Referenced in: none

Automatically associated channels: Kir6.2

Title: Engineering a glucose-responsive human insulin-secreting cell line from islets of Langerhans isolated from a patient with persistent hyperinsulinemic hypoglycemia of infancy.

Authors: W M Macfarlane, J C Chapman, R M Shepherd, M N Hashmi, N Kamimura, K E Cosgrove, R E O'Brien, P D Barnes, A W Hart, H M Docherty, K J Lindley, A Aynsley-Green, R F James, K Docherty, M J Dunne

Journal, date & volume: J. Biol. Chem., 1999 Nov 26 , 274, 34059-66

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/10567373

Abstract
Persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a neonatal disease characterized by dysregulation of insulin secretion accompanied by profound hypoglycemia. We have discovered that islet cells, isolated from the pancreas of a PHHI patient, proliferate in culture while maintaining a beta cell-like phenotype. The PHHI-derived cell line (NES2Y) exhibits insulin secretory characteristics typical of islet cells derived from these patients, i.e. they have no K(ATP) channel activity and as a consequence secrete insulin at constitutively high levels in the absence of glucose. In addition, they exhibit impaired expression of the homeodomain transcription factor PDX1, which is a key component of the signaling pathway linking nutrient metabolism to the regulation of insulin gene expression. To repair these defects NES2Y cells were triple-transfected with cDNAs encoding the two components of the K(ATP) channel (SUR1 and Kir6.2) and PDX1. One selected clonal cell line (NISK9) had normal K(ATP) channel activity, and as a result of changes in intracellular Ca(2+) homeostasis ([Ca(2+)](i)) secreted insulin within the physiological range of glucose concentrations. This approach to engineering PHHI-derived islet cells may be of use in gene therapy for PHHI and in cell engineering techniques for administering insulin for the treatment of diabetes mellitus.