In people with type 1 diabetes, the immune system kills off insulin-producing beta cells of the pancreas needed to control the amount of glucose in their bloodstream. As a result, they must monitor their blood glucose often and take replacement doses of insulin to keep it under control. Transplantation of donated pancreatic islets—tissue that contains beta cells—holds some promise as a therapy or even a cure for type 1 diabetes. However, such donor islets are in notoriously short supply . Recent advances in stem cell research have raised hopes of one day generating an essentially unlimited supply of replacement beta cells perfectly matched to the patient to avoid transplant rejection.
A couple of years ago, researchers took a major step toward this goal by coaxing induced pluripotent stem cells (iPSCs), which are made from mature human cells, to differentiate into cells that closely resembled beta cells. But a few things were troublesome. The process was long and difficult, and the iPSC-derived cells were not quite as good at sensing glucose and secreting insulin as cells in a healthy person. They also looked and, in some ways, acted like beta cells, but were unable to mature fully in the lab. Now, an NIH-funded team has succeeded in finding an additional switch that enables iPSC-derived beta cells to mature and produce insulin in a dish—a significant step toward moving this work closer to the clinical applications that many diabetics have wanted.
In healthy people, beta cells mature and develop their full capabilities soon after birth, usually as infants begin to take in nutrients. In the new study, reported recently in the journal Cell Metabolism, Michael Downes and Ronald Evans of the Salk Institute for Biological Studies, La Jolla, CA, and their colleagues wanted to know how gene expression changes in beta cells as they become fully functional . To find out, they compared gene expression in cells isolated at different points in development. Their search led them to a protein receptor inside cells known as ERR-gamma. They discovered that ERR-gamma, which binds DNA to influence the expression of other genes, is present at much higher levels in adult compared to fetal beta cells.
As luck would have it, Downes and Evans had studied the ERR-gamma receptor before in a very different context. ERR-gamma is found at naturally high levels in the muscles of endurance runners . In fact, mice with muscles expressing high levels of ERR-gamma can run much farther than an average mouse. The receptor appears to function as a metabolic switch, endowing cells with the extra energy needed to keep on going, in this case, to the finish line.
Downes and Evans now show that ERR-gamma also gives beta cells the energy and endurance needed to respond continuously to glucose by producing insulin. As evidence for the importance of ERR-gamma, the researchers found that mice whose beta cells lacked this protein receptor were unable to respond properly to a spike in glucose. When they forced stem-cell-derived beta cells to produce ERR-gamma, the cells began responding to glucose like fully mature cells, without first having to mature in a living animal.
The researchers compare what happens in beta cells lacking ERR-gamma to a power outage. All of the wires, switches, and other elements may be ready to go. But the cell doesn’t have the energy required to activate them. With ERR-gamma in place, the power switches on, and the cell can begin its work to produce insulin.
To further test the lab-grown beta cells, the researchers inserted them into mice with type 1 diabetes. Those fully mature, transplanted cells soon began producing insulin to rescue the animals from their diabetes.
The new discovery now makes it more feasible to create fully functional beta cells, without relying on other mysterious maturation processes to occur after transplantation. Before clinical trials in humans can begin, however, the lab-grown beta cells must first be tested in animals. In the meantime, there are still plenty of questions yet to be resolved, including how, when, and where beta cells should be delivered. It will also be important to learn how long the replacement beta cells will function after transplantation.
The good news is that this new work shows continued progress toward one of stem cell therapy’s many promising applications: to improve the lives of the many thousands of Americans living with type 1 diabetes.
 Pancreatic Islet Transplantation. September 2013. National Institute of Diabetes and Digestive and Kidney Diseases.
 ERRγ is required for the metabolic maturation of therapeutically functional glucose-responsive β cells. Yoshihara E, Wei Z, Lin CS, Fang S, Ahmadian M, Kida Y, Tseng T, Dai Y, Yu RT, Liddle C, Atkins AR, Downes M, Evans RM. Cell Metab. 2016 Apr 12; 23(4):622-634.
 Exercise and PGC-1α-independent synchronization of type I muscle metabolism and vasculature by ERRγ. Narkar VA, Fan W, Downes M, Yu RT, Jonker JW, Alaynick WA, Banayo E, Karunasiri MS, Lorca S, Evans RM. Cell Metab. 2011 Mar 2;13(3):283-293.
Stem Cell Information (NIH)
Your Guide to Diabetes: Type 1 and Type 2 (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)
Video News Release: Salk Scientists Find “Secret Sauce” for Personalized, Functional Insulin-Producing Cells (The Salk Institute for Biological Studies, La Jolla, CA)
Evans Laboratory (The Salk Institute)
NIH support: National Institute of Diabetes and Digestive and Kidney Diseases; National Heart, Lung, and Blood Institute; National Institute of Environmental Health Sciences