Insulin and IGF-1 receptor autocrine loops are not required for Exendin 4.pdf

2018-10-29T01:36:19Z (GMT) by Vinicius Fernandes Cruzat
p.p1 {margin: 0.0px 0.0px 0.0px 0.0px; font: 7.0px Times} span.s1 {font: 7.0px Helvetica}

Pharmacological long lasting Glucagon-like peptide-1 (GLP-1) analogues, such as Exendin-4, have become

widely used diabetes therapies. Chronic GLP-1R stimulation has been linked to β-cell protection and these prosurvival

actions of GLP-1 are dependent on the activation of the mammalian target of rapamycin (mTOR) leading

to accumulation of Hypoxia inducible factor 1 alpha (HIF-1α). Recent studies from our lab indicate that prolonged

GLP-1R stimulation promotes metabolic reprograming of β-cells towards a highly glycolytic phenotype

and activation of the mTOR/HIF-1α pathway was required for this action. We hypothesised that GLP-1 induced

metabolic changes depend on the activation of mTOR and HIF-1α, in a cascade that occurs after triggering of a

potential Insulin-like growth factor 1 receptor (IGF-1R) or the Insulin receptor (IR) autocrine loops. Loss of

function of these receptors, through the use of small interfering RNA, or neutralizing antibodies directed towards

their products, was undertaken in conjunction with functional assays. Neither of these strategies mitigated the

effect of GLP-1 on glucose uptake, protein expression or bioenergetic flux. Our data indicates that activation of

IGF-1R and/or the IR autocrine loops resulting in β-cell protection and function, involve mechanisms independent

to the enhanced metabolic effects resulting from sustained GLP-1R activation.

License

CC BY 4.0