Cellular Pathway for Insulin Release Described by New Research

Researchers from Uppsala University have identified a critical aspect of how our bodies produce insulin, perhaps paving the way for more effective future diabetes treatments. This study found that levels of the Epac2A protein compound are directly correlated to insulin release. By utilizing specialized microscopy techniques the research team was able to visualize the binding of Epac2A and cyclic Adenosine Monophosphate (cAMP) for the first time. This process was shown to be a primary pathway for the movement of Epac2A to the cellular membrane receptor sites which regulate granular insulin release [1]. This represents a deep insight to a before undescribed link between Epac2A, cAMP, and insulin release.

Shedding Light on Long Held Suspicions

Cyclic AMP has been well studied as a facilitator of intracellular transportation. This molecules’ role in cytosis has been well agreed upon—though many of its dynamics still aren’t well understood.  Previous research has shown that cAMP is integrally involved in the release of insulin, and also that Epac2A levels seem to be involved. [3] This research does well to identify many of the moving parts of the process underlying cellular insulin release, though there has still been much mystery as to how they all fit together. This new research shows that cAMP binds to the Epac2A protein and rapidly transports it to the cellular membrane, where it then binds to sites responsible for regulating insulin release. This suggests two important new understandings that one; Epac2A plays a direct role in regulating insulin granule release from pancreatic B-cells and two; cellular cAMP levels likely correlate to the effectiveness of this mechanism.

Understanding Cyclic Adenosine Monophosphate (cAMP)

Adenosine Triphosphate (ATP) is often associated with energy levels by nutritionists and doctors alike. This molecule plays an integral role in our bodies’ abilities to transfer energy to different areas, but it isn’t a direct source in most cases. It’s like crude oil, which can be further refined by different cells into different types of fuel to suit their purpose. Cyclic Adenosine Monophosphate (cAMP) is produced inside cells after the conversion of ATP via the enzyme Adenylate Cyclase. Once cells have generated cAMP, they utilize it through the binding with different proteins. In this case of this new study, researchers identified the messenger pathways with heightened activity after the binding of Epac2A and cAMP. This pathway was shown to transport the Epac2A compounds directly to the cellular plasma membrane, where they are then used to regulate insulin release. Simply put; it seems that both cAMP levels and Epac2A levels likely correlate directly to insulin-release.

Approaches of Treating Diabetes

Diabetes is now commonly being treated with drugs that inhibit the action of a compound known as dipeptidyl peptidase (DPP). These inhibitors, such as Sitagliptin (Januvia), work to effectively increase levels of a compound named Glucagon-Like Peptide (GLP). This class of compounds describes types of secretory hormones released by the gastrointestinal tract in response to eating, notably GLP-1. Previous research has shown GLP-1 to bind to increase intracellular cAMP levels after binding to pancreatic beta cell receptor sites. This entire process can be summarized by regarding DPP as increasing GLP which in turn increases cAMP, resulting in an increased release of insulin into the bloodstream. [2] This new research now sheds like on the final stages of this process by which cAMP ushers the Epac2A protein to the cellular membrane where it regulates insulin release.

Promising Natural Treatments

Research such as this offers great clarification towards complicated biochemical processes in our bodies. These new understandings will likely fuel the development more effective diabetes medications which take into account newly understood subtleties of cellular insulin release. This new understanding can also serve to help identify potential existing compounds that haven’t necessarily been investigated for their role in treating diabetes. With the concepts of this new research in mind, there are a few natural compounds that may show future promise in their ability to help treat diabetes naturally, or at least slow its progression.


Berberine is a compound found naturally in plants such as the Indian Barberry tree, Goldenseal, and Yellowroot. This compound has demonstrated the ability to impact blood glucose levels as significantly as other pharmaceuticals such as Metformin [4]. Berberine has also been shown to decrease serum lipid levels and total cholesterol significantly—something not seen with Metformin. Other research has shown that Berberines anti-glycemic action can be explained by its action as a DPP inhibitor, similar to the drug Sitagliptin mentioned above [5]. Further research is needed to better describe the role Berberine plays in this type of action, though it’s overall impact on blood glucose levels much better established.


Forskolin is an extract from the roots of the Coleus Forskohlii plant commonly marketed as a weight loss supplement. Much of that hype was generated from celebrity personalities such as Dr. Mehmet Oz sensationalizing the results of a study among 23 women. This study was a far cry from being comprehensive, and concluded only that forskolin may be useful as a means of mitigating fat gain. [6] Dr. Oz has subsequently been investigated by a Senate Subcommittee for making false claims about weight loss supplements. Forskolin has a considerable amount of research demonstrating its ability to increase cAMP levels. One study investigating signaling pathways involved in immunosuppressive diseases such as HIV round that Forskolin was an activator of adenylate cyclase which significantly increased intracellular cAMP levels [7]. The primary focus of this study was on signaling pathways involved in immunosuppression, though it provides valuable insight into forskolin as a potential treatment for diabetes in the future. In addition to this research, many other studies have investigated forskolin for various applications, all concluding that it has a serious impact on cAMP levels. [8][9][10]

Final Thoughts

Diabetes is a disease that has been rapidly increasing in prevalence within the United States in recent years. The most-recent data suggests that among the entire US Population; 15% of people are diabetic and another 38% are pre-diabetic [11]. This implicates more than 160 Million people as suffering from insulin-related issues. This new research provides valuable understanding of the cellular signaling pathways involved in reduced insulin production. By applying this knowledge, as well as using it to consider previous research, future diabetes treatments will likely become more efficient and effective. The understanding of the role cAMP plays in transporting Epac2A to the cellular membrane highlights the potential of natural compounds such as Forskolin as potential diabetic therapies.


  1. http://diabetes.diabetesjournals.org/content/early/2017/06/29/db17-0050
  2. http://diabetes.diabetesjournals.org/content/64/4/1262.long
  3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2148290/
  4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2410097/
  5. http://www.tandfonline.com/doi/full/10.1080/14756360802610761
  6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2129145/
  7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3591623/
  8. https://www.ncbi.nlm.nih.gov/pubmed/6299378
  9. http://dx.doi.org/10.3109/10520295.2014.883463
  10. http://molpharm.aspetjournals.org/content/22/1/109.long

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