Learn about the flu shot, COVID-19 vaccine, and our masking policy »
New to MyHealth?
Manage Your Care From Anywhere.
Access your health information from any device with MyHealth. You can message your clinic, view lab results, schedule an appointment, and pay your bill.
ALREADY HAVE AN ACCESS CODE?
DON'T HAVE AN ACCESS CODE?
NEED MORE DETAILS?
MyHealth for Mobile
Get the iPhone MyHealth app »
Get the Android MyHealth app »
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