it is now well recognized that obesity and asthma are epidemiologically linked [ 14 ] .
such a relationship is also seen between asthma and other markers of the metabolic syndrome such as insulin resistance and hypertension that can not be accounted for by increased body mass alone [ 47 ] . while both obesity and asthma are individually associated with an increased state of inflammation , interestingly , in obese asthmatics
, there is a dissociation between cellular inflammation and severity of symptoms , especially in women [ 9 , 10 ] .
this discordance would suggest that while obesity - related systemic inflammation can certainly be one mechanism for increased asthma risk , there is a need to examine mechanisms independent of cellular inflammation that may play a role in asthma in the context of conditions such as obesity and metabolic syndrome .
a number of cellular signaling and metabolism mechanisms could contribute to increased asthma risk in patients with obesity and/or metabolic syndrome .
considering the fact that altered glucose metabolism occurs in both cases , and hyperinsulinemia with reduced insulin sensitivity is involved , an obvious potential factor affecting the lung is insulin itself , particularly a direct effect on structural cells as well as immune cells in the airway . in a large danish cohort , it was observed that insulin resistance ( ir ) was more strongly related to asthma risk than any of the anthropometric parameters .
while this study did not specifically examine serum insulin , independent of blood glucose or diabetes , it is recognized that insulin resistance ( ir ) and consequent hyperinsulinemia are central molecular pathologies in the genesis of the metabolic syndrome [ 12 , 13 ] .
other markers of metabolic syndrome such as c - reactive protein and correlates such as hyperglycemia , diabetes , or hypertension have all been associated with reduced lung function , asthma , or even copd , in large clinical studies . yet
if insulin excess can directly alter lung cellular physiology , this would represent a fundamental common molecular link between asthma and the cardiometabolic syndrome .
this review focuses on the current stage of knowledge regarding the direct effects of insulin in lung cells in the context of airway remodeling and hyperresponsiveness . here
, it is important to emphasize that in fact there is a significant knowledge gap regarding insulin effects in the airway , and we therefore draw upon what is known in other cell types to generate hypotheses that could drive future research . certainly , our focus on insulin does not rule out several other potential mechanisms such as dysfunctional arginine metabolism and uncoupling of nitric - oxide synthase ( nos ) by increased asymmetric dimethyl arginine ( adma ) , effects of adipokines , and direct mechanical effects of thoracoabdominal obesity on lung mechanics .
insulin is one of the central homeostatic hormones with global effects that extend beyond glucose and lipid metabolism . as a pleiotropic hormone ,
insulin effects range from the well - known hypoglycemia to regulation of cell growth and differentiation [ 19 , 20 ] .
insulin regulates a number of key metabolic biological processes such as stimulation of glucose uptake , lipid synthesis , oxidation , storage of fat , and cell proliferation [ 2123 ] .
insulin - mediated signaling varies significantly between cells and tissues necessitating an understanding of its actions in the context of the lung and in specific cell types within the lung .
insulin resistance ( ir ) , that is , reduced responsiveness to insulin in liver , muscle , and adipose tissue , is closely associated with various metabolic diseases such as obesity , metabolic syndrome , nonalcoholic fatty liver disease , and type 2 diabetes mellitus . since ir in key metabolic tissues is associated initially with compensatory hyperinsulinemia , insulin - related effects that retain sensitivity in other tissues
this is a partial reflection of distinct physiological processes in multiple organs   and is important because ir is also associated with other putatively nonmetabolic diseases such as asthma [ 4 , 27 ] and some cancers [ 2832 ] .
while relative deficiency of insulin and hyperglycemia are well studied in diabetes , the harmful effects of insulin excess are poorly recognized except where they result in hypoglycemia .
importantly , given the cell- and tissue - specific heterogeneity in insulin signaling and the potential confounding role of disease states per se , effects on other tissues may not be easily extensible to the lung .
nonetheless , considerable insight into potential mechanisms by which insulin influences lung cellular components relevant to asthma may be gleaned from such prior data .
expression of insulin receptors in the lung has been verified ; however , their role has only been partially characterized using crude membrane of normal lung as well as plasma membrane fractions of lung tissue .
importantly , interaction of these receptors with insulin appears to be time and temperature dependent , and furthermore rapid , saturable , and highly reversible [ 34 , 35 ] .
the relevance of these findings is that insulin has the potential to dynamically influence lung structure and function at various life stages and thus modulating asthma predisposition .
insulin receptors are important during lung development with lung epithelial cells abundantly expressing insulin receptors during the pseudoglandular stage with receptor levels decreasing during later stages of development . assuming that maternal insulin is the agonist , these data fit well with prior evidence that maternal diabetes has substantial growth effects on fetal lungs .
others have shown that high insulin levels delay lung development in fetuses of diabetic mothers by inhibiting surfactant protein a ( sp - a ) . inhibition of sp - a and sp - b genes ' expression leads to increased incidence of respiratory distress syndrome ( rds ) in infants of diabetic mothers . in a large canadian study ,
what is less clear , but is likely , is whether these diabetic mothers had hyperinsulinemia .
furthermore , alternative mechanisms may be at play , including hyperglycemia , and altered cytokine / adipokine milieu .   while these clinical associations are clear , there is limited experimental evidence supporting a direct role for insulin per se in lung development .
in cultured lung epithelial cells , insulin reduces vegf expression and transcriptional activity of hif-2 on vegf promoter in an mtor - dependent manner .
the importance of the akt - mtor pathway in lung epithelium relates to the pathogenesis of infant rds   which predisposes towards asthma later in life .
animal models of hyperinsulinemia are more complex with at least one report of accelerated fetal lung maturation in pregnant rabbits by a two - day intravenous ( iv ) infusion of insulin , but with significant hypoglycemia .
accordingly , it is difficult to conclude whether insulin is promaturation when it comes to lung development , and here it is important to consider whether the timing of high versus low level of insulin receptor expression and activation is a confounding factor .  
other than effects of insulin on developing lungs , recent efforts towards developing inhaled insulin formulations for diabetes management have provided interesting insights into direct effects of insulin on the mature lung . since the pulmonary epithelium and the surfactant that lines the alveoli ( 0.1 - 0.2  m thick ) constitute physical barriers to pulmonary absorption , local deposition and action of insulin are to be expected .
locally high concentrations of protease inhibitors and acidic formulations seem to protect the insulin peptide from membrane - associated cells and intracellular proteases [ 4345 ] resulting in much of the inhaled insulin being absorbed systemically in the alveolar region .
however , despite good systemic delivery , there also appears to be substantial local effect of inhaled insulin .
for example , inhaled insulin in diabetic patients is associated with a decrease in forced expiratory volume in 1 second ( fev1 ) [ 46 , 47 ] , but the mechanisms are not clear . certainly , insulin can shift t cells towards a th2-type response , known to be a key event in the pathogenesis of asthma .
it has also been observed that insulin , via activation of pi3k pathway , promotes mast cell survival and degranulation , which facilitate bronchoconstriction .
nonspecific proinflammatory effects via activation of pulmonary macrophages are also possible , and in some studies it has been shown that inhaled insulin may deposit at air - tissue interfaces with characteristics of amyloid aggregates
. the relevance of these findings may be in that inhaled formulations of insulin that were once promising , approved strategies for treatment of diabetes mellitus in us and europe [ 51 , 52 ] have been withdrawn due to persistent reports of respiratory problems , including cough . on the other hand , it appears that insulin also has anti - inflammatory effect in the context of severe th1-type inflammation .
insulin has been found to reduce levels of inflammatory cytokines , attenuate acute lung injury and systemic inflammatory response , and promote survival in rodents exposed to lps .  
collectively , these limited data again suggest a dichotomous role for insulin where increased levels of insulin in the mature ( adult ) lung have found to be detrimental on the one hand but protective on the other .
what is important to determine is whether systemic hyperinsulinemia as occurring in metabolic syndrome leads to pathophysiological changes leading to asthma , or is protective , and the mechanisms by which insulin acts on the airway .
while asthma is usually defined as an inflammatory disease , a cardinal feature is airway hyperresponsiveness ( ahr ) : excessive narrowing of airways in response to normal constrictive stimuli .
ahr is associated with increase in airway smooth muscle ( asm ) mass , dysfunction of bronchial epithelium , and alterations in extracellular matrix ( ecm ) within the airway wall . increased asm mass
is considered to play a key role in the development of ahr   and activate epithelial mesenchymal trophic unit ( emtu ) that leads to airway remodeling . as a growth factor ,
the contribution of insulin to increased asm mass and/or contractility in the context of asthma is obviously important .
noveral and colleagues first showed that functional insulin - like growth factor-1 ( igf-1 ) receptors are present on rabbit asm and that their stimulation is sufficient to induce asm proliferation [ 56 , 57 ] .
these studies have been replicated in other animal model systems , and the pathway was determined to be activation of the map kinase system .
it is well known that insulin and igf-1 can crossactivate each other 's receptors ( insulin receptor ( insr ) and igf1r ) and that there is also significant crosstalk downstream to these receptors via the insulin receptor substrate proteins ( irs ; figure 1 ) .
it has been subsequently shown that high levels of insulin promote asm contraction   and enhance contractile responses to methacholine and kcl [ 60 , 61 ] .
these effects have been reported to occur via rho kinase- and pi3 kinase - dependent signaling pathways [ 62 , 63 ] .
other reports suggest that insulin increases ecm proteins such as laminin ( a2 , b1 , and g1 chain expression )   which are important in lung growth and differentiation of nave mesenchymal cells , leading to hypercontractile and hypoproliferative asm [ 65 , 66 ] . furthermore , limited studies suggest that aerosol administration of insulin leads to asm contraction but indirectly via production of procontractile prostaglandins that involve rho kinase .
overall , the data so far suggests that , if anything , insulin effects on asm are likely to result in increased airway contractility , cell proliferation , and fibrosis , all of which should lead to a thicker , stiffer , and hypercontractile airway reflective of an asthma phenotype . however , it is also important to recognize that much of the work has been in vitro , with high levels of insulin , typically applied for relatively short periods . whether prolonged hyperinsulinemia and/or activation of insulin receptors leads to different cellular effects in the airway , and whether such effects are reversible ( in the context of therapy ) remain to be determined
pi3k / akt signaling has a central role in the conserved downstream pathway of insulin signaling [ 68 , 69 ] and is an important regulator of diverse array of cellular events , including cell growth and cell survival in a number of cell types .
several studies have validated the functional significance of the pi3k pathway in glucose homeostasis and shown that pi3k inhibition leads to insulin resistance [ 71 , 72 ] .  
it has been also shown that insulin is a potent activator of pi3k in human bronchial epithelial cells and inhibits tlr3 mediated apoptosis .
it has been also shown that insulin , via activation of pi3k pathway , promotes mast cell survival and degranulation , which may leads to bronchoconstriction .  
this pathway is also thought to be important at least in prenatal lung development in the context of maternal diabetes where fetal hyperinsulinemia in response to maternal hyperglycemia [ 7477 ] results in pi3k / akt1/mtor activation and induces rds .
also , as mentioned previously , high levels of insulin through the pi 3-kinase signaling pathway may also inhibit surfactant protein production expressed in the lung epithelial cells and lung maturation [ 37 , 79 , 80 ] , thus predisposing the immature lung to airway diseases later in life .
while these data relate to the developing lung , the relevance of the enhanced pi3/akt signaling also lies in its well - recognized role in adult asthma .
for example , loss of function mutations in the principal inhibitory phosphatases ship , pten , and inpp4a , are associated with asthma , and knockdown of inpp4a induces airway remodeling and hyperresponsiveness .
activation of the pi3/akt pathway promotes survival of airway epithelial cells as well as asm and conversely can enhance proliferation , thus contributing to airway remodeling .
whether insulin activation of pi3k / akt is involved in this regard is not currently known .
however , insulin has been shown to act via pi3/akt to inhibit epithelial apoptosis that normally occurs with viral exposure and could thus promote airway remodeling in this context ( figure 2 ) .
some studies have also reported insulin regulation of wnt/-catenin pathway and stimulation of transcription of lef / tcf - dependent genes via activation of pi3k / akt and ras signaling pathways which normally inhibit gsk3- and activate the -catenin pathway in hepatocarcinogenesis .
dysregulation of wnt/-catenin pathway influences many biological processes , including cell fate decisions , stem cell proliferation , and axis specification [ 8588 ] .
while relationships between insulin and wnt/-catenin have not been reported in the lung per se , wnt/-catenin pathways are increasingly recognized as being important in regulation of lung cell proliferation and differentiation .
-catenin is required for normal lung morphogenesis , and deletion of -catenin during critical periods of lung development leads to blocked alveolar epithelial cell differentiation and disruption of alveolar formation .
furthermore , conditional activation of -catenin in respiratory epithelial cells leads to altered epithelial cell differentiation by induction of alveolar marker prosurfactant protein c ( sp - c ) and causes goblet cell hyperplasia , air space enlargement , and pulmonary tumors .
thus , -catenin signaling pathway has a critical role in the differentiation of the respiratory epithelium in the postnatal lung . accordingly , even during lung development , insulin could potentially promote morphogenesis via activation of the wnt/-catenin pathway , although it would be important to determine whether the relative timings of insulin versus wnt/-catenin activation are detrimental or beneficial .   in the adult airway , activated -catenin-/tcf-/lef - dependent gene transcription of vegf , matrix proteins such as fibronectin and versican , and proinflammatory enzymes
/ mediators such as cyclooxygenase ( cox)-2   and interleukin ( il-8 ) suggest the involvement of this pathway in regulation of inflammation and airway remodeling . here too , insulin - mediated activation of -catenin signaling could be involved in airway disease pathogenesis .
while there is currently no information in the context of asthma per se , data from fibroproliferative lung diseases may be suggestive where activation of -catenin signaling is involved .
inhibition of gsk3 and stabilization of -catenin is governed by tgf- signaling and leads to altered ecm . of relevance , diabetes and metabolic syndrome
have been associated with increased risk of idiopathic pulmonary fibrosis and copd [ 95 , 96 ] . whether insulin per se plays a role in these diseases is not known , but if so , modulation of wnt signaling pathway may be relevant .
also , in other systems like the heart , akt - mediated gsk3 phosphorylation leads to increased -catenin expression and causes cardiac smooth muscle hypertrophy , whether this may be mirrored in the airway smooth muscle , remains to be determined .
there is substantial data that mechanistically links insulin and insulin like growth factor-1 to lung development and function .
it is conceivable but not proven that hyperinsulinemia may lead to development of lung disease , particularly asthma .
 obesity , metabolic syndrome , and asthma are all rapidly increasing globally . 
 substantial emerging evidence suggests that these three conditions are epidemiologically and mechanistically linked . 
 since the link between obesity and asthma appears to extend beyond mechanical pulmonary disadvantage , molecular understanding is necessary . 
 insulin resistance is a strong , independent risk factor for asthma development , but it is unknown whether a direct effect of insulin on the lung is involved . 
 this review summarizes current knowledge regarding the effect of insulin on cellular components of the lung and highlights the molecular consequences of insulin - related metabolic signaling cascades that could adversely affect lung structure and function . 
 examples include airway smooth muscle proliferation and contractility and regulatory signaling networks that are associated with asthma . 
 these aspects of insulin signaling provide mechanistic insight into the clinical evidence for the links between obesity , metabolic syndrome , and airway diseases , setting the stage for novel therapeutic avenues targeting these conditions . 
1. Introduction
2. Insulin and IR
3. Insulin and the Lung
4. Insulin and Airway Smooth Muscle
5. Insulin and PI3/Akt Signaling
6. Insulin, Wnt/
7. Conclusion