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Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification by Exercise Training

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Abstract

Metabolic syndrome (MS) is a collection of cardiometabolic risk factors that includes obesity, insulin resistance, hypertension, and dyslipidemia. Although there has been significant debate regarding the criteria and concept of the syndrome, this clustering of risk factors is unequivocally linked to an increased risk of developing type 2 diabetes and cardiovascular disease. Regardless of the true definition, based on current population estimates, nearly 100 million have MS. It is often characterized by insulin resistance, which some have suggested is a major underpinning link between physical inactivity and MS. The purpose of this review is to: (i) provide an overview of the history, causes and clinical aspects of MS, (ii) review the molecular mechanisms of insulin action and the causes of insulin resistance, and (iii) discuss the epidemiological and intervention data on the effects of exercise on MS and insulin sensitivity. © 2013 American Physiological Society. Compr Physiol 3:1‐58, 2013.

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Figure 1. Figure 1.

Graph depicting the hyperbolic relation between insulin secretion and insulin sensitivity. Insulin secretion rises as insulin sensitivity falls when an individual goes from a state of exercise training/being physically active (point A) to detraining/sedentary (point B) and vice versa, that is, bidirectionality of the two arrows from B to A when undergoing exercise training/increasing physical activity levels. A failure of insulin secretion to compensate for a fall in insulin sensitivity is noted when both insulin secretion and insulin sensitivity decline from points B to C, leading to elevated fasting glucose and prediabetes (impaired glucose tolerance). A progressive decline in both insulin secretion and insulin sensitivity to point D indicates type 2 diabetes. Adapted from reference () with permission.

Figure 2. Figure 2.

Schematic of the insulin receptor and critical sites of tyrosine phosphorylation. CR, cysteine‐rich region; JM, juxtamembrane; KD, kinase domain; CT, C‐terminal domain; Y: tyrosine residue.

Figure 3. Figure 3.

Schematic of insulin signal transduction through canonical IRS1/PI3K pathway and through abbreviations: Cbl/CAP/TC10 pathway associated with lipid rafts in the plasma membrane. Akt or PKB, protein kinase B; APS, adapter protein with a PH and SH2 domain; CAP, c‐Cbl‐associated protein; Cbl, proto‐oncogene; GLUT4, insulin responsive glucose transporter highly expressed in myocytes and adipocytes; IRS, insulin receptor substrate; PDK1, phosphoinositide‐dependent kinase 1; PIP3, phosphatidylinositol (3,4,5)‐trisphosphate; PKC, protein kinase C; TC10, small Ras‐related GTPase, member of the Rho family.

Figure 4. Figure 4.

Schematic illustrating mechanisms promoting inflammation that is now recognized as an important underpinning contributing in the pathogenesis of insulin resistance via impairment of insulin signal transduction. Abbreviations: AP‐1, adaptor protein 1; IKK, I kappa B kinase; IKKkinase; IκB‐α, inhibitor of kappa B; IL, interleukin; IRAK, interleukin receptor‐associated kinase; JAK, janus kinase; JNK, c‐Jun N‐terminal kinase. Originally identified kinase family that binds and phosphorylates c‐Jun on Ser‐63 and Ser‐73 within its transcriptional activation domain. MAPK2, mitogen‐activated protein kinase 2; MAPK3, mitogen‐activated protein kinase 3; NF‐κB, nuclear factor κ B (nuclear factor kappa‐light‐chain‐enhancer of activated B cells); RIP, receptor‐interacting serine/threonine‐protein kinase; ROS, reactive oxygen species; STAT, signal transducer and activator of transcription; TLR, toll‐like receptor; TRADD, tumor necrosis factor receptor type 1‐associated DEATH domain protein (adaptor protein); TRAF, TNF receptor associated factors.

Figure 5. Figure 5.

Schematic of adipose tissue‐secreted factors that act on muscle and liver to promote insulin resistance.

Figure 6. Figure 6.

The role of macrophages in the development of obesity. (A) Increased abundance of F4/80 positive macrophages in visceral perigonadal adipose tissue obtained from obese mice. (a) Lean female, (b) Ay/+ female, (c) Lep o/ob female, (d) lean male, (e) diet‐induced obesity, and (f) Lep ob/ob male mice. F4/80 positive cells are small, dispersed and rarely aggregated in adipose tissue from lean animals (a and d), but found frequently in clusters “crowning” adipocytes in adipose tissue from high‐fat fed and genetically obese mice (c, e, and f). Reprinted, with permission, from reference (). (B) Schematic overview of the effects of adipose macrophage infiltration on the development of tissue inflammation and insulin resistance. Classically activated macrophages in adipose tissue from obese humans and rodents are shown to secrete insulin resistance producing proinflammatory cytokines and chemokines. Reprinted, with permission, from reference ().

Figure 7. Figure 7.

Prevalence of metabolic syndrome according to cardiorespiratory fitness quintiles in more than 7000 women enrolled in the Aerobics Center Longitudinal Study from 1979 to 2000. Number of subjects in each quintile is I: 796; II: 1173; III: 1241; IV: 1754; and V: 2140. Adapted from reference () with permission.

Figure 8. Figure 8.

(A) Age and smoking adjusted prevalence of metabolic syndrome in men according to level of muscular strength and cardiorespiratory fitness. Q1 represents the lowest and Q4 the highest muscular strength quartile. (B) Incidence of MS across muscular strength categories by age groups. Incidence rates per 1000 man‐years are shown labeled with bars. The number of subjects for each age group is 20‐39: 1239; 40‐49: 1249; and 50+: 745. Q1 represents the lowest and Q4 the highest muscular strength quartile. The linear trend p values for the age groups 20‐39, 40‐49, and 50+ are less < 0.001, 0.01, and 0.05, respectively. Adapted from references () with permission.

Figure 9. Figure 9.

Impact of fitness on relative risk for all‐cause and cardiovascular disease (CVD) mortality associated with metabolic syndrome before and after the inclusion of cardiorespiratory fitness (CRF) as a covariate in more than 19,000 men 20‐83 years of age from Aerobics Center Longitudinal Study. Error bars represent 95% confidence intervals and demonstrate that after inclusion of CRF as a covariate, all‐cause and CVD mortality were no longer statistically significant. Adapted from reference () with permission.

Figure 10. Figure 10.

All‐cause (A) and cardiovascular disease (B) mortality death rates per 10,000 mean‐years of follow‐up in “healthy” and subjects with metabolic syndrome (MS), adjusted for age and year of examination more than 19,000 men 20‐83 years of age from Aerobics Center Longitudinal Study. The theoretical contributions of fitness and MS are depicted by brackets. Adapted from reference () with permission.

Figure 11. Figure 11.

Relative risk (RR) of (A) all‐cause and (B) cardiovascular disease (CVD) mortality in more than 19,000 men from Aerobics Center Longitudinal Study, adjusted for age, examination year, smoking, alcohol consumption, possible existence of CVD, and parental history of premature CVD. Second and forth bars within a body mass index category refer to cardiorespiratory fitness (CRF)‐adjusted RR's. Data, with permission, from reference ().

Figure 12. Figure 12.

Adjusted cases of metabolic syndrome (MS) based on minutes per week of leisure time physical activity in fit and unfit men after an average 4‐year follow‐up (). Copyright 2002 American Diabetes Association. From Diabetes Care®, Vol. 25, 2002; 1612‐1618. Reprinted by permission of the American Diabetes Association.

Figure 13. Figure 13.

Schematic diagram of future directions to determine mechanisms by which aerobic training (AT) and resistance training (RT) increase insulin sensitivity. Although there is preliminary evidence, more research is needed to clearly identify the mechanisms that are involved, as denoted by the question marks linking AT and RT to enhance insulin signaling.

Figure 14. Figure 14.

Insulin sensitivity and physical activity measured by accelerometer by quartiles of average number of counts/min and quartiles of percent time sedentary in the insulin sensitivity and cardiovascular risk study. M/I is the unit measurement of insulin sensitivity (μmol.min−1kgFFM−1nmol/L−1) (). Copyright 2008 American Diabetes Association. From Diabetes Care®, Vol. 57, 2008; 2613‐2618. Reprinted by permission of the American Diabetes Association.

Figure 15. Figure 15.

Effects of training and age on area under the curve for (A) glucose and (B) insulin during an oral glucose tolerance test. Adapted, with permission, from reference ().

Figure 16. Figure 16.

Effects of chronic training (dashed line), inactivity (solid line) for 10 days and one single bout (dotted line) of aerobic exercise on (A) blood glucose and (B) insulin during an oral glucose tolerance test in well‐trained subjects. Adapted, with permission, from reference ().



Figure 1.

Graph depicting the hyperbolic relation between insulin secretion and insulin sensitivity. Insulin secretion rises as insulin sensitivity falls when an individual goes from a state of exercise training/being physically active (point A) to detraining/sedentary (point B) and vice versa, that is, bidirectionality of the two arrows from B to A when undergoing exercise training/increasing physical activity levels. A failure of insulin secretion to compensate for a fall in insulin sensitivity is noted when both insulin secretion and insulin sensitivity decline from points B to C, leading to elevated fasting glucose and prediabetes (impaired glucose tolerance). A progressive decline in both insulin secretion and insulin sensitivity to point D indicates type 2 diabetes. Adapted from reference () with permission.



Figure 2.

Schematic of the insulin receptor and critical sites of tyrosine phosphorylation. CR, cysteine‐rich region; JM, juxtamembrane; KD, kinase domain; CT, C‐terminal domain; Y: tyrosine residue.



Figure 3.

Schematic of insulin signal transduction through canonical IRS1/PI3K pathway and through abbreviations: Cbl/CAP/TC10 pathway associated with lipid rafts in the plasma membrane. Akt or PKB, protein kinase B; APS, adapter protein with a PH and SH2 domain; CAP, c‐Cbl‐associated protein; Cbl, proto‐oncogene; GLUT4, insulin responsive glucose transporter highly expressed in myocytes and adipocytes; IRS, insulin receptor substrate; PDK1, phosphoinositide‐dependent kinase 1; PIP3, phosphatidylinositol (3,4,5)‐trisphosphate; PKC, protein kinase C; TC10, small Ras‐related GTPase, member of the Rho family.



Figure 4.

Schematic illustrating mechanisms promoting inflammation that is now recognized as an important underpinning contributing in the pathogenesis of insulin resistance via impairment of insulin signal transduction. Abbreviations: AP‐1, adaptor protein 1; IKK, I kappa B kinase; IKKkinase; IκB‐α, inhibitor of kappa B; IL, interleukin; IRAK, interleukin receptor‐associated kinase; JAK, janus kinase; JNK, c‐Jun N‐terminal kinase. Originally identified kinase family that binds and phosphorylates c‐Jun on Ser‐63 and Ser‐73 within its transcriptional activation domain. MAPK2, mitogen‐activated protein kinase 2; MAPK3, mitogen‐activated protein kinase 3; NF‐κB, nuclear factor κ B (nuclear factor kappa‐light‐chain‐enhancer of activated B cells); RIP, receptor‐interacting serine/threonine‐protein kinase; ROS, reactive oxygen species; STAT, signal transducer and activator of transcription; TLR, toll‐like receptor; TRADD, tumor necrosis factor receptor type 1‐associated DEATH domain protein (adaptor protein); TRAF, TNF receptor associated factors.



Figure 5.

Schematic of adipose tissue‐secreted factors that act on muscle and liver to promote insulin resistance.



Figure 6.

The role of macrophages in the development of obesity. (A) Increased abundance of F4/80 positive macrophages in visceral perigonadal adipose tissue obtained from obese mice. (a) Lean female, (b) Ay/+ female, (c) Lep o/ob female, (d) lean male, (e) diet‐induced obesity, and (f) Lep ob/ob male mice. F4/80 positive cells are small, dispersed and rarely aggregated in adipose tissue from lean animals (a and d), but found frequently in clusters “crowning” adipocytes in adipose tissue from high‐fat fed and genetically obese mice (c, e, and f). Reprinted, with permission, from reference (). (B) Schematic overview of the effects of adipose macrophage infiltration on the development of tissue inflammation and insulin resistance. Classically activated macrophages in adipose tissue from obese humans and rodents are shown to secrete insulin resistance producing proinflammatory cytokines and chemokines. Reprinted, with permission, from reference ().



Figure 7.

Prevalence of metabolic syndrome according to cardiorespiratory fitness quintiles in more than 7000 women enrolled in the Aerobics Center Longitudinal Study from 1979 to 2000. Number of subjects in each quintile is I: 796; II: 1173; III: 1241; IV: 1754; and V: 2140. Adapted from reference () with permission.



Figure 8.

(A) Age and smoking adjusted prevalence of metabolic syndrome in men according to level of muscular strength and cardiorespiratory fitness. Q1 represents the lowest and Q4 the highest muscular strength quartile. (B) Incidence of MS across muscular strength categories by age groups. Incidence rates per 1000 man‐years are shown labeled with bars. The number of subjects for each age group is 20‐39: 1239; 40‐49: 1249; and 50+: 745. Q1 represents the lowest and Q4 the highest muscular strength quartile. The linear trend p values for the age groups 20‐39, 40‐49, and 50+ are less < 0.001, 0.01, and 0.05, respectively. Adapted from references () with permission.



Figure 9.

Impact of fitness on relative risk for all‐cause and cardiovascular disease (CVD) mortality associated with metabolic syndrome before and after the inclusion of cardiorespiratory fitness (CRF) as a covariate in more than 19,000 men 20‐83 years of age from Aerobics Center Longitudinal Study. Error bars represent 95% confidence intervals and demonstrate that after inclusion of CRF as a covariate, all‐cause and CVD mortality were no longer statistically significant. Adapted from reference () with permission.



Figure 10.

All‐cause (A) and cardiovascular disease (B) mortality death rates per 10,000 mean‐years of follow‐up in “healthy” and subjects with metabolic syndrome (MS), adjusted for age and year of examination more than 19,000 men 20‐83 years of age from Aerobics Center Longitudinal Study. The theoretical contributions of fitness and MS are depicted by brackets. Adapted from reference () with permission.



Figure 11.

Relative risk (RR) of (A) all‐cause and (B) cardiovascular disease (CVD) mortality in more than 19,000 men from Aerobics Center Longitudinal Study, adjusted for age, examination year, smoking, alcohol consumption, possible existence of CVD, and parental history of premature CVD. Second and forth bars within a body mass index category refer to cardiorespiratory fitness (CRF)‐adjusted RR's. Data, with permission, from reference ().



Figure 12.

Adjusted cases of metabolic syndrome (MS) based on minutes per week of leisure time physical activity in fit and unfit men after an average 4‐year follow‐up (). Copyright 2002 American Diabetes Association. From Diabetes Care®, Vol. 25, 2002; 1612‐1618. Reprinted by permission of the American Diabetes Association.



Figure 13.

Schematic diagram of future directions to determine mechanisms by which aerobic training (AT) and resistance training (RT) increase insulin sensitivity. Although there is preliminary evidence, more research is needed to clearly identify the mechanisms that are involved, as denoted by the question marks linking AT and RT to enhance insulin signaling.



Figure 14.

Insulin sensitivity and physical activity measured by accelerometer by quartiles of average number of counts/min and quartiles of percent time sedentary in the insulin sensitivity and cardiovascular risk study. M/I is the unit measurement of insulin sensitivity (μmol.min−1kgFFM−1nmol/L−1) (). Copyright 2008 American Diabetes Association. From Diabetes Care®, Vol. 57, 2008; 2613‐2618. Reprinted by permission of the American Diabetes Association.



Figure 15.

Effects of training and age on area under the curve for (A) glucose and (B) insulin during an oral glucose tolerance test. Adapted, with permission, from reference ().



Figure 16.

Effects of chronic training (dashed line), inactivity (solid line) for 10 days and one single bout (dotted line) of aerobic exercise on (A) blood glucose and (B) insulin during an oral glucose tolerance test in well‐trained subjects. Adapted, with permission, from reference ().

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Christian K. Roberts, Andrea L. Hevener, R. James Barnard. Metabolic Syndrome and Insulin Resistance: Underlying Causes and Modification by Exercise Training. Compr Physiol 2013, 3: 1-58. doi: 10.1002/cphy.c110062