SEARCH

SEARCH BY CITATION

Keywords:

  • Metabolic flexibility;
  • obesity;
  • youth

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Metabolic flexibility and regulation of adipose tissue metabolism
  5. Effect of ectopic fat storage on metabolic flexibility
  6. Muscle oxidative capacity and metabolic flexibility
  7. Dietary and physical activity determinants of metabolic flexibility
  8. Perspectives and conclusion
  9. Conflict of Interest Statement
  10. Acknowledgement
  11. References

The concept of metabolic flexibility describes the ability of skeletal muscle to switch between the oxidation of lipid as a fuel during fasting periods to the oxidation of carbohydrate during insulin stimulated period. Alterations in energy metabolism in adults with obesity, insulin resistance and/or type 2 diabetes induce a state of impaired metabolic flexibility, or metabolic inflexibility. Despite the increase in the prevalence of type 2 diabetes in obese children and youth, less is known about the factors involved in the development of metabolic inflexibility in the paediatric population. Metabolic flexibility is conditioned by nutrient partitioning in response to feeding, substrate mobilization and delivery to skeletal muscle during fasting or exercising condition, and skeletal muscle oxidative capacity. Our aim in this review was to identify among these factors those making obese children at risk of metabolic inflexibility. The development of ectopic rather than peripheral fat storage appears to be a factor strongly linked with a reduced metabolic flexibility. Tissue growth and maturation are determinants of impaired energy metabolism later in life but also as a promising way to reverse metabolic inflexibility given the plasticity of many tissues in youth. Finally, we have attempted to identify perspectives for future investigations of metabolic flexibility in obese children that will improve our understanding of the genesis of metabolic diseases associated with obesity.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Metabolic flexibility and regulation of adipose tissue metabolism
  5. Effect of ectopic fat storage on metabolic flexibility
  6. Muscle oxidative capacity and metabolic flexibility
  7. Dietary and physical activity determinants of metabolic flexibility
  8. Perspectives and conclusion
  9. Conflict of Interest Statement
  10. Acknowledgement
  11. References

Metabolic flexibility describes the ability to adapt substrate utilization to substrate availability. This concept is best illustrated by the ability of skeletal muscle to switch between the oxidation of lipid as a fuel during fasting periods to the oxidation of carbohydrate (CHO) during insulin stimulated periods (1). There is considerable evidence in adults that the alteration of metabolic flexibility is involved in the development of insulin resistance in obesity (1). Despite the increase in the prevalence of obesity in children and youth over the last decades (2), much less is known about the link between metabolic flexibility and the development of insulin resistance in the paediatric population. It has been speculated that the existence of type 2 diabetes in children and youth may indicate a faster transition from impaired glucose tolerance to type 2 diabetes in childhood when compared with adults. Thus, it is critical to identify early metabolic abnormalities in children rapidly gaining body fat because of the rapid deterioration in β-cell function that can occur in obese adolescents with glucose intolerance (3). No studies have to date specifically investigated metabolic flexibility in obese children and youth. However, experimental techniques used to assess metabolic flexibility have already been used in a number of studies in obese children and youth (4,5). The purpose of this review is therefore to describe the development of metabolic inflexibility associated with obesity in children defined as those before puberty and youth defined as those under the age of 18. Metabolic flexibility was originally described in studies using the hyperinsulinemic-euglycemic clamp technique (1). In addition, a number of experimental situations challenge the organism's ability to adapt substrate utilization and are therefore valuable to investigate metabolic flexibility. This includes the adaptation of substrate utilization to diets differing in nutrient composition and the ability to reach a high rate of fat oxidation during exercise. This review includes hyperinsulinemic-euglycemic clamp studies where substrate utilization was assessed and studies that reported the adaptation of substrate utilization in response to exercise and alterations in diet composition in obese children and youth. We paid particular attention to studies that compared (i) normal weight children and youth to overweight children and youth to assess the effect of obesity; (ii) overweight children and youth to overweight adults to assess changes linked with growth and maturation and (iii) different adipose tissue localization. Finally, we identify issues that could be addressed to improve our understanding of the development of metabolic inflexibility in obese children and youth and lead to enhanced clinical management and treatment.

Metabolic flexibility and regulation of adipose tissue metabolism

  1. Top of page
  2. Summary
  3. Introduction
  4. Metabolic flexibility and regulation of adipose tissue metabolism
  5. Effect of ectopic fat storage on metabolic flexibility
  6. Muscle oxidative capacity and metabolic flexibility
  7. Dietary and physical activity determinants of metabolic flexibility
  8. Perspectives and conclusion
  9. Conflict of Interest Statement
  10. Acknowledgement
  11. References

A tight regulation of adipose tissue lipolytic and antilipolytic activity is necessary to the shift in substrate utilization from fasting conditions to hyperinsulinemic conditions. Obesity is associated in most subjects with high-plasma free fatty acid (FFA) level and a poor suppression of lipolysis and FFA release in the circulation when insulin levels are increased.

However, the experimental maintenance of plasma FFA level during a hyperinsulinemic condition to the level of a fasting condition results in a low inhibition of fat oxidation in skeletal muscle (6,7). In addition, high-plasma FFA levels concomitant to hyperinsulinemia decrease glucose disposal rate. This is due first to a reduced glycogen synthesis caused by the inhibition of glycogen synthase activity and glucose transport/phosphorylation and second to a reduced glucose utilization caused by an inhibition of pyruvate dehydrogenase activity. In individuals with insulin resistance, the poor suppression of adipose tissue lipolysis during insulin-stimulated conditions leads to high-plasma FFA levels. As a consequence, lipid species accumulate in muscle cells, interfering with insulin signalling, thereby inhibiting insulin-stimulated glucose disposal. In adolescents, metabolic inflexibility is linked to an impaired adipose tissue lipolytic regulation. During hyperinsulinemia, high-plasma FFA levels in obese adolescents have been associated with a low-glucose disposal (140 ± 10 mg m−2 min−1) when compared with lean adolescents (220 ± 20 mg m−2 min−1) and lean adults (305 ± 15 mg m−2 min−1), as well as a low-glucose oxidation (8). Concomitantly, fat oxidation was not suppressed in obese adolescents during the insulin-stimulated condition compared with the fasted condition whereas there was a 40% decrease of fat oxidation in lean adolescents and an 80% reduction in lean adults.

As opposed to insulin stimulated conditions, the mobilization of FFA stored in adipose tissue is needed during fasted and exercise conditions to match the energy needs of the organism. To compare lipolytic rate in lean and obese children, Hershberger et al. (9) measured interstitial glycerol concentrations in adipose tissue and adipose tissue blood flow by using the microdialysis technique. They showed that under fasting conditions glycerol release in obese children was only 70% of the glycerol release in the lean group. However, by using isotope tracer techniques, Robinson et al. (8) did not observe any significant difference in glycerol turnover between lean and obese adolescents in a fasted condition. The difference between these studies is likely to be explained by the fact that microdialysis in adipose tissue enables to measure the lipolytic activity of specific adipose tissue regions whereas isotope tracer techniques are rather used to assess the whole body lipolytic activity (10).

In summary, during hyperinsulinemic conditions obese adolescents exhibit a higher release of FFA from adipose tissue into the circulation than lean children which may lead to an impaired suppression of plasma FFA oxidation, glucose oxidative disposal and glycogen storage (7,11). In addition, similarly to results in adults (12), the decrease in lipolysis observed locally in adipose tissue in obese children may not fully compensate for their high body fat mass, leading to high FFA plasma levels which blunt insulin-stimulated glucose uptake and metabolic flexibility during hypersinulinemic conditions.

The evidence of metabolic inflexibility in overweight children and youth are summarized in Table 1.

Table 1.  Evidence of metabolic inflexibility in overweight children during fasting and insulin – stimulated conditions
StudyParticipantsMethodsMain outcomes
  1. inline image, decrease; inline image, increase; C, control; EMCL, extramyocellular lipids; G, groups; GD, glucose disposal; GDR, glucose disposal rate; HEC, hyperinsulinemic-euglycemic clamp; IC, indirect calorimetry; IHTG, intrahepatic triglycerides; IMCL, intramyocellular lipids; IRS, insulin receptor substrate; IS, insulin sensitivity; IVGTT, iv glucose tolerance test; LBM, lean body mass; NOGD, non oxidative; OGD, oxidative glucose disposal; OGTT, oral glucose tolerance test; RER, respiratory exchange ratio; SIT, stable isotope technique; T2D, type 2 diabetes.

Caprio et al. 1996 (57)15 obese children 18 obese adolescentsHEC, ICinline imageOGD inline imageNOGD inline imageSuppression of fat oxidation in pre-pubertal obese children
Control group: 10 lean children 16 lean adolescents
Robinson et al. 1998(8)Seven obese and seven lean 13- to15-year-old adolescentsHEC (40 mU m−2 min−1), SITinline imageOGD (obese: 10 ± 2 to 17 ± 3 umol kgLBM−1 min−1 vs. lean 11 ± to 19 ± 4 umol kgLBM−1 min−1) inline imageTotal GD inline imageAbsolute glycerol turnover
Le Fur et al. 2002 (58)G1: 144 obese children without variant in IRS-1 or IRS-2 variants G2: 25 children one or two variant in both IRS-1 and IRS-2 G3: 39 lean control subjectsOGTT (insulin + glucose areas, insulin sensitivity index)Insulin area (×103 pmol−1 mL−1): G1 = 61.9 (2.8) G2 = 98.9 (12.6) G3 = 36.1 (9.4)
Glucose area (m mol−1 L−1): G1 = 73.8 (8) G2 = 77.8 (16) G3 = 73.0 (11)
Insulin Sensitivity Index (ISI): G1 = 3.3 (0.2) G2 = 2.2 (0.2) G3 = 4.8 (0.3)
Sinha et al. 2002 (22)Eight non-obese adolescents vs. 14 obese adolescentsHEC, 1H-NMR (intra and extramyocellular lipid)Significant correlations between IMCL and GDR (r = 0.59), and EMCL and GDR (r = 0.53)
Sunehag et al. 2005 (49)Thirteen 14-year-old obese subjects vs. lean controls7 days of low-CHO/high-fat diet or high-CHO/low-fat diet Pre- and post-diet measurements: IVGTT, SITAfter 7 days substrate oxidation matches nutrient intake 32% inline imageneoglucogenesis in obese adolescents High-fat diet: inline imageIS in lean, but not in obese adolescents
Gungor et al. 2005 (59)14 adolescents with type 2 diabetes, 20 control matched for body fatHEC, SIT (80 mU m−2 min−1), ICGD: T2D < C, OGD: T2D < C, NOGD: T2D < C.
Weiss et al. 2005 (4)14 obese insulin resistant adolescents vs. 14 obese insulin sensitive adolescentsHEC, SIT (80 mU m−2 min−1), ICinline imageRER change with hypersinsulinemia: +0.007 vs. +0.12, inline imageNOGD
Perseghin et al. 2006 (29)54 obese adolescentsMRI (intrahepatic fat content), OGTT, ICinline imageFasting RER in children with high intrahepatic fat content inline imageChange in RER with OGTT
Bell et al. 2007 (52)Fourteen 13-year-old obese adolescentsHEC pre- and post-8-week exercise training programme Submaximal exercise testing pre- and post-8-week exercise training programmeinline imageIS; glucose infusion rate: 8.20 mg kg−1 min−1 to 10.02 mg kg−1 min−1
Vitola et al. 2009 (60)Weight-loss programme in obese adolescentsHEC, magnetic resonance spectroscopy (IHTG content)8% weight loss associated with a 61% inline imagein IHTG and a 97% inline imageGD
Lazzer et al. 2009 (61)30 obese adolescents, 30 lean adolescentsGraded exercise, ICIdentical maximal rate of fat oxidation in obese and lean boys (0.32 g min−1) and obese and lean girls (0.25 g min−1).

Effect of ectopic fat storage on metabolic flexibility

  1. Top of page
  2. Summary
  3. Introduction
  4. Metabolic flexibility and regulation of adipose tissue metabolism
  5. Effect of ectopic fat storage on metabolic flexibility
  6. Muscle oxidative capacity and metabolic flexibility
  7. Dietary and physical activity determinants of metabolic flexibility
  8. Perspectives and conclusion
  9. Conflict of Interest Statement
  10. Acknowledgement
  11. References

Ectopic fat depots such as in the viscera, the skeletal muscle, the liver or the pancreas (13) rather than whole body adiposity are associated with metabolic abnormalities and defects in insulin signalling (13–15). On the other hand, subcutaneous adipose tissue is considered protective for the storage of excess energy intake. However, when peripheral depots fail to expand to store excess energy intake, fat accumulates in ectopic depots inducing metabolic alterations leading to type 2 diabetes (13).

The increase in the prevalence of abdominal obesity among youth in recent years exceeds the increase of simple obesity (16). Hence, in a large proportion of obese children and youth, the expansion of subcutaneous tissue through hyperplasic and hypertrophic processes may be limited and place them at risk for metabolic inflexibility because of the early development of ectopic fat depots. For this reason, we present the evidence regarding the relationship between characteristics of metabolic flexibility and heterogeneity in body fat distribution. Figure 1 displays the detrimental effects of excess adipose tissue growth during childhood.

image

Figure 1. Detrimental effects of excess adipose tissue growth during childhood. IL-6, interleukin-6; TNF-α, tumor necrosis factor-α.

Download figure to PowerPoint

Visceral and subcutaneous adipose tissue

Metabolic inflexibility is characterized in obese adolescents with high visceral fat content and insulin resistance by a reduced nonoxidative glucose disposal during a hyperinsulinemic-euglycemic clamp when compared with insulin sensitive obese adolescents (4). Glycogen synthesis accounts for most of the nonoxidative glucose disposal and a reduced ability to store CHO as glycogen has been reported to be a critical factor for weight gain (17,18). Hence, children and youth with insulin resistance and a reduced nonoxidative glucose disposal in the face of an excessive CHO intake may be at greater risk of becoming even more obese.

The negative effects of visceral fat deposition on metabolic flexibility may be mediated by decreased levels of adiponectin. Adiponectin is secreted by adipose tissue and has anti-inflammatory, antiatherogenic and insulin sensitizing properties (19). Adiponectin levels are decreased in obese adolescents with high visceral adipose tissue, insulin resistance and metabolic syndrome (5). Adiponectin secretion may also be responsible for chronic adaptations of fat oxidation as a primary fuel or the ability to switch between fuels (19). A positive correlation has been observed between plasma adiponectin concentration and metabolic flexibility during a hyperinsulinemic condition (20). Some studies also suggest that a low level of fasting plasma adiponectin characterizes metabolically inflexible adolescents (5,21). Bacha et al. (21) also observed that obese adolescents with severe insulin resistance had decreased adiponectin plasma levels, a lower glucose disposal rate because of both reduced oxidative and nonoxidative disposal rates, and a blunted suppression of fat oxidation during hyperinsulinemia when compared with insulin sensitive adolescents.

Intramuscular triglycerides

Intramuscular triglyceride (IMTG) accumulation is positively associated with abnormalities in glucose and fat metabolism and insulin resistance in obese children and youth (22). Increased levels of fatty acids metabolites (fatty acyl CoA, ceramides, diglycerides) induces lipotoxicity due because of defects in the insulin signalling cascade (23). High levels of lipid peroxidation also induce insulin resistance and mitochondrial damage (24).

The IMTG accumulation is positively associated with the development of peripheral insulin resistance in obese children and youth with prediabetes (22,25). In adolescents, intramyocellular and extramyocellular contents correlate with total glucose disposal during a hyperinsulinemic-euglycemic clamp (r = 0.59 and r = 0.53, respectively) (22). Moreover, Weiss et al. (4) indicated that obese insulin resistant adolescents with high IMTG deposition can be differentiated from insulin sensitive obese adolescents by a reduced glucose disposal rate and a poor suppression of lipid oxidation during a hyperinsulinemic-euglycemic clamp procedure.

However, some issues remain to be addressed in children and youth. E.g. the distribution of lipid droplets within muscle fibres is more central in obese than in lean adults (26). According to Van Loon and Goodpaster (27), the greater size of lipid droplets in obese individuals and persons with type 2 diabetes makes them less accessible to intramuscular lipase and is likely to induce an altered mobilization of IMTG and defects in insulin signalling. The mechanisms linking metabolic flexibility and IMTG content, however, remain a mystery in children and youth, because collecting skeletal muscle biopsies to measure enzyme activity and fatty acid transport proteins, e.g. is ethically restricted. Possibly, animal models of growth and development might provide some insight into the significance of IMTG accumulation in the obese state.

Hepatic fat deposition

Non-alcoholic fatty liver disease (NAFLD) is a pathological condition that can develop in obese, but also in lean individuals and is associated with increased insulin resistance as well as alterations of lipid and glucose metabolism. The percentage of obese adolescents considered to have NAFLD has been estimated between 22% and 77% (28).

Perseghin et al. (29) have shown in 11- to 18-year-old obese adolescents with a high intrahepatic fat content that basal respiratory exchange ratio (RER) was significantly higher than in obese adolescents with a low intrahepatic fat content, indicating a lower lipid oxidation in the fasted condition. Moreover, these adolescents exhibited a blunted RER increase during an insulin-stimulated condition, which is consistent with impaired metabolic flexibility. In this study, the association between intrahepatic fat content and RER in the fasting condition persisting even after controlling for body mass index and trunk fat content assessed by Dual-X Ray Absorptiometry, indicating that it is the fat localization in the liver which determines metabolic flexibility rather than whole body adiposity. No studies have specifically investigated defects in adipose tissue lipolysis in adolescents with NAFLD.

Indeed, more research is necessary to understand the early development of the association between NAFLD and metabolic flexibility. To our knowledge, the measurement of intrahepatic fat content has not been performed in pre-pubertal children who have a relatively shortened ‘history’ of obesity.

Muscle oxidative capacity and metabolic flexibility

  1. Top of page
  2. Summary
  3. Introduction
  4. Metabolic flexibility and regulation of adipose tissue metabolism
  5. Effect of ectopic fat storage on metabolic flexibility
  6. Muscle oxidative capacity and metabolic flexibility
  7. Dietary and physical activity determinants of metabolic flexibility
  8. Perspectives and conclusion
  9. Conflict of Interest Statement
  10. Acknowledgement
  11. References

Oxidative capacity

There is some evidence indicating a link between metabolic flexibility and oxidative capacity in youth. E.g. Nadeau et al. (30) have shown in lean adolescents and obese adolescents with or without type 2 diabetes that the glucose disposal rate was strongly and positively associated with the peak oxygen uptake during exercise testing. Even though rates of fat and CHO utilization were not measured, this is suggestive of altered metabolic flexibility because metabolic flexibility is mainly conditioned by the ability to increase cellular glucose uptake with hyperinsulinemia (20).

At the cellular level, mitochondrial abnormalities, low muscle carnitine palmitoyl transferase 1 activity and low level of enzyme activities of the tricarboxylic acid cycle, the electron transport chain, and β-oxidation have been observed in obese insulin resistant adults who concomitantly exhibited high RER under resting conditions (31,32). Such metabolic alterations may contribute to the higher RER observed in obese adolescents with NAFLD, but this remains unconfirmed as studies on muscle cells are not performed in obese children and youth. Moreover, fat oxidation capacity is greater in subsarcolemmal mitochondria that are also important for signal transduction or substrate transport at the cell surface (33). In an adult study by Ritov et al. (33), a reduced activity of the electron transport chain, an altered morphological structure, and a smaller size of subsarcolemmal mitochondria were observed in obese individuals and persons with type 2 diabetes, compared with lean controls. Hence, a specific dysfunction of this pool of mitochondria is linked with the development of insulin resistance. Given the essential role of these mitochondria in fat oxidation, it is possible that insulin action and glucose disposal contribute to a low maximal rate of fat oxidation and impaired metabolic flexibility. Finally, the lower RER change between fasting and hypersinsulinemic conditions in adults with type 2 diabetes compared with healthy subjects has been eliminated after adjusting for glucose disposal rate, indicating that at least in type 2 diabetes metabolic inflexibility might be more a consequence of defects in substrate delivery to skeletal muscle rather than low oxidative capacity per se(20).

Capacity for fat oxidation

In a recent review, Galgani et al. (20) presented exercise as a favourable condition to study metabolic flexibility because it requires an important regulation of the physiological mechanisms responsible for balancing substrate utilization with availability. Studies in adults have already provided evidence for metabolic inflexibility during exercise, such as a reduced ability for glycogen utilization in obese and insulin resistant subjects (34,35), or a 50% increase in the reliance on fatty acids from non plasma sources in obese men (35). There is a paucity of studies that have examined substrate oxidation during exercise in obese children and adolescents with insulin resistance and other features of metabolic inflexibility (visceral fat, high intramuscular and intrahepatic lipid content). In non-obese children and youth, a higher contribution of fat oxidation to energy expenditure during exercise has consistently been reported compared with adults (for review, see Riddell (36)). Indeed, Timmons et al. (37) observed in boys that serum levels of testosterone were negatively correlated with fat oxidation during exercise. In obese children and youth, several studies have also shown that the maximal capacity for fat oxidation during exercise is decreased at puberty (38,39). This is concordant with results suggestive of impaired metabolic flexibility. Increased insulin resistance and insulin secretion in response to glucose ingestion occurs in pubertal children compared to pre-pubertal children and adults (40) because of an increased activity of the GH/IGF-1 axis (41).

However, a number of studies have challenged the idea that obesity is associated with low fat oxidation rate. Defects in β-oxidation have been suggested to be rather characterized by an incomplete oxidation of fatty acids despite overall high rate of fat oxidation, which could be involved in the development of insulin resistance (42–44). In addition, a low oxidative capacity as a cause of IMTG accumulation and insulin resistance, showing that insulin resistance in patients or induced experimentally in animals could be associated with a normal oxidative capacity (45,46). There is no question that additional studies are urgently needed to investigate energy metabolism during exercise in children and youth with obesity and insulin resistance.

Figure 2 depicts the main characteristics of metabolic inflexibility in skeletal muscle.

image

Figure 2. Main characteristics of metabolic inflexibility of skeletal muscle. GLUT, glucose transporters; ROS, reactive oxygen species.

Download figure to PowerPoint

Dietary and physical activity determinants of metabolic flexibility

  1. Top of page
  2. Summary
  3. Introduction
  4. Metabolic flexibility and regulation of adipose tissue metabolism
  5. Effect of ectopic fat storage on metabolic flexibility
  6. Muscle oxidative capacity and metabolic flexibility
  7. Dietary and physical activity determinants of metabolic flexibility
  8. Perspectives and conclusion
  9. Conflict of Interest Statement
  10. Acknowledgement
  11. References

Chronic effect of high-fat or high-carbohydrate diets

The ability to adapt to a high-fat diet or a high-CHO diet by shifting substrate utilization to match the same proportion as the macronutrients in these diets is a critical factor to prevent weight gain (18,47). This ability was first mentioned as a component of metabolic inflexibility in a study showing that post-obese adults failed to increase fat oxidation to the level of fat intake with a high-fat diet (48). In both obese and lean children and youth, Sunehag et al. (49,50) have shown that the adaptation of substrate oxidation to high-fat or high-CHO diets occurs within a 7-day period. In contrast to lean subjects, however, insulin secretion in obese adolescents was increased because insulin sensitivity failed to adapt with the high-fat diet (49). In addition, neoglucogenesis increased by 32% while glycogenolysis was decreased. Collectively, these two mechanisms enabled the obese adolescents to maintain glucose production similar to lean individuals. However, the authors assumed that with more severe insulin resistance the β-cell would fail to produce enough insulin with a high-CHO diet and the suppression of glycogenolysis by insulin would be blunted with a high-fat diet. Ultimately, hyperglycemia occurs with severe insulin resistance independent of the diet composition. In summary, there is evidence of early signs of metabolic inflexibility in obese adolescents in their response to both high-fat and high-CHO diets.

Physical activity level and metabolic flexibility

Physical activity is defined as all bodily movements that increase energy expenditure above resting energy expenditure. A higher physical activity level has been related to improvements in outcomes related to metabolic flexibility. Indeed, young first degree relatives of persons with type 2 diabetes with a high physical activity level have a significantly higher glucose utilization during a hyperinsulinemic-euglycemic clamp compared with physically inactive relatives of persons with type 2 diabetes (8.6 ± 0.3 vs. 5.6 ± 0.3 mg glucose kg−1 min−1) (51). In addition, a high physical activity level in offspring of persons with type 2 diabetes was protective because glucose disposal was similar to physically inactive control subjects (9.3 ±  0.9 mg glucose kg−1 min−1) (51).

In children and youth only Bell et al. (52) have, to our knowledge, assessed changes in whole body glucose disposal in response to insulin completed an 8-week exercise-training programme with three sessions a week based on aerobic and resistance exercises. An improvement in glucose disposal rate from 8.0 mg kg lean body mass (LBM)−1 min−1 to 10.0 mg kgLBM−1 min−1 during a hyperglycemic-euglycemic clamp was observed in 13-year-old adolescents, together with a lower heart rate at a submaximal exercise intensity (indicating improved fitness), whereas body composition remained unchanged. In an observational study, Schmitz et al. (53) reported a positive association between the glucose disposal rate during a hyperinsulinemic-euglycemic clamp and physical activity level among 13- to 19-year-olds.

Exercise training and high physical fitness may therefore be beneficial to children and youth at risk for type 2 diabetes as fit children of parents with type 2 diabetes demonstrate higher insulin sensitivity than unfit children of parents with type 2 diabetes (51).

To summarize, physical activity level could be an important factor determining metabolic flexibility because of an increased ability to reach high-fat oxidation rates with exercise training and increased insulin stimulated glucose uptake. Unfortunately, despite the importance of type 2 diabetes among children and youth, no study has investigated the benefits of exercise of exercise intervention for the treatment of metabolic inflexibility and subsequently insulin resistance.

Perspectives and conclusion

  1. Top of page
  2. Summary
  3. Introduction
  4. Metabolic flexibility and regulation of adipose tissue metabolism
  5. Effect of ectopic fat storage on metabolic flexibility
  6. Muscle oxidative capacity and metabolic flexibility
  7. Dietary and physical activity determinants of metabolic flexibility
  8. Perspectives and conclusion
  9. Conflict of Interest Statement
  10. Acknowledgement
  11. References

There are important reasons to investigate metabolic flexibility in children and youth. Similar to adults, an obese and insulin resistant state in childhood is associated with an impaired switch from fat to CHO as the main substrate for energy from fasting to insulin-stimulated conditions. However, obese children and youth differ from adults because they are in a dynamic phase of weight gain characterized by processes of growth and maturation. Moreover, if pancreatic β-cell failure developed in early childhood, it would be irreversible so that these children would face a life-time of complex health management. Hence, it will be necessary to aggressively study the factors that can improve metabolic flexibility in obese children and youth.

Most investigations of metabolic flexibility have focused on the shift in substrate utilization in response to change in glucose availability. However, metabolic flexibility to lipid is also important because the ability to adapt fat utilization to availability determines the accumulation of fat in ectopic fat depots and the subsequent development of insulin resistance (54). Thus, the adaptation of fat utilization in response to high-fat diet and the assessment of the maximal fat oxidation rate during exercise can provide insights on metabolic flexibility to fat. Contrary to clamp techniques, these experimental approaches are not invasive and are therefore well suited for future studies on metabolic flexibility in children and youth. Finally, some evidence now indicates inflexibility of protein metabolism in the insulin resistant state. Studying flexibility in protein metabolism is of great importance because protein accretion is needed to support normal growth during childhood, and obese children and youth are often reported to have a greater muscle mass and accelerated growth. Despite this, an increased protein turnover (55) or an increase protein utilization during exercise have been proposed to compensate for low glycogen utilization consequent to its impaired storage or impaired mobilization (56). Hence, the study of flexibility in protein metabolism should be a fruitful area of future research.

In conclusion, there is already strong evidence that insulin resistance in obese children and youth is associated with a reduced metabolic flexibility. Programmes that include nutritional education and an increase in physical activity level are likely to restore impaired metabolic functions (i.e. glucose transport, insulin signalling, muscle oxidative capacity, glycogen storage) and therefore adequate growth and development. Mitochondrial dysfunction, defects in insulin signalling, increased oxidative stress and lipid overflow to muscle cells are all factors consistently associated in prediabetes or type 2 diabetes, but without clear understanding between cause and effect. Longitudinal studies in children and youth are needed to determine if there are early risk factors that might be genetically or environmentally determined and help to identify children and youth with impaired metabolic flexibility who are at increased risk of developing metabolic diseases associated with obesity.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Metabolic flexibility and regulation of adipose tissue metabolism
  5. Effect of ectopic fat storage on metabolic flexibility
  6. Muscle oxidative capacity and metabolic flexibility
  7. Dietary and physical activity determinants of metabolic flexibility
  8. Perspectives and conclusion
  9. Conflict of Interest Statement
  10. Acknowledgement
  11. References