Medical Research: What is the background for this study? What are the main findings?
Dr. Rehmann: We have developed a chemical modified version of the second messenger cAMP, Sp-8-BnT-cAMPS that allows selective activation of Epac2, a protein that augments glucose induced insulin secretion.
The second messenger cAMP activates a couple of receptor proteins, which controls such divergent physiological effects as gene transcription, pacemaker activity, olfaction, and cell adhesion. Almost any cell responses in one or the other way to cAMP and thus selective action on only one cAMP receptor would be a requirement for a drug to induce specific effects.
The study confirms that it is possible to pharmacologically discriminate between structurally highly related cAMP receptors. And indeed, Sp-8-BnT-cAMPS augments glucose induced insulin secretion in primary human islets. Epac2 is thus a putative target for the development of an antidiabetic drug.
Medical Research: What should clinicians and patients take away from your report?
Dr. Rehmann To be clear, what we have done is rather basic research without impact on daily clinical routine. The future has to show whether or not activation of Epac2 is a therapeutic option.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Rehmann: We are now able to activate Epac2 selectively with Sp-8-BnT-cAMPS. This is a putative starting point for the development of an antidiabetic drug. I believe the focus should be twofold:
– The pharmacokinetic properties of Sp-8-BnT-cAMPS are not optimal. This needs clear improvement or alternatively the development of a small molecule unrelated to cAMP.
– We do not fully understand the physiological function of Epac2. Sp-8-BnT-cAMPS will be a useful tool to analyse Epac2 mediated effects. This is not just an academic problem of understanding how Epac2 exactly impinges on insulin secretion. As more we know on the physiology as easier we can predict unwanted side effects or would at least be aware for what to watch out. The value of Epac2 as a therapeutic target needs to be evaluated.
Structure-Guided Design of Selective Epac1 and Epac2 Agonists
Schwede F1, Bertinetti D2, Langerijs CN3, Hadders MA4, Wienk H5, Ellenbroek JH6, de Koning EJ7, Bos JL8, Herberg FW2, Genieser HG1, Janssen RA3, Rehmann H8.
PLoS Biol. 2015 Jan 20;13(1):e1002038. doi: 10.1371/journal.pbio.1002038.