Repurposing cAMP-Modulating Medications to Promote β-Cell Replication

Loss of beta-cell mass is a cardinal feature of diabetes. Consequently, developing medications to promote beta-cell regeneration is a priority. cAMP is an intracellular second messenger that modulates beta-cell replication. We investigated whether medications that increase cAMP stability or synthesis selectively stimulate beta-cell growth. To identify cAMP-stabilizing medications that promote beta-cell replication, we performed high-content screening of a phosphodiesterase (PDE) inhibitor library. PDE3, -4, and -10 inhibitors, including dipyridamole, were found to promote beta-cell replication in an adenosine receptor-dependent manner. Dipyridamole's action is specific for beta-cells and not alpha-cells. Next we demonstrated that norepinephrine (NE), a physiologic suppressor of cAMP synthesis in beta-cells, impairs beta-cell replication via activation of alpha(2)-adrenergic receptors. Accordingly, mirtazapine, an alpha(2)-adrenergic receptor antagonist and antidepressant, prevents NE-dependent suppression of beta-cell replication. Interestingly, NE's growth-suppressive effect is modulated by endogenously expressed catecholamine-inactivating enzymes (catechol-O-methyltransferase and L-monoamine oxidase) and is dominant over the growth-promoting effects of PDE inhibitors. Treatment with dipyridamole and/or mirtazapine promote beta-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 beta-cells and highlights the potential of commonly prescribed medications to influence beta-cell growth.