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New discoveries highlight pathways for beta-cell regeneration in type 1, type 2 diabetes
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The promise of beta-cell regeneration — restoring the insulin-producing cells lost in type 1 and type 2 diabetes — has long been considered an ambitious goal. Research now demonstrates that most people with diabetes have residual beta cells with the ability to proliferate; however, researchers have struggled to translate the findings into viable pathways in humans.
“The one thing we have learned over the years is that not all beta cells are dead by the time someone is diagnosed with diabetes,” Anath Shalev, MD, professor of medicine and director of the Comprehensive Diabetes Center at the University of Alabama at Birmingham, told Endocrine Today. “Even when it seems by our current measurements that all beta cells are dead as there is no C-peptide left, that is still not true. We see now that, when you create the right environment, you may be able to ‘revive’ some beta cells.”
In just the past 2 years, progress has accelerated rapidly in the field of beta-cell regeneration. In December, researchers announced the identification of a novel combination of two distinct classes of molecules shown to induce proliferation in adult human beta cells at a rate of 5% to 8% in in vitro and 2% in in vivo transplant models, far exceeding rates from other experimental drugs. Other groups have identified novel signaling pathways and new uses for FDA-approved agents, including a calcium channel blocker, that promote beta-cell health and survival. Still other discoveries in immunotherapy may hold the keys to altering the course of the disease by preserving beta-cell function.
The findings could potentially offer a cure for type 2 diabetes and may even hold promise for people with type 1 diabetes, although researchers continue to search for ways to protect beta cells from an attack by the body’s own immune system.
Source: Jill Rollet for Endocrine Today
“It’s been increasingly recognized over the last decade that type 2 diabetes is also a disease of loss of beta-cell function, not just insulin resistance,” Dawn Belt Davis, MD, PhD, associate professor in the division of endocrinology, diabetes and metabolism at the University of Wisconsin School of Medicine and Public Health in Madison and at the William S. Middleton Memorial Veterans Hospital, told Endocrine Today. “The idea is that if we had the capacity to promote beta cell-proliferation in type 2, ideally even very early on in the prediabetes stage, we could slow down progression of the disease — potentially prevent or reverse it — and help patients avoid becoming insulin dependent. That is our goal.”
Davis, an Endocrine Today Editorial Board Member whose research focuses on the role of gut hormones in the islets and beta-cell response to stressors like obesity, said studies show an increase in beta-cell proliferation early on in obesity to compensate for the insulin resistance that ultimately leads to type 2 diabetes. Similar adaptations have been observed during pregnancy, she said.
“We are trying with our research to understand how those proliferative signals work in these adaptive ways, and maybe we can identify pathways there that we can then harness for the patients who are not adapting [to beta-cell stressors] adequately or those who passed the threshold of too low beta-cell mass.”
New drug combination
Currently, none of the clinically available diabetes drugs can drive human beta-cell regeneration, according to Andrew F. Stewart, MD, director of the Diabetes, Obesity and Metabolism Institute at the Icahn School of Medicine at Mount Sinai. However, a novel combination of two distinct classes of molecules may: the hallucinogenic alkaloid harmine, which inhibits DYRK1A, and the transforming growth factor (TGF)-beta superfamily inhibitor LY364947.
In findings published in Cell Metabolism in December, the two molecules worked synergistically to induce “previously unattainable” rates of human beta-cell proliferation in human islet donors, human stem cell-derived beta cells and stem cells from people with type 2 diabetes, according to researchers.
“We have, for the first time, drugs that are capable of making the human beta cell regenerate at rates that are fast enough to reverse type 1 and type 2 diabetes,” Stewart told Endocrine Today. “What we don’t have is a way to deliver them specifically to the pancreatic beta cell. The way I like to think of it is, we’re Amazon, and we have a parcel for you, but we don’t know your address.”
In gene expression profiles from fluorescence-activated cell-sorted human beta cells, Stewart and colleagues observed an abundance of certain members of the TGF-beta superfamily, multifunctional peptides that control proliferation and differentiation in many cell types. Application of harmine, also known as telepathine, resulted in changes in TGF-beta superfamily members, Stewart said. The researchers then explored the effects of TGF-beta superfamily inhibitors on human beta-cell proliferation in human cadaver islets. Used alone, such inhibitors had no effect; however, when combined with harmine, the researchers observed a dramatic increase in human beta cells, as measured by Ki67 labeling.
“Proliferation rates (labeling indices) averaged in the 5% to 8% range; the large error bars reflect even higher proliferation rates in occasional human islet preparations, sometimes achieving Ki67 labeling indices as high as 15% to 18%,” the researchers wrote.
The researchers demonstrated that the findings were part of a class effect that extended to other DYRK1A and TGF-beta superfamily inhibitors, they wrote.
Stewart said researchers must learn how to target the drugs specifically to the beta cell so that they do not adversely affect other tissues. Harmine, for example, is a hallucinogen and affects the brain.
“We’ve gone from ‘it’s impossible’ 3 years ago to ‘it’s clearly possible’ now, and we even have grades of proliferation that are therapeutically realistic and relevant,” Stewart said. “This is, for us, the next stop on the train to elimination of diabetes.”
Roles of GLP-1, CCK
In a study published in The American Journal of Physiology-Endocrinology and Metabolism, in 2015, Davis and colleagues demonstrated that cholecystokinin, or CCK, a peptide hormone produced in the gut and brain but also in pancreatic islets, protects beta cells from apoptotic stress, as demonstrated in mouse models that overexpressed CCK in beta cells. More recently, Davis and colleagues found that the expression of CCK in islets is regulated by another key gut hormone, GLP-1, as part of a newly identified intra-islet incretin network that protects beta cells from apoptotic stressors, such as obesity and insulin resistance. GLP-1 receptor agonists, already widely prescribed for glycemic management in type 2 diabetes, enhance insulin secretion and may improve pancreatic islet cell function; mechanisms behind any association continue to be explored.
“What we’re really excited about is both of those hormones, which classically are known as gut peptides, can be made within the pancreatic islet itself,” Davis said. “What we’ve been studying is the local production of these non-classic islet hormones. These are hormones that we typically don’t think of as being made in the islet, which are actually being turned on and made in endocrine cells in the islet, again primarily in response to stress.”
In a review published in 2016 in the Journal of Diabetes Investigation, Davis and colleagues wrote that activation of intra-islet GLP-1 signaling is a natural physiological response, or adaptation, to obesity.
“Given what we now know regarding the ability of both GLP-1 and CCK to regulate one another and prevent beta-cell death, we propose that long-term treatment with these hormones might impact islet peptide production to allow maintenance of beta-cell mass,” the researchers wrote. “Examination of how GLP-1 and CCK specifically signal in the islet might also provide new therapeutic targets that could minimize non-islet side effects.”
A ‘lucky chance’ therapy
Verapamil, an FDA-approved calcium channel blocker commonly prescribed for hypertension, may help reduce levels of a key protein that is enhanced in beta cells stressed by type 1 or type 2 diabetes and leads to beta-cell deterioration.
In a human pancreatic islet microarray study, Shalev and colleagues found that thioredoxin-interacting protein, or TXNIP, was the most dramatically upregulated gene in response to glucose, suggesting that it might play an important role in diabetes and beta-cell biology.
“That is when we wondered about its role in beta-cell death,” Shalev said. “Many studies after that have proven the role of elevated TXNIP in beta-cell stress and beta-cell apoptosis, whereas beta cells are protected against various stresses when TXNIP is down. The goal of our research is to find ways to normalize the diabetes-associated detrimental increase in TXNIP levels and not to eliminate its expression altogether.”
It was by “lucky chance,” Shalev said, that researchers in her lab discovered that verapamil could reduce TXNIP levels.
“A technician of mine had conducted a couple of experiments with verapamil in a beta-cell line for unrelated reasons, and we got curious,” Shalev said. “We said, ‘Well, we’re studying TXNIP. Let’s see if it changes.’ Sure enough, it was downregulated. It was so early in the process that we didn’t make anything out of it. It was only later on when we saw that the genetic deletion of TXNIP is so protective against diabetes and we were starting to look for a tool to downregulate it that we remembered that we had observed this.”
Shalev said she went back to the technician’s notebook, wondering if the accidental discovery could be replicated.
“Sure enough, it was still true; verapamil downregulated TXNIP, including in human islets,” Shalev said. “This is why it is important to keep good notebooks.”
Shalev and colleagues conducted a randomized, double-blind, placebo-controlled, phase 2 clinical trial in 32 adults with recent-onset type 1 diabetes who received daily oral verapamil or placebo added to a standard insulin regimen for 12 months. The findings, published in July 2018 in Nature Medicine, demonstrated that verapamil treatment, compared with placebo, was well-tolerated and associated with an improved mixed-meal-stimulated C-peptide area under the curve, a measure of endogenous beta-cell function, at 3 and 12 months. Patients assigned verapamil also had lower insulin requirements and fewer hypoglycemic events. There were no safety issues observed in the study.
“Having seen the results in the human islets and in different mouse models, I wasn’t really surprised,” Shalev said. “Now, the extent of how strong the effect was in humans, that I was positively surprised by.”
Shalev said she is working closely with JDRF, which awarded the grants that funded this verapamil trial, to conduct a follow-up study with the drug in children.
Immunotherapy discoveries
A groundbreaking therapy that transformed the treatment of chronic myelogenous leukemia and several other cancers may have the potential to prevent or even reverse type 1 diabetes.
Researchers are currently exploring the potential role of short-term therapy with imatinib, a first-in-class tyrosine kinase inhibitor, to induce tolerance and possibly lead to a durable long-term remission of type 1 diabetes.
The phase 2 study, led by Stephen E. Gitelman, MD, professor of pediatrics and director of the pediatric diabetes program and the University of California at San Francisco, enrolled 67 adults newly diagnosed with type 1 diabetes who were randomly assigned to 400 mg imatinib once daily or placebo. Primary outcome was mean area under the stimulated C-peptide curve over the first 2 hours or a 4-hour mixed-meal tolerance test conducted at the 1-year visit. In an interim study presented at the 2017 American Diabetes Association Scientific Sessions, the researchers found that participants in the imatinib group had improved beta-cell function vs. the placebo group, in addition to lower supplemental insulin needs.
Longer-term follow-up of the study participants has recently concluded, and the researchers are pursuing a series of mechanistic studies to better understand how imatinib may have benefited those in the treatment group. Based on findings in the NOD mouse strain from Jeffrey A. Bluestone, PhD, professor in the Diabetes Center and the School of Medicine at University of California, San Francisco, the researchers expected that this approach would alter the immune response and continue once the treatment was withdrawn, according to Gitelman.
“Bluestone did not find significant changes in the immune response, but recently reported ... that imatinib appears to lower endoplasmic reticulum stress directly in beta cells, by blocking hyperactivation of IRE1-alpha through ABL interactions,” Gitelman told Endocrine Today. “Coupling a novel agent such as imatinib with another agent more specifically targeting T cells, such as anti-CD3 monoclonal antibody or anti-thymocyte globulin, may offer a synergistic means to preserve beta-cell function in those with residual beta-cell mass.”
Engineering an islet
At the Mayo Clinic’s Center for Regenerative Medicine, Quinn P. Peterson, PhD, assistant professor of physiology at the Mayo Clinic, and colleagues are primarily focused on using stem cell technology to generate pancreatic islet cell types. Using a large-scale, 3D culture system, the researchers can mass produce the cells for chemical screens and transplantation studies.
“The approach that we are taking differs from some of the other efforts in this regard by virtue of the cell platform that we are developing,” Peterson told Endocrine Today. “Rather than focusing solely on the beta cell, we are generating whole islets with multiple endocrine cell types. We’re doing this using a bottom-up, tissue-engineering approach.”
Peterson and colleagues developed protocols for generating several different endocrine cell types — pancreatic alpha cells, beta cells and delta cells — as well as technologies for bringing these cell types together to build islet organoids with defined composition, in which the researchers control the percentage of each cell type. The influence the alpha, beta and delta cells have on one another, Peterson said, is an area of intense study.
The goal is transplantation of these “designer” islets, which could ultimately restore the ability to produce insulin and regulate blood glucose in people with type 1 diabetes, Peterson said.
“It’s been appreciated in the field for a long time that the islet functions as a unit,” Peterson said. “Our view is that beta cells are going to function best in an environment that most closely resembles their native environment, and that is with alpha and delta cells present. We have been able to demonstrate some benefits of having multiple cell types present and look forward to being able to further understand the different contributions of the different cell types in the islet.”
Peterson said researchers in his lab hope to begin human trials with islet transplantation in the next few years.
No single approach
In a review paper published in 2018 in Diabetologia, Esra Karakose, PhD, a researcher at the Diabetes, Obesity and Metabolism Institute at the Icahn School of Medicine at Mount Sinai, and colleagues wrote that progress in therapeutic human beta-cell replication has been remarkable; however, difficult challenges remain. Those challenges include generating higher rates of proliferation, developing tools to allow beta-cell-specific drug targeting and imaging in humans, and overcoming or preventing continuing autoimmunity. Additionally, if regenerative pathways are driven too aggressively, there may be oncogenic consequences, the researchers noted.
“Anytime you are talking about stimulating, proliferating and inhibiting cell death, you worry about cancer,” Davis said. “I often joke that, in many ways with the research I do, I’m like an anticancer biologist. I’m trying to activate all of the pathways that they are trying to turn off. We have to be mindful of that when we are developing ideas and potential therapeutics.”
Peterson said the new beta-cell discoveries happening on all fronts could contribute to a treatment — or even a cure — in the decades to come.
“At the end of the day, the answer is unlikely to be one single approach,” Peterson said. “All of these approaches are complementary. As we deepen our understanding of the potential of cell replacement therapy and things being done in terms of beta-cell replication or in terms of mechanisms of insulin secretion or engineering aspects of these cells, the reality is all of these things interplay and are likely to be contributing factors to the ultimate result we all hope for, which is a therapy that is effective for the individual.” – by Regina Schaffer
- References:
- Buse JB, et al. Diabetes Care. 2018;doi:10.2337/dc18-0343.
- Karakose E, et al. Diabetologia. 2018;doi:10.1007/s00125-018-4639-6.
- Lavine JA, et al. Am J Physiol Endocrinol Metab. 2015;doi:10.1152/ajpendo.00159.2015.
- Linnermann AK, et al. J Diabetes Investig. 2016;doi:10.1111/jdi.12465.
- Morita S, et al. Cell Metab. 2017;doi:10.1016/j.cmet.2017.03.018.
- Ovalle F, et al. Nat Med. 2018;doi:10.1038/s41591-018-0089-4.
- Wang P, et al. Cell Metab. 2019;doi:10.1016/j.cmet.2018.12.005.
- For more information:
- Dawn Belt Davis, MD, PhD, can be reached at the University of Wisconsin, Madison, 4147 MFCB, 1685 Highland Ave., Madison, WI 53705; email: dbd@medicine.wisc.edu.
- Stephen E. Gitelman, MD, can be reached at the University of California at San Francisco, Mission Hall, 550 16th St., 4th Floor, Box 0434, San Francisco, CA 94143; email: Stephen.gitelman@ucsf.edu.
- Quinn P. Peterson, PhD, can be reached at the Mayo Clinic College of Medicine, 200 1st St. SW, Rochester, MN 55905; email: Peterson.quinn@mayo.edu.
- Anath Shalev, MD, can be reached at the University of Alabama at Birmingham, 1825 University Blvd., SHEL 1206, Birmingham, AL 35294; email: shalev@uab.edu.
- Andrew F. Stewart, MD, can be reached at the Icahn School of Medicine at Mount Sinai, Diabetes, Obesity and Metabolism Institute, 1 Gustave L. Levy Place, New York, NY 10029; email: andrew.stewart@mssm.edu.
Disclosures: Stewart reports he and one of his study co-authors are inventors on a patent that has been filed by the Icahn School of Medicine at Mount Sinai. Davis, Shalev and Peterson report no relevant financial disclosures.
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