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J Biol Chem, Vol. 274, Issue 48, 34059-34066, November 26, 1999

Engineering a Glucose-responsive Human Insulin-secreting Cell Line from Islets of Langerhans Isolated from a Patient with Persistent Hyperinsulinemic Hypoglycemia of Infancy

Wendy M. MacFarlane, Joanna C. Chapman^§, Ruth M. Shepherd^§, Molly N. Hashmi^§, Noritaka Kamimura^§, Karen E. Cosgrove^§, Rachel E. O'Brien^§, Philippa D. Barnes^§, Alan W. Hart, Hilary M. Docherty, Keith J. Lindley^¶, Albert Aynsley-Green^¶, Roger F. L. James, Kevin Docherty, and Mark J. Dunne^§

From the  Department of Molecular and Cell Biology, University of Aberdeen, Institute of Medical Sciences, Aberdeen AB25 2ZD, the ^§ Institute of Molecular Physiology and Department of Biomedical Science, Sheffield University, Western Bank, Sheffield S10 2TN, the ^¶ Institute of Child Health, University of London, 30 Guilford Street, London WC1N 1EH, and  Department of Surgery, University of Leicester, Leicester Royal Infirmary, Leicester LE2 7LX, United Kingdom

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 Ca²⁺ homeostasis ([Ca²⁺]_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.

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