Repurposing cAMP-Modulating Medications to Promote β-Cell Replication

• Published in: Molecular endocrinology (Baltimore, Md.) Vol. 28; no. 10; pp. 1682 - 1697
• Main Authors: Zhao, Zhenshan, Low, Yen S, Armstrong, Neali A, Ryu, Jennifer Hyoje, Sun, Sara A, Arvanites, Anthony C, Hollister-Lock, Jennifer, Shah, Nigam H, Weir, Gordon C, Annes, Justin P
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01-10-2014; Oxford University Press
• Subjects: Animals; Cell Division - drug effects; Cell Division - physiology; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - physiology; Male; Norepinephrine - pharmacology; Original Research; Pancreas - drug effects; Pancreas - physiology; Phosphodiesterase Inhibitors - pharmacology; Rats; Rats, Sprague-Dawley; Regeneration - drug effects
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2014-1120

Loss of β-cell mass is a cardinal feature of diabetes. Consequently, developing medications to promote β-cell regeneration is a priority. cAMP is an intracellular second messenger that modulates β-cell replication. We investigated whether medications that increase cAMP stability or synthesis selectively stimulate β-cell growth. To identify cAMP-stabilizing medications that promote β-cell replication, we performed high-content screening of a phosphodiesterase (PDE) inhibitor library. PDE3, -4, and -10 inhibitors, including dipyridamole, were found to promote β-cell replication in an adenosine receptor-dependent manner. Dipyridamole's action is specific for β-cells and not α-cells. Next we demonstrated that norepinephrine (NE), a physiologic suppressor of cAMP synthesis in β-cells, impairs β-cell replication via activation of α2-adrenergic receptors. Accordingly, mirtazapine, an α2-adrenergic receptor antagonist and antidepressant, prevents NE-dependent suppression of β-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 β-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 β-cells and highlights the potential of commonly prescribed medications to influence β-cell growth.