Researchers have tried many approaches to induce beta cells to proliferate and improve function, and most have failed. But several new approaches have emerged, including embryonic stem cells, genetic-based drug discovery, and novel signaling pathways.
“Genome-wide association studies have identified more than 100 loci that are associated with type 1, type 2, or neonatal diabetes,” said Shuibing Chen, PhD, Associate Professor of Chemical Biology in Surgery at Weill Cornell Medical College, the first speaker at Friday’s Chemical Modulation of Beta-Cell Function symposium. “The problem is that the biological function of these genes or variants on the beta cells and other cells that are involved in diabetes is largely unknown.”
Mouse models are helpful but the most effective way to obtain useful information about the effect of particular genetic variants in humans is to use human systems. Dr. Chen’s lab uses gene editing in embryonic stem cell and pluripotent stem cell lines to maintain isogenic control of specific gene variations and their effects on human beta cells.
“Our initial study using this model allowed us to validate the biological function of three specific genes in human beta cells,” she explained. “The most exciting part was adapting this platform to drug discovery. We have found a drug that is already in human clinical trials for inflammatory disease that cures the loss of CDKAL1-induced beta-cell dysfunction. To our knowledge, this is the first time a gene-specific drug has been found in type 2 diabetes.”
Knocking out the CDKAL1 gene leaves human beta cells highly sensitive to glucotoxicity and lipotoxicity, Dr. Chen said. This heightened sensitivity has no effect in a normal environment. But in a high-glucose or high-lipid environment, loss of the gene leads to loss of beta-cell response to glucose stimulation.
“High-glucose and high-lipid conditions are major environmental factors that contribute to type 2 diabetes,” Dr. Chen said. “We adapted this stressful condition to drug screening and found T5224, a drug that is in clinical trials in the U.S. and in Japan for arthritis and other inflammatory diseases. It has not been studied in diabetes, as far as we know.”
Stem cell-based screening platforms have the potential to bring genetic-based precision medicine to diabetes. Genomic data suggest that most genes associated with diabetes interact with other genes as they affect the development of diabetes.
“We see genes interacting in very specific ways that allow us to classify genes into groups based on their activity,” Dr. Chen said. “We see this platform as a first step to developing drugs that target the genetic activities of each group. That’s how we see precision medicine for diabetes patients.”
Other research shows promise for inducing beta-cell differentiation and proliferation. Bridget K. Wagner, PhD, Director of Pancreatic Cell Biology and Metabolic Disease at the Broad Institute, described efforts to identify a pathway and a molecule to selectively promote beta-cell proliferation.
“If you can get cells to divide and replicate, that could be a problem for drug treatment because enhanced cell division and replication could lead to cancer,” Dr. Wagner explained. “We have found a small molecule, 5-iodotubercidin, or 5-IT, that inhibits a specific kinase, DYRK1a, to stimulate beta-cell proliferation in mouse and rat models and in human cell culture.
“What’s so surprising is that 5-IT is such a selective treatment,” she continued. “We were confident that we could find compounds to stimulate beta-cell proliferation, but we expected that they would also cause all sorts of other cells to divide. So far, we have not found other cell types that divide when we treat them with this compound.”
Other compounds that inhibit DYRK1a also stimulate beta-cell proliferation. 5-IT works well in mice, but it also affects other enzymes in human cells. Dr. Wagner’s lab is working on more selective analogues of 5-IT with fewer potential side effects, with an eye toward future clinical trials.
Shoen Kume, PhD, Professor of Biological Information at the Tokyo Institute of Technology Graduate School of Bioscience and Technology in Japan, shared new data on signals that regulate beta-cell differentiation and mass. Inhibiting vesicular monoamine transporter 2 reduces concentrations of monoamine neurotransmitters and enhances beta-cell differentiation in both mouse and human pluripotent stem cells, she explained.
“Monoamines are negative signals that arrest differentiation at the pancreatic progenitor state,” Dr. Kume said. “Decreasing the levels of monoamines using the monoamine-depleting drugs tetrabenazine or reserpine results in potentiated differentiation.”
Domperidone, an antagonist against dopamine receptor D2, can also increase beta-cell mass by preventing dedifferentiation in adult islet beta cells. The dopamine receptor functions as an inhibitor signal by forming a heteromer with stimulatory signals such as adenosine.
A different pathway can be used to manipulate cell metabolism and enhance beta-cell differentiation in induced pluripotent stem (iPS) cells. Removing methionine from the growth medium decreases S-adenosyl methionine and kills iPS cells after 24 hours, Dr. Kume said. But shorter term methionine deprivation leaves cells more sensitive to differentiation signals, which improves differentiation into beta cells at later stages.
“We are studying the molecular mechanism for potentiation of beta-cell differentiation,” Dr. Kume said. “Our eventual goal is the encapsulation and transplantation of mature beta cells to treat diabetes.”
Andrew F. Stewart, MD, the Irene and Dr. Arthur M. Fishberg Professor of Medicine, Endocrinology, Diabetes and Bone Diseases at the Icahn School of Medicine at Mount Sinai, also spoke during the session, presenting his latest findings in beta-cell signaling and proliferation.