%0 Journal Article %A Fernandes Cruzat, Vinicius %D 2018 %T Insulin and IGF-1 receptor autocrine loops are not required for Exendin 4.pdf %U https://torrens.figshare.com/articles/journal_contribution/Insulin_and_IGF-1_receptor_autocrine_loops_are_not_required_for_Exendin_4_pdf/7264217 %R 10.6084/m9.figshare.7264217.v2 %2 https://torrens.figshare.com/ndownloader/files/13381490 %K insulin gene expression %K Cell Biology %K Physiology %X 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.
%I Torrens University Australia