Glomerular podocytes are directly regulated by insulin (1) and podocyte insulin resistance is implicated in diabetic kidney disease. Information theory derived statistical measures can be used to quantify information transfer via cell signalling pathways (2). This novel approach takes into account cell-cell variation in responses and the impact that this noise has on information transfer but has not yet been applied to signalling in podocytes. Here we quantify the mutual information (MI) between insulin concentration and effects in podocytes as a measure of information transfer via insulin receptors (IR), and use this to address how features of the IR signalling network influence information transfer. To do so, human IR expressing podocytes (ABIR cells) were stimulated with insulin, prior to immunofluorescence staining of phosphorylated Akt, quantification by high content imaging, and calculation of MI between insulin and the response (I(pAkt;insulin)). Insulin caused the expected concentration and time-dependent increases in pAkt, but MI values were low (<0.5 Bits, irrespective of whether S473 or T308 phosphorylation was measured). Inhibition of PTEN and PTP1B (negative regulators of IR signalling) increased pAkt levels but did not increase I(pAkt;insulin). Akt-mediates negative feedback control of its own activation and Akt inhibition (GSK690693) reduced I(pAkt;insulin) values. Thus, by quantifying information transfer via podocyte IR we have found a) that individual podocytes are unreliable insulin sensors with most information lost through signalling, b) that population averaged measures of pAkt cannot be equated to information transfer and c) that Akt-mediated negative feedback can protect information transfer in this model.
1. Garner KL et al. (2017) Information transfer via GnRHR to ERK and NFAT: Sensing GnRH and sensing dynamics. J Endocr Soc 1:260.
2. Welsh GI et al. (2010) Insulin signaling to the glomerular podocyte is critical for normal kidney function. Cell Metabolism 12:329.