UCSF diabetes researchers unfold method for saving stressed-out insulin-producing cells
New evidence may speed up treatment for type 1, type 2 diabetes
BY KATHLEEN JAY
SAN FRANCISCO (July 10, 2014) --Today, two UCSF Diabetes Center researchers, Scott Oakes, M.D. and Feroz Papa, M.D., Ph.D., co-published a ground-breaking study on insulin-producing beta cells -- and methods on saving stressed out ones – in a paper released today in the journal Cell.
The team’s paper -- entitled “Allosteric inhibition of the IRE1a RNase preserves cell viability and function during endoplasmic reticulum stress” – points at promising, new evidence that may speed up treatment for those with type 1 and type 2 diabetes.
Understanding stressed out beta cells
“Each pancreatic beta cell is an insulin factory -- capable of releasing as much as one million molecules of insulin per minute in response to high blood glucose,” Oakes said. “However, secreting such high amounts of insulin can overwork the protein folding machinery in the cell and trigger a life/death switch called IRE1 to activate a suicide program. There is growing evidence that IRE1 contributes to beta cell loss in both type 1 and type 2 diabetes.”
To study this trigger, the Oakes-Papa teams, in collaboration with those of Dustin J. Maly, PhD. at the University of Washington, Seattle, and Bradley J. Backes, PhD., at UCSF, designed a first-in-class drug called KIRA6, which turns IRE1 off and allows stressed cells to continue to live and function for a much longer time.
“We found that when murine and human islets are treated with KIRA6 in a dish, they continue to secrete insulin properly even when challenged with conditions that stress their ability to fold proteins,” Papa said. “Moreover, when put into the blood, KIRA6 protected mice against a very aggressive form of diabetes called Akita that results from a mutation in insulin that causes the protein to misfold and kill the beta cell.”
“This intracellular suicide pathway is responsible for the cell loss that causes some of the most devastating diseases of our era, such as diabetes, Alzheimer’s disease, Parkinson’s disease and retinal degeneration, which can eventually lead to blindness,” Oakes said. “We are focused on understanding how it kills cells and figuring out how to defeat it with drugs.”
“The idea that beta cell stress is common to both types 1 and 2 diabetes is gaining traction,” Papa added. “If the treatments work in one diabetes context, they are likely to work in others.”
Two researchers, four years, seven labs, and 100 experiments
The team’s paper was a collaboration between senior authors Oakes and Papa, as well as researchers from seven labs across four U.S. cities.
“This was a gigantic project that took more than four years – and over 100 separate experiments, not counting replicates,” Oakes said.
The project -- funded by multiple grants to Oakes and Papa by the National Institutes of Health, Harrington Discovery Institute, Juvenile Diabetes Research Foundation, Burroughs Wellcome Fund, American Cancer Society and the Howard Hughes Medical Institute – included a research team of scientists from UCSF, the University of Washington, Seattle, the University of Miami, and Albert Einstein College of Medicine.
“We are thrilled with their findings and the paper,” Mathias Hebrok, Ph.D., Director of the UCSF Diabetes Center, said. “Their collaborative efforts raise great promise in our mission to find a cure for diabetes.”
For more information, visit diabetes.ucsf.edu.
Allosteric inhibition of the IRE1a RNase preserves cell viability and function during endoplasmic reticulum stress
Rajarshi Ghosh1,2,5,6,7,12, Likun Wang1,5,6,7,12, Eric S. Wang2,12, B. Gayani K. Perera8, Aeid Igbaria1,5,6,7, Shuhei Morita1,5,6,7, Kris Prado1,5,6,7, Maike Thamsen1,5,6,7, Deborah Caswell2, Hector Macias1,5, Kurt F. Weiberth1,5,6,7, Micah J. Gliedt1,6, Marcel V. Alavi3, Sanjay B. Hari8, Arinjay K. Mitra8, Barun Bhhatarai10, Stephan C. Schürer9,10, Erik L. Snapp11, Douglas B. Gould3,4, Michael S. German1,5, Bradley J. Backes1,6, Dustin J. Maly8,
Scott A. Oakes2.5*, Feroz R. Papa1,5,6,7*
Department of Medicine1, Department of Pathology2, Department of Ophthalmology3, Department of Anatomy4, Diabetes Center5, Lung Biology Center6, California Institute for Quantitative Biosciences7, University of California, San Francisco. San Francisco, CA 94143. U.S.A.
Department of Chemistry8, University of Washington, Seattle. Seattle, WA 98195. U.S.A.
Center for Computational Science9, Department of Molecular and Cellular Pharmacology10, Miller School of Medicine, University of Miami, FL 33136, U.S.A.
Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, Bronx, NY 10461, U.S.A. Equal contribution12 Correspondence*
[email protected] (Tel: 415-476-1777/ FAX: 415-514-3165)
[email protected] (Tel: 415-476-2117/ FAX: 415-514-9656)