Endocrine Abstracts

Introduction: Congenital hyperinsulinism (CHI) is a clinically heterogeneous condition. Mutations in ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A, UCP2 and HNF1A are known to cause CHI. There are two histological subtypes of CHI: diffuse and focal. Apart from the functional channel defect, β-cell hyperplasia has been observed in diffuse CHI. We aimed to understand the gene expression pattern in pancreatic tissue of patients with diffuse CHI when compared to normal controls and to compare the expression pattern in patients with known genetic aetiology of CHI with that of patients without a genetic aetiology.

Methods: Fresh frozen pancreatic tissue samples were obtained from six children with diffuse CHI who underwent near total pancreatectomy. RNA was extracted by standard techniques (TRIzol reagent). RNA Integrity was assessed by Agilent-derived RNA integrity number (RIN) and the presence of intact 18 and 28 s bands on the Agilent Bioanalyzer trace. Gene expression microarray (standard Affymetrix techniques) was undertaken on the six diffuse CHI (four with ABBC8 mutation and two without any known mutation) and two normal RNA samples.

Results: We observed significant overexpression of growth factors and their regulatory proteins like IGF1, IGF2 and IGF2BP3 in diffuse CHI patients. Uncoupling proteins like UCP2 are up regulated in diffuse CHI patients. An anti-apoptotic factor OLFM4 is overexpressed in one of the diffuse CHI patients without any known mutation. Growth factor receptor-binding protein (Grb14) is significantly downregulated in the other diffuse patient without any known mutation possibly enhancing insulin-induced signalling. The markers of cellular proliferation Ki-67 and FOXM1 were significantly overexpressed in diffuse CHI.

Conclusions: The data, first of its kind in CHI, has suggested the potential role of growth factors and anti-apoptotic factors in the β-cell hyperplasia in diffuse CHI. Agents targeting IGF pathways can be a potential therapeutic option to ameliorate the β-cell proliferation in CHI.