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Paper text:
insulin resistance is a disorder characterized by the improper utilization of glucose by the cells .
this is because of an existing and/or acquired impairment of the cell 's ability to respond to exogenous or endogenous insulin .
this , in turn , results in -cell compensation failure and excessive blood glucose levels in the midst of hyperinsulinemia . insulin resistant subjects are predisposed to a cluster of risk factors that increase their risk of having cardiovascular diseases .
these risk factors include high blood pressure , obesity , type 2 diabetes , elevated triglycerides , and lowered high density lipoprotein cholesterol ( hdl - c ) . alarmingly , over one third of canadian adults have insulin resistance , and about half of saltsensitive subjects are insulin resistant .
these elevated numbers of insulin resistant cases reflect the enormous economic burden that comes from the treatment modalities of several comorbidities per patient .
the molecular mechanism of insulin resistance in hypertension , particularly in salt - sensitive hypertension , is not fully characterized .
insulin resistance might lead to hypertension because of diminished insulin - induced vasodilation and the imbalance between its pressor and depressor effects . in hypertension
, there is resistance to the actions of insulin on glucose uptake , but no resistance to the renal and sympathetic actions of insulin .
this hypothesis proposes that the compensatory hyperinsulinemia that occurs with insulin resistance increases sodium reabsorption and sympathetic activity , which combine to cause an increased vascular resistance and an elevated arterial pressure .
owing to the fact that insulin resistance in dahl salt - sensitive ( s ) rats precedes salt - sensitive hypertension in this model , we directed our attention to highlighting the putative role of insulin receptor substrates 1 and 2 ( irs-1 and -2 ) genetic variants in the pathogenesis of insulin resistance in dahl s rats .
dahl s rats represent an ideal model of insulin resistance syndrome because of its genetically predetermined insulin resistance , hypertriglyceridemia , abdominal obesity , and salt - sensitive hypertension .
regarding insulin concentrations , dahl rats in general have higher values for insulin concentration than control sprague dawley rats implying their increased genetic susceptibility to insulin resistance .
additionally , dahl s rats have an increased serum insulin response to an oral glucose load independent of different salt intakes compared to dahl salt - resistant ( r ) rats . regarding insulin sensitivity ,
dahl s rats have decreased sensitivity to insulin , as evidenced by a decreased insulin - stimulated glucose uptake by skeletal muscles obtained from dahl s vs. dahl salt - resistant ( r ) rats . regarding insulin receptors distribution , number , and affinity , they were all comparable in skeletal muscle and kidney of dahl s and -r rats , with no change in binding parameters in either group on high or low salt chow .
hepatic , muscular , and renal insulin receptor mrna levels were comparable in dahl s and -r rats fed either low or high salt chow . regarding the impact of salt diet , dahl s vs. -r rats had significant insulin resistance on high salt diet ( 8% nacl ) for four weeks vs. normal salt diet .
dahl s rats insulin resistance on a high salt diet was characterized by an activation of the early steps in insulin signaling . on the other hand , salt retention was significantly greater at weeks 1 and 2 in insulin - infused vs. saline - infused dahl s rats receiving 0.3% nacl vs. dahl r rats , where insulin did not influence sodium retention , mean arterial pressure , or plasma epinephrine . in conclusion , genetic background and excessive sodium intake are key factors contributing to the development of insulin resistance and salt sensitive hypertension in dahl s rats .
the decreased sensitivity to insulin in this model may involve a post - receptor defect possibly a genetic variant(s ) in the irs-1 and/or irs-2 that contribute to their susceptibility to insulin resistance .
variations in candidate genes encoding irs-1 and -2 proteins involved in the insulin signaling pathway may be implicated in insulin resistance .
insulin actions in skeletal muscles , liver , kidney , fat , and brain result in increased renal sodium retention , modulation of transmembrane cation transport , induction of growth promoting effects of vascular smooth muscle cells , and vascular hyperreactivity .
the insulin signal transduction pathway is initiated when insulin binds to a highaffinity heterotetrameric transmembrane protein receptor that is present in all mammalian cells .
the insulin - receptor complex then triggers tyrosine phosphorylation of second messengers , also called docking proteins , such as the insulin receptor substrates-1 , -2 , -3 , and 4 ( irs-1 , -2 , -3 , and -4 ) .
this in turn activates the phosphoinositide 3 kinase ( pi3k ) enzyme , the activation of which stimulates the serine phosphorylation of akt ( protein kinase b ) . the latter enzyme ( pkb ) stimulates glucose transport in muscle and adipose tissue through the translocation of the glucose transporter glut4 isoform from the cytoplasm to the plasma membrane .
pkb also stimulates glycogen synthesis in the liver and muscle , and stimulates lipogenesis in adipose tissue . while irs-3 and -4 play a role in cell growth and differentiation , irs-1 and -2 play an important role in glucose metabolism .
genes encoding for irs-1 and/or -2 therefore may represent attractive candidate genes to study for insulin resistance .
associations between insulin resistance and common variants in irs-1 and -2 have been reported in several human populations , including obese caucasian children and adults , asian indians , mexicans , and african - americans .
mechanisms underlying the contributions of irs-1 and/or irs-2 variants to insulin resistance include : ( i ) altered expression and/or function of irs-1 and/or -2 ; ( ii ) diminished irs-1 and/or -2 binding to the insulin receptor ; ( iii ) hindered binding of irs-1 and/or -2 variant(s ) to the p85 regulatory subunit of the pi3-kinase and a decreased pi3-kinase activity .
as a result , a decrease in glut4 translocation to the plasma membrane and a reduced glucose transport and glycogen synthesis will ensue .
additionally , an impairment in the ability of irs-1 and/or -2 to decrease phosphorylation of glycogen synthase kinase-3 ( gsk-3 ) , an enzyme that is important in glycogen synthesis , will reduce glycogen synthesis ; and ( iv ) decreased irs-1 protein levels that are not counterbalanced by a concomitant increase in the irs-2 protein content .
this , in turn , causes a reduction in insulinstimulated pi3-kinase activity and a significant decrease in akt phosphorylation and activity . in conclusion ,
irs-1 and/or -2 variant(s ) appear to contribute to the impaired ability of insulin to activate the irs / pi3-kinase / akt / gsk-3 signaling pathway , which ultimately results in defects in glucose transport and glycogen synthesis .
irs-1 and -2 tyrosine phosphorylation activates irs proteins to bind to signaling molecules in the insulin signaling pathway ( such as pi3k ) . on the other hand ,
serine phosphorylation of irs proteins attenuates insulin signaling and explains an additional mechanism of insulin resistance in rodents .
for example , increased serine phosphorylation of irs-1 was demonstrated in the liver of an insulin resistant rat model , supporting the role of serine phosphorylation in precipitating insulin resistance in this model .
owing to the fact that irs proteins have three times more serine residues than tyrosine residues , the significance of serine phosphorylation has been markedly highlighted .
serine phosphorylation of irs-1 and irs-2 can suppress insulin signaling in the following ways : it can ( i ) allow dissociation of irs proteins from the insulin receptor ; ( ii ) diminish tyrosine phosphorylation on usual sites by covering up phosphorylation sites and enhancing the release of irs proteins from intracellular complexes that maintain them in close proximity to the receptor ; ( iii ) enhance irs proteolytic degradation ; or ( iv ) switch irs proteins to inhibitors of the insulin receptor .
it is worth mentioning at this point that dahl s rats have chronic hyperinsulinemia , which potentially might enhance serine phosphorylation of irs-1 and/or -2 and possibly explain an additional mechanism of insulin resistance in dahl s rats .
knowledge of which genetic variants along the insulin signaling pathway are important in the genesis of salt - dependent insulin resistance ( a disease that comprises a large subgroup [ over 30% ] of canadian adults ) would enhance the understanding of the basic pathophysiology of the disease .
in addition it may create one or more specific targets for the development of a novel anti - insulin resistance drug or gene therapy .
variations in genes encoding the irs-1 or -2 proteins might be at the level of dna ( genetic variants ) or at the level of serine phosphorylation as explained above .
insulin resistance is a common finding in hypertensive humans and animal models . 
 the dahl salt - sensitive ( s ) rat is an ideal model of genetically predetermined insulin resistance and salt - sensitive hypertension . along the insulin signaling pathway , 
 the insulin receptor substrates 1 and 2 ( irs-1 and -2 ) are important mediators of insulin signaling . 
 irs-1 and/or irs-2 genetic variant(s ) and/or enhanced serine phosphorylation correlate with insulin resistance . 
 the present commentary was designed to highlight the significance of irs-1 and/or -2 in the pathogenesis of insulin resistance . 
 an emphasis will be given to the putative role of irs-1 and/or -2 genetic variant(s ) and serine phosphorylation in precipitating insulin resistance .