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Institute of Biomedical and Clinical Science, Peninsula Medical School, Universities of Exeter and Plymouth, Research Way, Plymouth, Devon PL6 8BU, UK
¹ Institut für Zellbiologie, Universitätsklinikum Essen, D-45122 Essen, Germany

(Requests for offprints should be addressed to N G Morgan; Email: noel.morgan{at}pms.ac.uk)

Mutations in the gene encoding hepatocyte nuclear factor (HNF)1ß result in maturity-onset diabetes of the young-(MODY)5, by impairing insulin secretory responses and, possibly, by reducing ß-cell mass. The functional role of HNF1ß in normal ß-cells is poorly understood; therefore, in the present study, wild-type (WT) HNF1ß, or one of two naturally occurring MODY5 mutations (an activating mutation, P328L329del, or a dominant-negative form, A263insGG) were conditionally expressed in the pancreatic ß-cell line, insulin-1 (INS-1), and the functional consequences examined. Surprisingly, overexpression of the dominant-negative mutant did not modify any of the functional properties of the cells studied (including insulin secretion, cell growth and viability). By contrast, expression of WT HNF1ß was associated with a time- and dose-dependent inhibition of INS-1 cell proliferation and a marked increase in apoptosis. Induction of WT HNF1ß also inhibited the insulin secretory response to nutrient stimuli, membrane depolarisation or activation of protein kinases A and C and this correlated with a significant decrease in pancrease-duodenum homeobox-1 protein levels. The attenuation of insulin secretion was, however, dissociated from the inhibition of proliferation and loss of viability, since expression of the P328L329del mutant led to a reduced rate of cell proliferation, but failed to induce apoptosis or to alter insulin secretion. Taken together, the present results suggest that mature rodent ß-cells are sensitive to increased expression of WT HNF1ß and they imply that the levels of this protein are tightly regulated to maintain secretory competence and cell viability.

This article has been cited by other articles:

				H. J Welters, A. Oknianska, K. S Erdmann, G. U Ryffel, and N. G Morgan The protein tyrosine phosphatase-BL, modulates pancreatic {beta}-cell proliferation by interaction with the Wnt signalling pathway J. Endocrinol., June 1, 2008; 197(3): 543 - 552. [Abstract] [Full Text] [PDF]

				A. I. Tarasov, H. J. Welters, S. Senkel, G. U. Ryffel, A. T. Hattersley, N. G. Morgan, and F. M. Ashcroft A Kir6.2 Mutation Causing Neonatal Diabetes Impairs Electrical Activity and Insulin Secretion From INS-1 {beta}-Cells Diabetes, November 1, 2006; 55(11): 3075 - 3082. [Abstract] [Full Text] [PDF]