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A Step Closer To A Cure: Reprogramming Beta Cells

Mar 4, 2017

Type 1 beta cells succumb to autoimmunity, leaving significantly reduced beta-cell mass and lifelong dependence on insulin replacement therapy, while type 2 beta cells fail to secrete sufficient insulin to overcome prevailing insulin resistance.

In looking for a cure for type 1, it could be to find a way to regenerate beta cells that we know still exist for type 1’s and just keep that bucket at least half filled. For type 2 diabetes, it could be a whole different issue with insulin resistance.

Most if not all forms of diabetes can be traced to a failure of beta-cell mass, beta-cell function, or both.  With the FDA approval of the first artificial pancreas insulin pump with a CGM, this is not considered a cure but a treatment.

We have FDA-approved therapies for type 2 diabetes as meglitinides, sulfonylureas, incretin-based and SGLT-2 inhibitor drugs and others, and some of these new FDA-approved therapies for type 2 diabetes directly enhance beta-cell function, but no therapies for any form of diabetes led to the growth of healthy, new beta cells to replace those that were lost or dysfunctional, for now.

They have been researching many strategies to replace beta cells in individuals with diabetes. Perhaps the most extensively studied is transplantation of cadaveric islets into persons with type 1 diabetes. Despite initial successes, this approach has largely proved disappointing, with most individuals requiring exogenous insulin therapy within five years of transplantation. As a result, the momentum for cadaveric islet transplantation has diminished considerably.

A more appealing strategy involves the transplantation of beta cells grown from stem cells, particularly with recent advances in generating large numbers of beta cells from human stem cells.  Clinical trials are currently under way on the safety, tolerability, and efficacy of transplanting such cells in encapsulated forms in persons with type 1 diabetes, with results to be announced soon, possibly at the 77th ADA Scientific Sessions this June 2017.

What is still missing is the attempt to induce regeneration or replication of endogenous beta cells in the pancreas, an approach that would be physiologically desirable. In a study by Zhou, it provided early insight into how endogenous cells in the pancreas could be coaxed into becoming beta cells. They showed that injection of just three genes into the pancreatic parenchyma of mice leads to conversion of exocrine cells to functional beta cells, a process popularly known as “reprogramming. Those studies, among the first to suggest that reprogramming could occur, exposed still other technical challenges. For example, how can genes be delivered at the precise dose to cells in humans? How can specific cells be targeted for reprogramming? Are there ways to mimic the effects of genes with hormones or small molecules?

In two new studies published just last month (Jan. 2017), in the journal Cell, some of these challenges have been addressed. In one of these studies, a team led by Stefan Kubicek in Vienna, Austria, hypothesized that small molecules could effectively recreate the reprogramming effects of a gene to become insulin-secreting cells.

The investigators showed that a class of antimalarial drugs known as artemisinins, typified by the FDA-approved drug artemether, were capable of inhibiting ARX levels, reducing glucagon, and increasing insulin in an in vitro alpha-cell model. The drug ameliorated hyperglycemia in a rat model of diabetes and enhanced insulin secretion from human islets. The mechanism of action appears to be through the stabilization of gephyrin, a protein that augments the ARX-suppressing GABAA-receptor signaling pathway.

The observation by Kubicek’s group was notable not only for the identification of an FDA-approved compound that initiates alpha-cell reprogramming, but also for suggesting that GABA signaling may also be exploited as an alternative or synergistic means to augment formation of new beta cells.

To demonstrate that these new beta cells are capable of ameliorating or reversing diabetes, the authors repeatedly induced diabetes in mice using a beta-cell–specific toxin (streptozotocin), and demonstrated that after each dose of the toxin, GABA administration reversed hyperglycemia by regenerating beta cells.

This and other studies provide the first evidence that small molecules and hormones that target the GABA signaling pathway can reprogram another cell type to regenerate new beta cells. But some uncertainties still remain: How will human beta cells respond when these therapies are delivered systemically? Are there pathways in humans (not present in mice) that would alter these small molecules or hormones in ways that prevent their action on beta cells? Can we be certain that other cell types in the body will not respond negatively to these therapies?

Hopefully with the funding that is available for research, and the advancement in technology, we are very close to what you could call a CURE!  We have learned more in the last couple of years than in the past 50 years. Although we cannot say that cellular reprogramming therapy is “there” yet, such discoveries as those described here are paving a new road to diabetes therapies that only a decade ago were considered science fiction.

Practice Pearls:

  • Right now we have approved therapies for type 2 diabetes that directly enhance beta-cell function.
  • Many studies are going on showing that it might be possible to regenerate insulin producing beta cells.
  • The scientific community believes that it is just a matter of time before we can say the word  “Cure.”


  1. US Food and Drug Administration. FDA approves first automated insulin delivery device for type 1 diabetes. September 28, 2016. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm522974.htm Accessed January 27, 2017.
  2. Ryan EA, Paty BW, Senior PA, et al. Five-year follow-up after clinical islet transplantation. Diabetes. 2005;54:2060-2069. Abstract
  3. Pagliuca FW, Millman JR, Gürtler M, et al. Generation of functional human pancreatic beta cells in vitro. Cell. 2014;159:428-439. Abstract
  4. ClinicalTrials.gov. A Safety, Tolerability, and Efficacy Study of VC-01™ Combination Product in Subjects With Type I Diabetes Mellitus. NCT02239354. https://clinicaltrials.gov/ct2/show/NCT02239354 Accessed January 27, 2017.
  5. ClinicalTrials.gov. Three Year Follow-up Safety Study in Subjects Previously Implanted With VC-01™. NCT02939118. https://clinicaltrials.gov/ct2/show/NCT02939118 Accessed January 27, 2017.
  6. Zhou Q, Brown J, Kanarek A, Rajagopal J, Melton DA. In vivo reprogramming of adult pancreatic exocrine cells to beta-cells. Nature. 2008;455:627-632. Abstract
  7. Ben-Othman N, Vieira A, Courtney M, et al. Long-term GABA administration induces alpha cell-mediated beta-like cell neogenesis. Cell. 2017;168:73.e11-85.e11.