Repurposing cAMP-modulating medications to promote β-cell replication

Z Zhao, YS Low, NA Armstrong, JH Ryu… - Molecular …, 2014 - academic.oup.com
Z Zhao, YS Low, NA Armstrong, JH Ryu, SA Sun, AC Arvanites, J Hollister-Lock, NH Shah
Molecular endocrinology, 2014academic.oup.com
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 …
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.
Oxford University Press