glucose concentration and plasma concentration of insulin, FGF21, and adiponectin were determined during an oral glucose tolerance test (OGTT). Results During the OGTT, glucose concentrations were 9% higher (P = 0.008) and FGF21 concentrations were 58% higher (P = 0.014) in the older than the younger group, independent of activity status. Active participants had 40% lower insulin concentration and 53% lower FGF21 concentration than sedentary participants, independent of age (all P < 0.001). Adiponectin concentration during the OGTT did not differ by age (P = 0.448) or activity status (P = 0.611). Within the younger group, postprandial glucose, insulin and FGF21 concentrations during the OGTT were lower in active than in sedentary participants. In the older group, only postprandial insulin and FGF21 concentrations were lower in active participants. Conclusions FGF21, but not adiponectin, response during the OGTT is higher in older than younger adults and lower in active than sedentary individuals. Exercise-associated reduction in OGTT glucose concentrations was observed in younger but not older adults.
AB - Introduction Aging increases the prevalence of glucose intolerance, but exercise improves glucose homeostasis. The fibroblast growth factor 21 (FGF21)-adiponectin axis helps regulate glucose metabolism. However, the role of FGF21 in mediating glucose metabolism with aging and exercise remains unknown. Purpose This study examined whether FGF21 responses to a glucose challenge are associated with habitual exercise, aging and glucose regulation. Methods Eighty age- A nd sex-matched healthy individuals were assigned to young sedentary and active (≤36 yr, n = 20 each group) and older sedentary and active (≥45 yr, n = 20 each group) groups. Fasted and postprandial blood glucose concentration and plasma concentration of insulin, FGF21, and adiponectin were determined during an oral glucose tolerance test (OGTT). Results During the OGTT, glucose concentrations were 9% higher (P = 0.008) and FGF21 concentrations were 58% higher (P = 0.014) in the older than the younger group, independent of activity status. Active participants had 40% lower insulin concentration and 53% lower FGF21 concentration than sedentary participants, independent of age (all P < 0.001). Adiponectin concentration during the OGTT did not differ by age (P = 0.448) or activity status (P = 0.611). Within the younger group, postprandial glucose, insulin and FGF21 concentrations during the OGTT were lower in active than in sedentary participants. In the older group, only postprandial insulin and FGF21 concentrations were lower in active participants. Conclusions FGF21, but not adiponectin, response during the OGTT is higher in older than younger adults and lower in active than sedentary individuals. Exercise-associated reduction in OGTT glucose concentrations was observed in younger but not older adults.
KW - Adiponectin
KW - Healthy
KW - Insulin
KW - Oral Glucose Tolerance Test
UR - http://www.scopus.com/inward/record.url?scp=85077935657&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85077935657&partnerID=8YFLogxK
U2 - 10.1249/MSS.0000000000002150
DO - 10.1249/MSS.0000000000002150
M3 - Article
C2 - 31490857
AN - SCOPUS:85077935657
VL - 52
SP - 370
EP - 380
JO - Medicine and Science in Sports and Exercise
JF - Medicine and Science in Sports and Exercise
SN - 0195-9131
IS - 2
ER -