Endocrine Abstracts

Background: The pancreatic β-cell KATP channel plays a key role in glucose stimulated insulin secretion and is encoded by the genes ABCC8 and KCNJ11. Recessive mutations in ABCC8/KCNJ11 cause severe medically unresponsive HH. Recently, dominant mutations in these genes have been described that cause mild, medically responsive HH. Controversy exists on whether these dominant ABCC8/KCNJ11 mutations predispose to diabetes mellitus in ad...

CHI is a disorder of dysregulated insulin release characterised by severe recurrent hypoglycaemia. Mutations in genes encoding the beta-cell sulphonylurea receptor (ABCC8) and inward-rectifying potassium-channel (KCNJ11) are the commonest genetic cause of CHI, followed by that encoding glutamate dehydrogenase (GLUD-1). Histologically, disease pathology is subdivided into diffuse or focal disease; the latter associated with paternal mutations and somatic lo...

Type 2 diabetes (T2DM) has emerged in youth, disproportionately affecting ethnic minorities. Maturity Onset Diabetes of the Young (MODY) has been reported in exclusively white UK children. We report the first UK Asian children with MODY, highlighting differences from T2DM.Child 1 is a slim (BMI SDS−0.14) female of Indian descent without acanthosis nigricans (AN). She presented aged 12 years with polydipsia and polyuria (HbA1c 8.6%). Hypoglycaemia w...

Introduction: Hyperinsulinaemic hypoglycaemia (HH) is the most common cause of severe and persistent hypoglycaemia in neonates. The treatment of diazoxide unresponsive HH involves pancreatectomy. Mammalian target of rapamycin (mTOR) is a protein kinase that regulates cellular proliferation. We aimed to evaluate the efficacy of mTOR inhibitor Sirolimus and assess mTOR expression in the pancreas of infants with severe HH.Methods: Four infants with severe, ...

Hyperpolarisation-activated cyclic nucleotide-gated channels (HCNCs). are selective for Na+/Ca2+ under physiological conditions and are responsible for the rhythmical electrical behaviour of pacemakers in the heart and brain. Their role in human pancreas has not been reported previously. Congenital hyperinsulinism of infancy (CHI) is an inherited disorder of inappropriate insulin secretion often caused by gene defects in the subunits of KATP ch...

Congenital hyperinsulinism (CHI) is characterised by unregulated insulin secretion from pancreatic β-cells. The most severe forms are associated with defects in SUR1 and Kir6.2 (encoded by ABCC8 and KCNJ11), which form KATP channels in β-cells. Diazoxide therapy often fails in the treatment of CHI and may be due to reduced cell surface expression of KATP channels. We investigated methods to increase surface expression of KATP<...

Congenital Hyperinsulinism (CHI), a common cause of persistent hypoglycaemia in infancy can be associated with feeding problems (FP). The extent of FP in CHI is not known. The commonest genetic cause of CHI is mutations in ATP-sensitive potassium (K+ATP) channel genes (ABCC8 and KCNJ11).Aims: To define FP in CHI patients presenting to a regional centre, in relation to medication and K+ATP ...

Mutations in the co-chaperone molecule AIP account for a predisposition to pituitary tumours in some families with familial isolated pituitary adenomas (FIPA). We now report on four apparently-unrelated families with the same mutation and originating from the same geographical area, suggesting a possible founder mutation.The index patient had gigantism (19 years, 208 cm) and had a female 4th cousin, once removed (13 years, 191 cm) with a large pituitary ...

Introduction: Approximately 25% of medullary thyroid cancer (MTC) cases arise in a familial setting, either as MEN2 or fMTC. While most of these are caused by mutations in the RET gene, a few families have unidentified mutations. Recently, a frameshift mutation in the ESR2 gene (coding oestrogen receptor beta) was found in a family with RET-negative fMTC associated with C-cell hyperplasia. In vitro, transfection of mutant ESR2 led t...

The islet-enriched transcription factor MAFA regulates the expression of genes critical to beta cell function and insulin secretion. We previously described anovel MAFA mutation (c.191C > T, p.S64F) causing familial insulinomatosis and diabetes mellitus, with male carriers more often developing diabetes and females more prone to insulinomatosis. The exact molecular mechanisms underlying these phenotypes are unclear. In this study, we assessed glucose metabolism an...