Salk scientists found a master genetic switch (ERR?) critical for prompting pancreatic cells to detect and respond successfully 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. [Salk Institute]
Salk scientists found a master genetic switch (ERR?) critical for prompting pancreatic cells to detect and respond successfully 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. [Salk Institute]

Would-be replacements for pancreatic β cells that have been grown in the laboratory tend to stumble through insulin production. But now they may move beyond baby steps and finally go the replacement-tissue distance, report Salk Institute scientists. These scientists, led by Ronald Evans, Ph.D., an expert in cell regulation, say that they have found a protein that activates the maturation process, inducing dish-dwelling, insulin-producing cells to respond to glucose.

The Salk team began with induced pluripotent cells (iPSCs) that were reprogrammed to become pancreatic β cells. Actually, like many other research groups, the Salk team initially produced pre-β cells, which produce insulin but are not yet fully functional.

The Salk scientists persisted, closely studying the basic biology of the β cell. They uncovered several molecular switches—transcription factors—that were switched off but might control the transition to a fully functional state. One switch in particular drew the scientists’ attention. This switch, called estrogen-related receptor γ (ERRγ), was one that the Evans lab had studied for years for its role in cell signaling. This protein switch, it turned out, is capable of activating silent β-like cells, causing them to respond to glucose and release insulin accordingly.

The details of this work appeared April 12 in the journal Cell Metabolism, in an article entitled, “ERRγ Is Required for the Metabolic Maturation of Therapeutically Functional Glucose-Responsive β Cells.” This article described how postnatal induction of ERRγ “drives a transcriptional network activating mitochondrial oxidative phosphorylation, the electron transport chain, and ATP production needed to drive glucose-responsive insulin secretion.”

“Mice deficient in β cell-specific ERRγ expression are glucose intolerant and fail to secrete insulin in response to a glucose challenge,” the article continued. “Notably, forced expression of ERRγ in iPSC-derived β-like cells enables glucose-responsive secretion of human insulin in vitro, obviating in vivo maturation to achieve functionality. Moreover, these cells rapidly rescue diabetes when transplanted into β cell-deficient mice.”

“In muscle, ERRγ induces greater mitochondrial growth and promotes oxidative use of sugars and lipids to generate energy,” explained Dr. Evans. “It was a little bit of a surprise to see that β cells produce a high level of this regulator, but β cells have to release massive amounts of insulin quickly to control sugar levels. It's a very energy-intensive process.”

Dr. Evans suggested that under constant lab conditions, grown β cells simply become stuck in the fetal stage. When a fetus is developing, it receives steady levels of glucose from the mother and doesn't have to produce insulin to control its blood sugar.

“We think this molecular ERRγ switch is a critical event to achieving the adult functionality,” emphasized Dr. Evans, adding that the switch is likely flipped normally when an infant takes its first breath, which oxygenates the blood and helps trigger oxidative metabolism.

“This advance will result in a better controlled insulin response than currently available treatments,” predicted Michael Downes, Ph.D., a co-senior author and a Salk senior staff scientist. “Previously there was nothing known about the maturation process in β cells. We peeked into that black box and now we know what's going on.”

“I believe this work transitions us to a new era in creating functional β cells at will,” concluded Dr. Evans. The researchers, who are planning to explore this process in more complicated models for treating diabetes, hope to move to human trials within the next few years.

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