Repurposing cAMP-Modulating Medications to Promote beta-Cell Replication MOLECULAR ENDOCRINOLOGY Zhao, Z., Low, Y. S., Armstrong, N. A., Ryu, J. H., Sun, S. A., Arvanites, A. C., Hollister-Lock, J., Shah, N. H., Weir, G. C., Annes, J. P. 2014; 28 (10): 1682-1697

Abstract

Loss of ß-cell mass is a cardinal feature of diabetes. Consequently, developing medications to promote ß-cell regeneration is a priority. 3'-5'-Cyclic adenosine monophosphate (cAMP) is an intracellular second messenger that modulates ß-cell replication. We investigated whether medications that increase cAMP stability or synthesis selectively stimulate ß-cell growth. To identify cAMP stabilizing medications that promote ß-cell replication we performed high-content screening of a phosphodiesterase-inhibitor (PDE-I) library. PDE3,4 and 10 inhibitors, including dipyridamole, were found to promote ß-cell replication in an adenosine receptor-dependent manner. Dipyridamole's action is specific for ß-cells and not a-cells. Next we demonstrated that norepinephrine (NE), a physiologic suppressor of cAMP synthesis in ß-cells, impairs ß-cell replication via activation of a2-adrenergic receptors. Accordingly, mirtazapine, an a2-adrenergic receptor antagonist and antidepressant, prevents NE-dependent suppression of ß-cell replication. Interestingly, NE's growth-suppressive effect is modulated by endogenously expressed catecholamine-inactivating enzymes (COMT and MAO) and is dominant over the growth-promoting effects of PDE-Is. Treatment with dipyridamole and/or mirtazapine promote ß-cell replication in mice and treatment with dipyridamole is associated with reduced glucose levels in humans. This work provides new mechanistic insights into cAMP-dependent growth regulation of ß-cells and highlights the potential of commonly prescribed medications to influence ß-cell growth.

View details for DOI 10.1210/me.2014-1120

View details for Web of Science ID 000346837000010

View details for PubMedID 25083741