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Mount Sinai Researchers Discover New Drug Cocktail That Increases Human Beta Cell Proliferation at Rapid Rates
Date:12/13/2018

Researchers at the Icahn School of Medicine at Mount Sinai have discovered a novel combination of two classes of drugs that induces the highest rate of proliferation ever observed in adult human beta cells—the cells in the pancreas that produce insulin. The result is an important step toward a diabetes treatment that restores the body’s ability to produce insulin.

The finding involved one drug that inhibits the enzyme dual specificity tyrosine-regulated kinase 1A (DYRK1A) and another that inhibits transforming growth factor beta superfamily members (TGFßSF). Together, they caused the cells to proliferate at a rate of 5 to 8 percent per day. The study, titled "Combined Inhibition of DYRK1A, SMAD and Trithorax Pathways Synergizes to Induce Robust Replication in Adult Human Beta Cells," was published today in Cell Metabolism. For a video about this study click here.

“We are very excited about this new observation because for the first time, we are able to see rates of human cell beta cell replication that are sufficient to replenish beta cell mass in human beings,” said Andrew Stewart, MD, Director of the Mount Sinai Diabetes, Obesity, and Metabolism Institute and lead author of the study. “We have discovered a drug combination that makes beta cells regenerate at rates that are suitable for treatment. The next big hurdle is figuring out how to deliver them directly to the pancreas.”

According to Dr. Stewart, none of the diabetes drugs currently on the market can induce beta cell regeneration in people with diabetes. In parallel with the Mount Sinai work, other researchers are studying pancreatic transplantation, beta cell transplantation, and stem cell replacement of beta cells for people with diabetes, but none of these approaches is in widespread use.

Approximately 30 million people in the United States have diabetes and nearly 50 to 80 million more are living with prediabetes (also called “metabolic syndrome”). Diabetes occurs when there are not enough beta cells in the pancreas, or when those beta cells secrete too little insulin, the hormone required to keep blood sugar levels in the normal range. Diabetes can lead to major medical complications: heart attack, stroke, kidney failure, blindness, and limb amputation.

Loss of insulin-producing beta cells has long been recognized as a cause of type 1 diabetes, in which the immune system mistakenly attacks and destroys beta cells. In recent years, researchers have concluded that a deficiency of functioning beta cells is also an important contributor to type 2 diabetes, the most common type that occurs in adults. Thus, developing drugs that can increase the number of healthy beta cells is a major priority in diabetes research.

This current paper builds upon a study that Dr. Stewart and his team published in Nature Medicine in 2015, showing that a drug called harmine drove sustained division and multiplication of adult human beta cells in culture. They also learned that harmine treatment led to normal control of blood sugar in mice whose beta cells had been replaced with human beta cells. While this was a major advance, the proliferation rate was lower than needed to rapidly expand beta cells in people with diabetes.

In 2017, Dr. Stewart and his team published a second paper, in Nature Communications, which revealed the genetic abnormalities in insulinomas, a benign type of human beta cell tumor, and served as a “genetic recipe” to reveal targets for new drugs that can make beta cells regenerate.

In this current paper, Dr. Stewart and his team took advantage of the insulinoma “genetic recipe” which suggested that a combination of two classes of drugs—a DYRK1A inhibitor such as harmine with a TGFßSF inhibitor drug—would be able to synergistically increase beta cell regeneration. This proved to be true. However, this new drug combination is not without its hurdles. “Since these drugs have effects on other organs in the body, we now need to develop methods to deliver these drugs specifically to the beta cell in humans,” said Dr. Stewart. “We have the packages to deliver, but now we need a courier system to deliver them to the exact beta cell address.”

“Beta cell regeneration is a ‘holy grail’ for the treatment of diabetes,” said Peng Wang, PhD, Associate Professor of Medicine (Endocrinology, Diabetes, and Blood Disease) at Mount Sinai and first author on the study. “We are excited to finally have drugs that can induce beta cell proliferation at rates that are likely to be effective in people with type 1 and type 2 diabetes.”

“This is one of the most exciting series of discoveries in the field of diabetes and is a key next step in drug development for this disease,” said Dennis S. Charney, MD, Anne and Joel Ehrenkranz Dean, Icahn School of Medicine at Mount Sinai. “In a very short time, Dr. Stewart and his team of researchers have made incredible progress. Their important work truly holds promise for so many people.”

“We know that in order to achieve a cure for type 1 diabetes and to bring people to insulin independence, we will have to find ways to increase the numbers of functional beta cells,” said Francis J. Martin, PhD, Associate Director of Research and leader of the JDRF Beta Cell Regeneration and Survival Program, who also contributed to the study. “Now, through the work of Drs. Stewart and Wang, we see that we can increase the rates of human beta cell reproduction to levels that were previously thought to be impossible. There are still challenges ahead, but this work brings us a little closer to therapies that can restore insulin production in people with the disease, and ultimately produce a cure.”

This work was supported by seed funding from the Icahn School of Medicine at Mount Sinai, by NIDDK grants R-01 DK 105015, R01 DK108905, UC4 DK104211, P-30 DK 020541, R-01 DK116873, by JDRF grant 2-SRA-2017 514-S-B, and by ADA grant 1-16-ICTS-029.

Also making key research contributions were Esra Karakose, PhD; Hongtao Liu; Ethan Swartz; Courtney Ackeifi; Viktor Zlatanic; Jessica Wilson; Bryan J. González, MPhil; Aaron Bender; Karen K. Takane, PhD; Lillian Ye; George Harb, PhD; Felicia Pagliuca, PhD; Dirk Homann, MD; Dieter Egli, PhD; Carmen Argmann, PhD; Donald K. Scott, PhD; and Adolfo Garcia-Ocaña, PhD, from the Diabetes, Obesity, and Metabolism Institute, the Department of Genetics and Genomic Sciences, the Icahn Institute for Genomics and Multiscale Biology, and the Icahn School of Medicine at Mount Sinai.

Additional investigators included researchers from The Naomi Berrie Diabetes Center at Columbia University and Semma Therapeutics in Cambridge, Massachusetts.

About the Mount Sinai Health System

The Mount Sinai Health System is New York City's largest integrated delivery system encompassing (with the addition of South Nassau Communities Hospital) eight hospital campuses, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai's vision is to produce the safest care, the highest quality, the highest satisfaction, the best access and the best value of any health system in the nation. The Health System includes approximately 7,480 primary and specialty care physicians; 11 joint-venture ambulatory surgery centers; more than 410 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. The Icahn School of Medicine is one of three medical schools that have earned distinction by multiple indicators: ranked in the top 20 by U.S. News & World Report's "Best Medical Schools", aligned with a U.S. News & World Report's "Honor Roll" Hospital, No. 12 in the nation for National Institutes of Health funding, and among the top 10 most innovative research institutions as ranked by the journal Nature in its Nature Innovation Index. This reflects a special level of excellence in education, clinical practice, and research. The Mount Sinai Hospital is ranked No. 18 on U.S. News & World Report's "Honor Roll" of top U.S. hospitals; it is one of the nation's top 20 hospitals in Cardiology/Heart Surgery, Gastroenterology/GI Surgery, Geriatrics, Nephrology, and Neurology/Neurosurgery, and in the top 50 in six other specialties in the 2018-2019 "Best Hospitals" issue. Mount Sinai's Kravis Children's Hospital also is ranked nationally in five out of ten pediatric specialties by U.S. News & World Report. The New York Eye and Ear Infirmary of Mount Sinai is ranked 11th nationally for Ophthalmology and 44th for Ear, Nose, and Throat. Mount Sinai Beth Israel, Mount Sinai St. Luke's, Mount Sinai West, and South Nassau Communities Hospital are ranked regionally.

For more information, visit http://www.mountsinai.org/, or find Mount Sinai on Facebook, Twitter and YouTube.

About JDRF

JDRF is the leading global organization funding type 1 diabetes (T1D) research. Our mission is to accelerate life-changing breakthroughs to cure, prevent and treat T1D and its complications. To accomplish this, JDRF has invested more than $2.2 billion in research funding since our inception. We are an organization built on a grassroots model of people connecting in their local communities, collaborating regionally for efficiency and broader fundraising impact, and uniting on a national stage to pool resources, passion, and energy. We collaborate with academic institutions, policymakers, and corporate and industry partners to develop and deliver a pipeline of innovative therapies to people living with T1D. Our staff and volunteers throughout the United States and our six international affiliates are dedicated to advocacy, community engagement and our vision of a world without T1D. For more information, please visit jdrf.org or follow us on Twitter: @JDRF

Read the full story at https://www.prweb.com/releases/mount_sinai_researchers_discover_new_drug_cocktail_that_increases_human_beta_cell_proliferation_at_rapid_rates/prweb15986631.htm.


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