COMMENTARY

Reprogramming Beta Cells in Diabetes: Step Closer to Cure

Raghavendra G. Mirmira, MD, PhD

February 13, 2017

Editorial Collaboration

Medscape &

In recent years, we have come to appreciate that loss or dysfunction of insulin-producing islet beta cells underlies virtually all major forms of diabetes mellitus. In type 1 diabetes, beta cells succumb to autoimmunity, leaving individuals with significantly reduced beta-cell mass and a lifelong dependence on insulin replacement therapy. In type 2 diabetes, beta cells fail to secrete sufficient insulin to overcome the prevailing insulin resistance.

The pathogenesis of other forms of diabetes (eg, gestational diabetes) can similarly be traced to a failure of beta-cell mass, beta-cell function, or both. Insulin remains the ultimate therapy for all forms of diabetes; the recent approval by the US Food and Drug Administration (FDA) of the first "artificial pancreas"[1] provides promise that closed-loop mechanical systems may enable tight glycemic control with minimal patient intervention.

Although a few FDA-approved therapies for type 2 diabetes (meglitinides, sulfonylureas, incretin-based drugs) directly enhance beta-cell function, no therapies for any form of diabetes lead to the growth of healthy, new beta cells to replace those that were lost or dysfunctional.

Multiple strategies to replace beta cells in individuals with diabetes have been considered. 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 5 years of transplantation.[2] 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.[3] 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 in the coming years.[4,5]

Coaxing Pancreatic Cells to Become Beta Cells

Still missing from these approaches is any attempt to induce regeneration or replication of endogenous beta cells in the pancreas, an approach that would be physiologically desirable. A 2008 study by Zhou and colleagues[6] provided early insight into how endogenous cells in the pancreas could be coaxed into becoming beta cells. This team showed that injection of just three genes—Neurog3, Mafa, and Pdx1—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?

Some of these challenges have been addressed in two studies published in the January 2017 issue of the journal Cell.[7,8] As background, in 2009, Collombat and colleagues[9] showed that pancreatic misexpression of the gene Pax4 led to the conversion of glucagon-producing alpha cells into functional beta cells. Using careful, state-of-the-art cell tracking techniques, the same group subsequently showed that Pax4 misexpression initially caused the conversion of cells lining the ducts to become alpha cells, which were then converting to beta cells.[10]

More striking, the pancreas in these mice appeared relatively normal, with well-demarcated islets, suggesting that Pax4 misexpression was inducing an orderly and spatially correct program of cellular conversion that probably recapitulated the normal cellular differentiation process. These findings then brought researchers to the recently published studies.[7,8]

Pushing Theory Toward Reality

In one of these studies,[8] a team led by Stefan Kubicek in Vienna, Austria, hypothesized that small molecules could effectively recreate the reprogramming effects of Pax4 misexpression, and generated cell lines that function as "reporters" for the effects of drugs that mimic the effects of Pax4. These cell lines reported on the levels of ARX, an alpha-cell master regulator that appears to be inhibited when Pax4 activity increases.

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.

In an accompanying study,[7] Collombat's team performed an unbiased gene expression analysis from the islets of mice in which Pax4 was misexpressed, and found that several genes involved in GABA signaling were significantly increased. Because the addition of GABA to cell cultures of alpha cells led to a reduction in Arx gene expression, the investigators hypothesized that systemically administering GABA to mice would lead to reprogramming of alpha cells to become beta cells.

When normal mice were treated with GABA, islet size increased in direct proportion to the duration of therapy—up to a 3.5-fold increase after 3 months of therapy—without any evidence of hypoglycemia. The response to GABA was unaffected by the age at which GABA treatment was initiated; this is important because the ability of beta cells to grow and multiply naturally declines dramatically with age in both mice and humans.[11,12]

Using cell tracing studies, the authors demonstrated that, as with Pax4 misexpression, the new beta cells arose from alpha cells, which in turn originated from cells lining the pancreatic duct.

Finally, 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 (whereas control animals eventually died of severe hyperglycemia). These findings are especially relevant to type 1 diabetes, where the autoimmunity is likely to repeatedly target regenerating beta cells for destruction—a process that could be countered by repeated administration of GABA.

Taken together, these two new 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.

Studies such as these, however, are not without precedent. For example, Wang and colleagues[13] recently identified a small molecule, harmine, that is capable of inducing human beta-cell replication, and when administered in vivo was able to ameliorate hyperglycemia in diabetic mice harboring human islets. Thus, the concept that endogenous beta cells can be induced to replicate or regenerate by systemic administration of hormones or small molecules—once thought to be the ultimate goal of diabetes research—is slowly becoming a reality.

Several uncertainties 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? What about tumorigenic transformation of duct-lining cells, alpha cells, or beta cells? Is the supply of the progenitor cell types (in this case, duct-lining cells or alpha cells) limited in humans?

The Human Islet Research Network

Although it is easy to conduct these studies in mice, from which pancreas and other tissues can be harvested and scrutinized, in humans the only measurable outcomes are glycemic control and insulin levels—outcomes that are relevant but do not establish mechanisms of action. Thus, we are many years away from such therapies finding their way into mainstream diabetes care.

Fortunately, a major initiative funded by the National Institutes of Health (NIH) called the Human Islet Research Network (HIRN) is addressing these and other issues related to replication- and regeneration-based therapies. This network is currently focusing on several relevant areas, including the generation of "humanized" mouse models (in which the human immune system is recapitulated in mice to better model the autoimmunity seen in type 1 diabetes); identifying circulating biomarkers of beta-cell stress, death, and regeneration; and developing novel technologies that allow cell-specific drug targeting, among others.

The interaction of HIRN with existing NIH-funded clinical trial networks (for example, T1D TrialNet, Immune Tolerance Network, and RISE) is designed to allow a pipeline of vetted therapies to find their way into appropriately and safely designed clinical trials. 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.

In association with the Endocrine Society

Comments

3090D553-9492-4563-8681-AD288FA52ACE
Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as:

processing....