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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 newwork was published in

Cell

Metabolism

on April 12, 2016.

The Salk technology begins with

induced pluripotent stem cells (iPSCs),

a technique where tissue from a patient

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

3

INSIDE SALK

SUMMER 2016

WWW.SALK.EDU

METABOLISM

FINDING THE “SECRET SAUCE”

for personalized, functional insulin-producing cells

Researchers uncovermolecular

switch tomake effective sugar-

responsive, insulin-releasing

cells in a dish, offering hope

for diabetes therapy.

to glucose and produce insulin,” says

Evans. “No one had been able to figure

out how to make pancreatic cells from

human patients that can do both until

now.”

Eiji Yoshihara, first author and Salk

research associate, together with Evans

and Salk colleagues, 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 awakening silent beta-like

cells that could now respond to glucose

and release insulin accordingly. The

team found that when the matured

beta cells were transplanted into type

1 diabetic mice, the procedure quickly

rescued their diabetes.

“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. 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. The

researchers hope to move to human

trials within the next few years.

www.salk.edu/news

To learn more about these discoveries, visit