In a recent study, a group of researchers has unveiled a new approach that revitalizes human insulin-producing beta cells, offering a potential breakthrough for diabetes treatment.
Researchers from Mount Sinai Health System in New York City and City of Hope in Los Angeles have revealed fresh insights into a therapeutic combination that rejuvenates human insulin-producing beta cells, opening up possibilities for a new diabetes treatment. Their findings were published in Science Translational Medicine.
Driven by Andrew F. Stewart, MD, Irene and Dr. Arthur M. Fishberg Professor of Medicine and Director of the Mount Sinai Diabetes, Obesity and Metabolism Institute, the research commenced at the Icahn School of Medicine at Mount Sinai in 2015. The collaboration across institutions involved Adolfo Garcia-Ocaña, PhD, previously from Mount Sinai and now at City of Hope, a renowned diabetes and cancer research institute in the U.S. The team’s innovative approach, utilizing beta cells from donors, culminated in the promising results presented in a study conducted at City of Hope in 2023.
The investigation paired harmine, a natural compound found in certain plants, with a commonly used type 2 diabetes medication known as GLP-1 receptor agonists. The team transplanted a small quantity of human beta cells into mice devoid of an immune system, a standard diabetes model for type 1 and type 2, and administered the combination therapy. The mice displayed rapid reversal of diabetes, with human beta cell numbers surging by 700% over three months with this medication duo.
“This marks the first instance where a drug regimen has successfully augmented adult human beta cell quantities in vivo. This research kindles hope for future regenerative therapies to potentially address the vast population affected by diabetes,” stated Dr. Garcia-Ocaña, the lead author of the study.
“The narrative that has unfolded over the past 15 years has been truly remarkable,” noted Dr. Stewart, who, together with Peng Wang, PhD, Professor of Medicine (Endocrinology, Diabetes and Bone Disease) at Icahn Mount Sinai, initiated the initial drug screening which led to the discovery of harmine as reported in Nature Medicine in 2015. “The progression from fundamental human beta cell biology to drug screening and now advancing to human studies underscores the pivotal role of clinician-scientists in academia and pharmaceuticals.”
Fostering New Beta Cells
With over 10% of the global adult populace grappling with diabetes, characterized by elevated blood sugar levels, the dwindling population and efficacy of insulin-producing beta cells drive the ailment. Regrettably, existing diabetes treatments fail to bolster human beta cell counts, thereby falling short of completely reversing diabetes.
Encouragingly, most diabetic individuals retain residual beta cells, prompting the research team to explore means to replenish their numbers. Previous studies had indicated that inhibiting an enzyme in beta cells called DYRK1A could prompt the proliferation of adult human beta cells in vitro briefly. However, this study stands as the first to demonstrate the expansion of human beta cell numbers in vivo within human islet grafts implemented in an animal model across several months.
To accurately gauge human beta cell mass within the islet grafts, the team turned to Sarah A. Stanley, MBBCh, PhD, Associate Professor of Medicine (Endocrinology, Diabetes and Bone Disease) and Neuroscience at Icahn Mount Sinai. Leveraging an advanced laser microscopy tool known as iDISCO+, capable of rendering biological tissue transparent, Dr. Stanley observed a significant augmentation in beta cell mass through mechanisms enhancing proliferation, function, and survival of human beta cells. This technology enabled a precise and thorough quantitative appraisal of engrafted human beta cells for the first time.
Translating Findings into Clinical Practice
The Mount Sinai team concluded a phase 1 clinical trial of harmine in healthy volunteers to evaluate its safety and tolerability. Concurrently, Robert J. DeVita, PhD, Professor of Pharmacological Sciences and Director of the Marie-Josée and Henry R. Kravis Drug Discovery Institute at Mount Sinai, engineered next-generation DYRK1A inhibitors. Mount Sinai is conducting assessments to assess potential toxicity and determine dosing for future clinical trials while also preparing for the onset of initial human trials with independent research groups next year. Mount Sinai possesses an extensive patent collection encompassing these technologies.
Further endeavors aim to address the predicament in type 1 diabetes patients, where the immune system persists in eliminating fresh beta cells. At City of Hope, Dr. Garcia-Ocaña and colleague Alberto Pugliese, MD, Samuel Rahbar Chair in Diabetes & Drug Discovery, are strategizing testing inducers of beta cell regeneration alongside immunomodulators to regulate the immune system. Their objective is for this combined approach to cultivate new beta cells and enhance insulin levels.
“Our studies set the stage for moving DYRK1A inhibitors into human trials, and the prospect of witnessing this innovative treatment benefiting patients is truly exhilarating,” expressed Dr. Garcia-Ocaña. “This is an unprecedented treatment not currently available to patients.”
The research spotlighted in the Science Translational Medicine publication received funding from the National Institutes of Health (NIH), the National Institute of Diabetes Digestive and Kidney Disease, BreakthroughT1D (formerly JDRF), alongside Mount Sinai’s philanthropic contributions, support from The Wanek Family Project for Type 1 Diabetes at City of Hope, and additional generous philanthropic donations.
Other essential team members from Mount Sinai include Carolina Rosselot, PhD; Yansui Li, PhD; and Alexandra Alvarsson, PhD. Notable City of Hope contributors to the study are Geming Lu, MD, and Randy Kang, BS, both part of Dr. Garcia-Ocaña’s research team.
Drs. Stewart and DeVita hold co-inventor status on patent applications for DYRK1A inhibitors, including harmine, for diabetes treatment. These patent applications are under the auspices of the Icahn School of Medicine at Mount Sinai and are presently unlicensed.
