insulin resistance is a metabolic disorder that reflects low capability to wash glucose out of the bloodstream to target tissues .
unlike type 1 diabetes mellitus , which results from disrupted insulin secretion from pancreatic  cells , type 2 diabetes mellitus is a representative metabolic disease attributable to increased insulin resistance and decreased insulin sensitivity .
type 2 diabetes mellitus comprises > 90% of all cases of diabetes and affected > 350 million people in 2011 .
in particular , the population of diabetes mellitus is gradually increasing in korea , and about 15,000 diabetic patients die every year owing to the associated complications .
metabolic syndrome , a clinically prediabetic condition characterized by abdominal obesity , hypertension , hyperglycemia , and dyslipidemia , is closely associated with increased insulin resistance in etiology .
approximately 25% of the adult population is considered to be at risk of metabolic syndrome globally , and about 35% of the adult population in the united states is reported to have metabolic syndrome . in korea , the population with metabolic syndrome increased from 25% in 1998 to 31% in 2007 .
metabolic syndrome and type 2 diabetes mellitus are etiologically similar because they share two common causes : insulin resistance and abdominal obesity .
thus , patients with metabolic syndrome have about five times higher possibility to progress into type 2 diabetes mellitus compared with those without metabolic syndrome .
patients with type 2 diabetes mellitus or metabolic syndrome are usually at elevated risk of cardiovascular disease.2 , 8 , 9 degenerative alterations in vascular structure and function in the metabolic diseases result in atherosclerosis , a main cause of cardiovascular disease .
atherosclerosis results from dysfunction of the vascular endothelium , which is closely related to decreased no bioavailability and increased endothelium - derived contraction factors in blood vessels .
previous studies have indicated that excessive oxidative stress in the vasculature of patients with with metabolic disease is a possible mechanism to cause reduction in no bioavailability and to impair vascular endothelial function.9 , 11 , 12 , 13 however , few studies have demonstrated the physiological mechanisms from vascular cells in patients with metabolic disease .
regular physical activity is known as a strategy to reverse vascular dysfunction and to prevent future cardiovascular disease . however , a few studies have investigated the effect of exercise training on vascular function in patients with type 2 diabetes mellitus and metabolic syndrome.14 , 15 , 16 , 17 thus , the purpose of this review is to introduce potential physiological mechanisms by which vascular function is impaired in augmented insulin resistance , to summarize previous studies to investigate the effects of exercise training on vascular function in type 2 diabetes mellitus and metabolic syndrome , and to facilitate related studies in the future .
increased insulin resistance leads to augmented glucose level in the bloodstream . since vascular endothelium is the single innermost layer in the vascular structure , vascular endothelial cells are likely to be damaged by hyperglycemic stress , suggesting that metabolic dysfunction such as insulin resistance and type 2 diabetic mellitus may result in vascular dysfunction .
it has been demonstrated that the generation of reactive oxygen species ( ros ) is increased in both large and small vascular beds collected from hyperglycemic animal models . in a hyperglycemic environment , elevated ros generation in vascular cells can be influenced by various biological signaling pathways .
aldose reductase , in hyperglycemic conditions , converts glucose to sorbitol by using nicotinamide adenine dinucleotide phosphate as a cofactor , thus the regeneration of reduced glutathione is reduced and intracellular oxidative stress level is increased.2 , 20 , 21 increased advanced glycation end - products lead to increased receptor activity , which facilitates ros and inflammatory cytokine production.2 , 22 , 23 activation of the diacylglycerol 
protein kinase c pathway also contributes to the elevated generation of ros and inflammatory cytokines.2 , 24 , 25 , 26 in the overloaded glycolytic pathway induced by hyperglycemia , uridine diphosphate n - acetyl glucosamine has a negative effect on endothelial no synthase activity by obstructing its phosphorylation at serine 1177 and increases the expression of proinflammatory cytokines such as transforming growth factor-1 and plasminogen activator inhibitor-1.2 , 27 , 28 , 29 in the vascular endothelium , oxidative stress induced by increased ros generation not only directly plays a pivotal role in reducing no bioavailability , but also leads to increased expression of proinflammatory cytokines so that proatherogenic and prothrombotic processes are abnormally facilitated .
thus , the structural and functional integrity of vascular endothelium is likely to be damaged with insulin resistance , which increases the risk of cardiovascular disease in those who are continuously exposed to hyperglycemia in the circulation .
thus , the increase in insulin resistance in the vasculature has a negative effect on vascular endothelial function and cardiovascular morbidity and mortality .
regular physical activity and exercise are known to promote cardiovascular health in those with insulin resistance .
there are no specific exercise guidelines for metabolic syndrome patients to preserve and promote their cardiovascular health .
even though their joint statements were published in both 2000 and 2010 , the american college of sport medicine and the american diabetes association only provide generic exercise regimens for diabetic patients.32 , 33 in the two previous position standards , the experts recommended aerobic exercise or aerobic exercise combined with resistance exercise to prevent and promote cardiovascular disease risk in patients with diabetes . however , the effect of either aerobic or combined exercise training on both micro- and macrovascular endothelial function is still in debate .
some studies presented positive results of exercise training,17 , 34 , 35 , 36 but others did not show any positive effect of exercise on vascular health in type 2 diabetic patients.37 , 38 , 39 for individuals with metabolic syndrome , a small number of studies have explored the effect of exercise training on vascular endothelial function , but the training effect has presented a positive tendency,14 , 15 , 40 , 41 and had a close relationship with increased no bioavailability .
it is established that insulin resistance contributes to impaired vascular endothelial function , and either aerobic or combined exercise training programs might help to reverse endothelial dysfunction in those who have insulin resistance.14 , 15 , 17 , 34 , 35 , 36 , 40 , 41 exercise intensity also seems to be a main factor influencing exercise effects in people with insulin resistance .
although both moderate - intensity continuous training and high - intensity interval training have shown improvement in vascular endothelial function , in the same caloric expenditure , high - intensity interval training presents superior effect on vascular endothelial function and glycemic control.15 , 36 the physiological mechanisms by which either aerobic or combined exercise training enhances vascular endothelial function in insulin resistance are not fully elucidated .
positive changes in oxidative stress and inflammatory biomarkers after exercise training are thought to be potential mechanisms from animal and systemic biomarker studies,8 , 43 , 44 , 45 but no study has investigated the local alterations of potential biomarkers in human vasculature in response to acute or chronic exercise training in insulin resistance .
furthermore , it is also necessary to figure out a mechanistic linkage between exercise intensity and functional alteration of vascular endothelium .
table 1 shows a summary of studies examining the effect of exercise on endothelial function in individuals with insulin resistance .
current evidence indicates that metabolic disease such as insulin resistance or metabolic syndrome induced vascular dysfunction in various animal models ( table 2 ) .
even though a majority of previous studies have indicated that insulin resistance or metabolic syndrome induced vascular dysfunction , some studies also showed that these prediabetic conditions did not change endothelial function .
these discrepant conclusions suggest that alteration of vascular function is affected by multiple factors including duration of certain diseases and vascular beds .
for example , a number of studies showed that obesity ( high - fat diet ) induced insulin resistance caused acetylcholine - induced endothelial dysfunction in various blood vessels , including coronary arterioles , gracilis artery , femoral artery and aorta in mouse models,46 , 47 , 48 , 49 whereas some studies indicated that insulin resistance did not induce vascular dysfunction in femoral artery , mesentery arterioles and aorta.48 , 50 , 51 in addition , some studies showed that type of agonists induced inconsistent results in the same vascular beds.50 , 52 , 53 for instance , insulin resistance caused impaired insulin - dependent vasorelaxation , however , acetylcholine - induced vasorelaxation was identical in mesenteric arterioles of c57bl/6j mice.50 , 52 by contrast , in the femoral artery of c57bl/6j mice , insulin resistance did not change insulin - induced vasorelaxation , but acetylcholine - induced vasorelaxation was reduced by insulin resistance . 

table 2 summarizes the effect of insulin resistance or metabolic syndrome on vasorelaxation in various vasculatures in experimental animal models .
it is well documented that exercise or regular physical activity has beneficial effects on metabolic diseases in animal models .
considering previous studies , most exercise protocols improved vascular function in various vascular beds such as coronary arterioles , arterioles , feed arteries from skeletal muscle and aorta ( table 3 ) .
however , it is still unclear which mechanisms are involved in these beneficial effects of exercise .
table 3 summarizes the effect of exercise on vascular dysfunction induced by insulin resistance or metabolic syndrome in experimental animal models .
there are no specific exercise guidelines for metabolic syndrome patients to preserve and promote their cardiovascular health .
even though their joint statements were published in both 2000 and 2010 , the american college of sport medicine and the american diabetes association only provide generic exercise regimens for diabetic patients.32 , 33 in the two previous position standards , the experts recommended aerobic exercise or aerobic exercise combined with resistance exercise to prevent and promote cardiovascular disease risk in patients with diabetes . however , the effect of either aerobic or combined exercise training on both micro- and macrovascular endothelial function is still in debate .
some studies presented positive results of exercise training,17 , 34 , 35 , 36 but others did not show any positive effect of exercise on vascular health in type 2 diabetic patients.37 , 38 , 39 for individuals with metabolic syndrome , a small number of studies have explored the effect of exercise training on vascular endothelial function , but the training effect has presented a positive tendency,14 , 15 , 40 , 41 and had a close relationship with increased no bioavailability .
it is established that insulin resistance contributes to impaired vascular endothelial function , and either aerobic or combined exercise training programs might help to reverse endothelial dysfunction in those who have insulin resistance.14 , 15 , 17 , 34 , 35 , 36 , 40 , 41 exercise intensity also seems to be a main factor influencing exercise effects in people with insulin resistance .
although both moderate - intensity continuous training and high - intensity interval training have shown improvement in vascular endothelial function , in the same caloric expenditure , high - intensity interval training presents superior effect on vascular endothelial function and glycemic control.15 , 36 the physiological mechanisms by which either aerobic or combined exercise training enhances vascular endothelial function in insulin resistance are not fully elucidated .
positive changes in oxidative stress and inflammatory biomarkers after exercise training are thought to be potential mechanisms from animal and systemic biomarker studies,8 , 43 , 44 , 45 but no study has investigated the local alterations of potential biomarkers in human vasculature in response to acute or chronic exercise training in insulin resistance .
furthermore , it is also necessary to figure out a mechanistic linkage between exercise intensity and functional alteration of vascular endothelium .
table 1 shows a summary of studies examining the effect of exercise on endothelial function in individuals with insulin resistance .
current evidence indicates that metabolic disease such as insulin resistance or metabolic syndrome induced vascular dysfunction in various animal models ( table 2 ) .
even though a majority of previous studies have indicated that insulin resistance or metabolic syndrome induced vascular dysfunction , some studies also showed that these prediabetic conditions did not change endothelial function .
these discrepant conclusions suggest that alteration of vascular function is affected by multiple factors including duration of certain diseases and vascular beds .
for example , a number of studies showed that obesity ( high - fat diet ) induced insulin resistance caused acetylcholine - induced endothelial dysfunction in various blood vessels , including coronary arterioles , gracilis artery , femoral artery and aorta in mouse models,46 , 47 , 48 , 49 whereas some studies indicated that insulin resistance did not induce vascular dysfunction in femoral artery , mesentery arterioles and aorta.48 , 50 , 51 in addition , some studies showed that type of agonists induced inconsistent results in the same vascular beds.50 , 52 , 53 for instance , insulin resistance caused impaired insulin - dependent vasorelaxation , however , acetylcholine - induced vasorelaxation was identical in mesenteric arterioles of c57bl/6j mice.50 , 52 by contrast , in the femoral artery of c57bl/6j mice , insulin resistance did not change insulin - induced vasorelaxation , but acetylcholine - induced vasorelaxation was reduced by insulin resistance . 

table 2 summarizes the effect of insulin resistance or metabolic syndrome on vasorelaxation in various vasculatures in experimental animal models .
it is well documented that exercise or regular physical activity has beneficial effects on metabolic diseases in animal models .
considering previous studies , most exercise protocols improved vascular function in various vascular beds such as coronary arterioles , arterioles , feed arteries from skeletal muscle and aorta ( table 3 ) .
however , it is still unclear which mechanisms are involved in these beneficial effects of exercise .
table 3 summarizes the effect of exercise on vascular dysfunction induced by insulin resistance or metabolic syndrome in experimental animal models .
there is no doubt that physical activity or regular exercise has beneficial effects on vascular function .
however , it should be noted that some discrepancies exist among these studies according to experimental design including type of exercise , intensity and duration of exercise , and heterogeneity of vascular beds .
it seems that vascular function in smaller resistant arteries may be altered differently compared to larger vessels such as aorta and conduit arteries , based on the status of disease , exercise type , duration , and intensity .
 insulin resistance associated with metabolic syndrome and type 2 diabetes mellitus is an epidemic metabolic disorder , which increases the risk of cardiovascular complications . 
 impaired vascular endothelial function is an early marker for atherosclerosis , which causes cardiovascular complications . 
 both experimental and clinical studies indicate that endothelial dysfunction in vasculatures occurs with insulin resistance . 
 the associated physiological mechanisms are not fully appreciated yet , however , it seems that augmented oxidative stress , a physiological imbalance between oxidants and antioxidants , in vascular cells is a possible mechanism involved in various vascular beds with insulin resistance and hyperglycemia . 
 regardless of the inclusion of resistance exercise , aerobic exercise seems to be beneficial for vascular endothelial function in both large conduit and small resistance vessels in both clinical and experimental studies with insulin resistance . in clinical cases , 
 aerobic exercise over 8 weeks with higher intensity seems more beneficial than the cases with shorter duration and lower intensity . 
 however , more studies are needed in the future to elucidate the physiological mechanisms by which vascular endothelial function is impaired in insulin resistance and improved with aerobic exercise . 
Introduction
Insulin resistance and oxidative stress: a putative physiological mechanism to cause vascular dysfunction
Insulin resistance and exercise: effects on vascular function
Effect of exercise training on vascular function in individuals with insulin resistance
Effect of exercise on vascular dysfunction in experimental animal models
Conclusion
Conflicts of interest