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Originally published In Press as doi:10.1074/jbc.M411727200 on November 15, 2004

J. Biol. Chem., Vol. 280, Issue 6, 4992-5003, February 11, 2005
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Reduced Expression of the Insulin Receptor in Mouse Insulinoma (MIN6) Cells Reveals Multiple Roles of Insulin Signaling in Gene Expression, Proliferation, Insulin Content, and Secretion*{boxs}

Mitsuru Ohsugi, Corentin Cras-Méneur, Yiyong Zhou, Ernesto Bernal-Mizrachi, James D. Johnson, Dan S. Luciani, Kenneth S. Polonsky, and M. Alan Permutt{ddagger}

From the Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Missouri 63110

The role of insulin signaling in pancreatic {beta} cells has become increasingly apparent. Stably transformed insulinoma cell lines (MIN6) were created with small interfering RNA resulting in the reduction of insulin receptor (IR) expression up to 80% (insulin receptor knockdown, IRKD{Delta}80). Functionally perturbed IR signaling was confirmed with the absence of insulin-stimulated insulin receptor substrate 1 tyrosine phosphorylation. Additionally, Akt phosphorylation was reduced and responded poorly to glucose stimulation. Gene expression profiling revealed that reduced IR expression was associated with alterations in expression of >1,500 genes with diverse functions. IRKD cells exhibited low rate of proliferation due to delay in transition from G0/G1 to S phase, whereas susceptibility to apoptosis did not differ from that of control cells. Insulin content was reduced in proportion to the reduction of IR. IRKD cells maintained glucose responsiveness as measured by NAD(P)H generation, whereas Ca2+ responses and insulin secretion were enhanced. IRKD{Delta}80 and control cells were treated with glucose (25 mM) or insulin (100 nM) for 45 min, and gene expression profiles were assessed. Transcriptional activation of several hundred early response genes common to both glucose and insulin stimulation was observed in control cells. In IRKD{Delta}80 cells, insulin failed to activate any genes as anticipated. Importantly, glucose stimulation of gene expression in IRKD{Delta}80 cells showed that most genes previously activated by glucose were no longer activated, suggesting a major autocrine/paracrine effect of insulin on glucose-regulated gene expression. On the other hand, there were a number of glucose-regulated genes in the IRKD{Delta}80 cells that were not previously observed in control cells, suggesting a feedback regulation of insulin signaling on glucose-regulated gene expression. These results demonstrate important roles of the insulin receptor in islet {beta} cell gene expression and function and may serve to elucidate molecular defects in animal models with diminished {beta} cell insulin signaling.

Received for publication, October 14, 2004 , and in revised form, November 9, 2004.

* This work was supported in part by American Diabetes Association Mentor-based Fellowship (to M. O.), Canadian Institutes of Health Research Senior Fellowship (to J. D. J.), National Institutes of Health Grants DK16746, DK56954, and DK99007 (to M. A. P.), and the Washington University Diabetes Research and Training Center.

{boxs} The on-line version of this article (available at http://www.jbc.org) contains Supplemental Tables 1S and 2S.

{ddagger} To whom correspondence should be addressed: Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8127, St. Louis, MO 63110. Tel.: 314-362-8680; Fax: 314-747-2692; E-mail: apermutt{at}im.wustl.edu.


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