April 12, 2016

Salk scientists find “secret sauce” for personalized, functional insulin-producing cells

Researchers uncover molecular switch to make effective sugar-responsive, insulin-releasing cells in a dish, offering hope for diabetes therapy

Salk News

Salk scientists find “secret sauce” for personalized, functional insulin-producing cells

Researchers uncover molecular switch to make effective sugar-responsive, insulin-releasing cells in a dish, offering hope for diabetes therapy

LA JOLLA—Salk scientists have solved a longstanding problem in the effort to create replacement cells for diabetic patients. The team uncovered a hidden energy switch that, when flipped, powers up pancreatic cells to respond to glucose, a step that eluded previous research. The result is the production of hundreds of millions of lab-produced human beta cells—able to relieve diabetes in mice.

For more than a decade, scientists across the globe strived to replace failing pancreatic beta cells linked to immune destruction in children (type 1 diabetes) or obesity-associated diabetes in adults (type 2 diabetes). Although cells made in a dish were able to produce insulin, they were sluggish or simply unable to respond to glucose.

“We found the missing energy switch needed to produce robust and functional human beta cells, potentially turning this discovery into a viable treatment for human diabetes,” says Ronald Evans, co-senior author and director of the Gene Expression Laboratory at Salk. The new work was published in Cell Metabolism on April 12, 2016.

ibeta in Kidney Ins-Green, Gcg-Red, Nucleus-Blue x20
Salk scientists have successfully created pancreatic beta cells that could be transplanted into patients for a potential new diabetes therapy. The ability of these cells to secrete insulin in response to high glucose levels may provide better regulation of blood sugar levels ( insulin, green; glucagon, red;  nuclei, blue).

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Credit: Salk Institute

The Salk technology begins with induced pluripotent cells (iPSC), a stem cell technique where tissue from a patient—such as skin—is reprogrammed into other types of cells, such as from the pancreas. This step yields the pre-beta cells, which produce insulin but are not yet functional. While several research groups reached this juncture, the road forward to functional cells was not clear.

“Pancreatic beta cells must be able to do two things to work effectively: respond to glucose and produce insulin,” says Evans, who is also a Howard Hughes Medical Institute investigator and the March of Dimes Chair in Molecular and Developmental Biology. “No one had been able to figure out how to make pancreatic cells from human patients that can do both until now.”

Salk scientists found a master genetic switch (ERR-gamma) critical for prompting pancreatic cells to successfully detect and respond to sugar in the blood. This discovery allows the team to grow patient-derived, functional beta cells for transplantation in a potential new diabetes therapy.

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Credit: Salk Institute

The Salk team closely studied the basic biology of a beta cell and uncovered several molecular switches, called transcription factors, that were switched off but might control the transition to a fully functional state. The ‘secret sauce,’ the Salk team found, was one particular switch the Evans lab had studied for years for its role in cell signaling. This protein switch, called ERR-gamma, turned out to be crucial to awaken silent beta-like cells that could now respond to glucose and release insulin accordingly.

“This advance will result in a better controlled insulin response than currently available treatments,” says Michael Downes, co-senior author and a Salk senior staff scientist. “Previously there was nothing known about the maturation process in beta cells. We peeked into that black box and now we know what’s going on.” He adds that the team’s technique is an easy, fast and inexpensive way to make transplantable human pancreatic beta cells in a dish that genetically match patients.

Ron Evans - Michael Downes - Eiji Yoshihara IMG_0475e
From Left: Michael Downes, Ron Evans and Eiji Yoshihara

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Credit: Salk Institute

“When we added ERR-gamma to pre-diabetic beta cells in a dish, we successfully created a glucose-responsive, beta-like cell,” says Eiji Yoshihara, first author of the paper and a Salk research associate. “And when we remove ERR-gamma from animals, the glucose response is eliminated, proving that the factor is the master regulator of maturation for the beta cell.”

But can these beta cells successfully treat diabetes? The Salk researchers found that, indeed, when the matured beta cells were transplanted into type 1 diabetic mice, the procedure quickly rescued their diabetes. “Hopefully, this mirrors what would happen in the clinic—after someone is diagnosed with diabetes they could potentially get this treatment,” says Evans. “It’s exciting because it suggests that cells in a dish are ready to go.”

The researchers hope to move to human trials within the next few years.

Other authors on the paper were Zong Wei, Chun Shi Lin, Sungsoon Fang, Maryam Ahmadian, Yasuyuki Kida, Tiffany Tseng, Yang Dai, Ruth T. Yu and Annette R. Atkins of the Salk Institute; and Christopher Liddle of the University of Sydney.

The work was supported by the National Institutes of Health, the Glenn Foundation for Medical Research, the Leona M. and Harry B. Helmsley Charitable Trust, Ipsen/Biomeasure, California Institute for Regenerative Medicine (CIRM), The Ellison Medical Foundation, and by gifts from Steven Kirsch and Steven and Lisa Altman.

Frequently Asked Questions

What is a pancreatic beta cell?
These are cells created by the pancreas to detect blood sugar levels and produce insulin, a hormone that helps sugar from the blood move into cells. When pancreatic beta cells are missing or not functioning correctly, diabetes results.

How is this discovery different than other developments?
Salk scientists in the laboratory of Ronald Evans discovered a single gene that overcomes a crucial hurdle in developing personalized and functional beta cells for diabetes patient. This discovery is the first to use patient-derived tissue to grow fully functional and mature beta cells in a dish.

When will this therapy be available for humans?
Salk researchers have completed mouse studies and are now seeking industry partners and funding to test for safety and efficacy before moving to clinical trials. For more information, please contact: communications@salk.edu.

To see what related clinical trials are in your area, please visit: www.clinicaltrials.gov.



Cell Metabolism


ERRγ is required for the metabolic maturation of therapeutically functional glucose responsive β cells


Eiji Yoshihara, Zong Wei, Chun Shi Lin, Sungsoon Fang, Maryam Ahmadian, Yasuyuki Kida, Tiffany Tseng, Yang Dai, Ruth T. Yu, Christopher Liddle, Annette R. Atkins, Michael Downes, and Ronald M. Evans

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Unlocking the secrets of life itself is the driving force behind the Salk Institute. Our team of world-class, award-winning scientists pushes the boundaries of knowledge in areas such as neuroscience, cancer research, aging, immunobiology, plant biology, computational biology and more. Founded by Jonas Salk, developer of the first safe and effective polio vaccine, the Institute is an independent, nonprofit research organization and architectural landmark: small by choice, intimate by nature, and fearless in the face of any challenge.