SFEBES2014 Poster Presentations Obesity, diabetes, metabolism and cardiovascular (80 abstracts)
Novel syndromes of hypoinsulinaemic, hypoketotic hypoglycaemia
Sarah Leiter 1 , Marina Minic 1 , Victoria Parker 1 , Julie Harris 1 , Julian Hamilton-Shield 2 , Rachel Williams 3 , Eckhard Korsch 4 , Khalid Hussain 5 & Robert Semple 1
1Institute of Metabolic Science, University of Cambridge, Cambridge, UK; 2Royal Bristol Hospital for Children, Bristol, UK; 3Department of Paediatrics, Addenbrookes Hospital, Cambridge, UK; 4Department of Paediatrics, Cologne Hospitals, Cologne, Germany; 5Institute of Child Health, University College London, London, UK.
Congenital hyperinsulinaemic hypoglycaemia is generally characterised by low levels of ketone bodies, fatty acids and branched chain amino acids at the time of severe hypoglycaemia, and by a requirement for a relatively high rate of glucose infusion (>10 mg/kg per min) to maintain euglycaemia. It is caused by physiologically inappropriate insulin secretion from the pancreatic beta cells due to mutations that uncouple insulin secretion from normal hyperglycaemic and other stimuli.
We have recently described a novel form of sustained hypoglycaemia presenting in infancy, featuring a similar metabolic profile to hyperinsulinism, but with undetectable insulin, a lower requirement for glucose infusion and left sided hemihypertrophy. This is due to partial activation of a key arm of the insulin signalling pathway caused by the p.Glu17Lys mutation in the signal-transducing serine/threonine kinase AKT2.
We now present a further case series of five patients presenting in infancy or childhood with hypoglycaemia and a similar metabolic profile in the absence of detectible serum insulin. This severe metabolic derangement was associated with a heterogeneous range of associated clinical features including left sided hemihypertrophy with congenital adrenal carcinoma, symmetrical and severe obesity, small bowel atresia, and facial dysmorphism. Genomic sequencing of lymphocyte DNA, and DA from skin fibroblasts where available, failed to identify any mutations in AKT2. Moreover studies of primary dermal fibroblasts in two patients have failed to demonstrate basal hyperphosphorylation of AKT and its substrates GSK3 and PRAS40, and show no evidence of the blunted peak phosphorylation of the same proteins in response to insulin that is seen in primary cells harbouring the AKT2 mutation.
Collectively these clinical and biochemical studies suggest the existence of a heterogenous group of disorders which are metabolic phenocopies of basal AKT2-dependent hyperactivation of insulin signalling, but without cell autonomous evidence of basal AKT signalling. Further investigation of this group promises to yield novel information.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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