Endocrine Abstracts

AKT serine-threonine kinases are critical mediators of both growth and metabolic actions of insulin. AKT2 is believed to exert predominantly metabolic effects, while AKT1 has been more strongly implicated in growth. We have recently reported that the de novo AKT2 p.Glu17Lys mutation produces a sporadic syndrome of severe persistent hypoinsulinaemic hypoglycaemia associated with left-sided hemihypertrophy. Glucose requirements in affected patients are far lower than seen in hyperinsulinism, arguing that the activation of AKT2 is partial rather than complete. Two patients with the mutation studied at the age of 17 had no fatty liver, nor elevated triglyceride, at odds with murine models of liver-specific AKT2 activation. We set out to characterise the cellular phenotype associated with AKT p.Glu17Lys in more detail in an attempt to account for these observations. The E17K mutation was found to target AKT2 constitutively to the plasma membrane, a process which was blocked by the pan-AKT inhibitor, perifosine. AKT2 E17K expression also resulted in tonic nuclear exclusion of the key AKT2 substrate FOXO1a, which is implicated in many transcriptional responses to insulin in the liver. Despite these findings it was not possible to discern increased basal phosphorylation of AKT2 in the systems studied, and no difference in basal or insulin-stimulated deoxyglucose uptake between 3T3-L1 cells stably expressing either wild-type AKT2 or the E17K mutant was observed. These findings confirm that AKT2 p.E17K shows constitutive but partial activation of signalling, and establish relevant cellular models in which to test novel treatment strategies. More detailed analysis of signalling pathways downstream from AKT2 is currently underway to refine further understanding of the human syndrome associated with AKT2 p.E17K.

Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding: Declaration of Funding: SOR, IB and RKS are supported by the Wellcome Trust (grant numbers 078986/Z/06/Z, 077016/Z/05/Z and 080952/Z/06/Z, respectively), the Medical Research Council Centre for Obesity and Related Disorders, and the United Kingdom National Institute for Health Research Cambridge Biomedical Research Centre. MM is supported by Gates Cambridge Trust.