title: Repurposing cAMP-modulating medications to promote β-cell replication.
abstract: 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 α(2)-adrenergic receptors. Accordingly, mirtazapine, an α(2)-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.
authors.affiliation: Department of Medicine and Division of Endocrinology, Gerontology, and Metabolism (Z.Z., N.A.A., S.A.S., J.P.A.) and Stanford Center for Biomedical Informatics Research (Y.S.L.), Stanford University School of Medicine, Stanford, California 94306; Department of Stem Cell and Regenerative Biology (J.H.R., A.C.A.), Harvard University, Cambridge, Massachusetts 02138; and Section of Islet Cell and Regenerative Biology (J.H.-L., G.C.W.), Joslin Diabetes Center, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Zhenshan
authors.initials: Z
authors.lastname: Zhao
authors.forename: Yen S
authors.initials: YS
authors.lastname: Low
authors.forename: Neali A
authors.initials: NA
authors.lastname: Armstrong
authors.forename: Jennifer Hyoje
authors.initials: JH
authors.lastname: Ryu
authors.forename: Sara A
authors.initials: SA
authors.lastname: Sun
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Arvanites
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hollister-Lock
authors.forename: Nigam H
authors.initials: NH
authors.lastname: Shah
authors.forename: Gordon C
authors.initials: GC
authors.lastname: Weir
authors.forename: Justin P
authors.initials: JP
authors.lastname: Annes
mesh_terms: D000818:Animals; D002455:Cell Division / Q000187:drug effects* / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D010179:Pancreas / Q000187:drug effects* / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012038:Regeneration / Q000187:drug effects*
chemical_list: D010726:Phosphodiesterase Inhibitors; D009638:Norepinephrine
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