Background: The gene expression microarray and morphoproteomics in diffuse congenital hyperinsulinism (CHI) revealed activation of the mammalian target of rapamycin (mTOR) pathway and the subsequent treatment of four diffuse CHI patients with sirolimus (mTOR inhibitor) avoided pancreatectomy.
Objective and hypotheses: To further evaluate the mechanism of action of sirolimus by studying the expression of mTORC1/RagGTPase and IGF1R/mTORC2/Akt pathways in pancreases from four infants with diffuse CHI. The clinical use of sirolimus was further studied in eight infants with medically unresponsive diffuse CHI.
Methods: Immunohistochemical probes were applied to detect the expression of p-mTOR, RagGTPase, p-Akt, insulin, and IGF-1R. Eight infants with diffuse CHI unresponsive to diazoxide and octreotide were trialled on sirolimus therapy. The genetic aetiology in these patients included homozygous ABCC8 mutation (×3), maternal ABCC8 mutation (×2), paternal ABCC8 mutation (×1), compound heterozygous ABCC8 mutation (×1), and no identified mutation (×1).
Results: Morphoproteomic analysis revealed overexpression of p-Akt and IGF1R in the islets and plasmalemmal overexpression of p-mTOR and variable cytoplasmic expression of RagGTPase in the acinar cells. Seven out of the eight infants responded to sirolimus therapy and were able to come off intravenous fluids and glucagon infusions thereby preventing the need for a major surgery. Subsequent follow up (range 618 months) revealed that the patients were normoglycaemic on sirolimus (with or without concomitant octreotide therapy). One infant with homozygous ABCC8 mutation did not respond to sirolimus therapy.
Conclusions: The sirolimus-sensitive mTORC1 pathway is present in the exocrine pancreas and the relatively sirolimus-resistant IGF1R/mTORC2/Akt pathway is overexpressed in the β-cells, thereby suggesting that sirolimus is effective in treating diffuse CHI by reducing the transdifferentiation of exocrine elements to insulin-producing cells. The response to sirolimus is clinically more marked in patients with possible pancreatic β-cell hyperplasia than those with homozygous KATP channel mutations.
20 - 22 Sep 2014
European Society for Paediatric Endocrinology