Conditional expression of hepatocyte nuclear factor-1β, the maturity-onset diabetes of the young-5 age product, influences the viability and functional competence of pancreatic β-cells

Hannah J. Welters, Sabine Senkel, Ludger Klein-Hitpass, Silke Erdmann, Heike Thomas, Lorna W. Harries, Ewan R. Pearson, Coralie Bingham, Andrew T. Hattersley, Gerhart U. Ryffel, Noel G. Morgan

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    Abstract

    Mutations in the gene encoding hepatocyte nuclear factor (HNF)1β result in maturity-onset diabetes of the young-(MODY)5, by impairing insulin secretory responses and, possibly, by reducing β-cell mass. The functional role of HNF1β in normal β-cells is poorly understood; therefore, in the present study, wild-type (WT) HNF1β, or one of two naturally occurring MODY5 mutations (an activating mutation, P328L329del, or a dominant-negative form, A263insGG) were conditionally expressed in the pancreatic β-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 HNF1β was associated with a time- and dose-dependent inhibition of INS-1 cell proliferation and a marked increase in apoptosis. Induction of WT HNF1β 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 β-cells are sensitive to increased expression of WT HNF1β and they imply that the levels of this protein are tightly regulated to maintain secretory competence and cell viability.

    Original languageEnglish
    Pages (from-to)171-181
    Number of pages11
    JournalJournal of Endocrinology
    Volume190
    Issue number1
    Early online date27 Apr 2006
    DOIs
    Publication statusPublished - Jul 2006

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    Welters, H. J., Senkel, S., Klein-Hitpass, L., Erdmann, S., Thomas, H., Harries, L. W., Pearson, E. R., Bingham, C., Hattersley, A. T., Ryffel, G. U., & Morgan, N. G. (2006). Conditional expression of hepatocyte nuclear factor-1β, the maturity-onset diabetes of the young-5 age product, influences the viability and functional competence of pancreatic β-cells. Journal of Endocrinology, 190(1), 171-181. https://doi.org/10.1677/joe.1.06768