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J. Biol. Chem., Vol. 282, Issue 16, 12030-12037, April 20, 2007

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Inhibition of GSK3 Promotes Replication and Survival of Pancreatic Beta Cells^*

From the DeveloGen AG, Marie-Curie-Strasse 7, Göttingen 37079, Germany

Recent developments indicate that the regeneration of beta cell function and mass in patients with diabetes is possible. A regenerative approach may represent an alternative treatment option relative to current diabetes therapies that fail to provide optimal glycemic control. Here we report that the inactivation of GSK3 by small molecule inhibitors or RNA interference stimulates replication of INS-1E rat insulinoma cells. Specific and potent GSK3 inhibitors also alleviate the toxic effects of high concentrations of glucose and the saturated fatty acid palmitate on INS-1E cells. Furthermore, treatment of isolated rat islets with structurally diverse small molecule GSK3 inhibitors increases the rate beta cell replication by 2–3-fold relative to controls. We propose that GSK3 is a regulator of beta cell replication and survival. Moreover, our results suggest that specific inhibitors of GSK3 may have practical applications in beta cell regenerative therapies.

Received for publication, October 12, 2006 , and in revised form, January 16, 2007.

^* This work was supported by a grant from the Juvenile Diabetes Research Foundation (to DeveloGen AG). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed. Tel.: 49-551-50558-652; Fax: 49-551-50558-588; E-mail: mussmann{at}develogen.com. ² To whom correspondence may be addressed. Tel.: 49-551-50558-550; Fax: 49-551-50558-588; E-mail: austen{at}develogen.com.

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