Although the circuitry controlling insulin release consists of molecular pathways instead of wires, it does seem to act like a dimmer switch. When the switch fails, insulin secretion may still occur, but it will not be sufficiently amplified. That, at least, has been the speculation.

Insulin release is known to be triggered by increases in blood glucose that alter ion traffic into and out of pancreatic islet cells. But other factors may be at play. Candidate factors include certain molecular pathways. Now, according to scientists based at the University of Alberta, one particular pathway—the mitochondrial export of isocitrate and engagement with cytosolic isocitrate dehydrogenase (ICDc)—has been directly implicated in the control of insulin secretion.

This pathway not only manages the amount of insulin produced by pancreatic cells, it also appears to be lost in type 2 diabetes. Moreover, according to the University of Alberta scientists, the pathway can be restored, reinstating proper control of insulin secretion.

The scientists, led by Patrick MacDonald, Ph.D., examined pancreatic islet cells from 99 human organ donors. “Without access to this critical tissue through the Alberta Diabetes Institute IsletCore and the generosity of organ donors and their families, we would not have been able to carry out this study,” said Dr. MacDonald. “If we want to learn about diabetes, and how to treat and prevent it, studying the insulin-producing cells from donors with diabetes is a powerful way to do it.”

Having acquired donor material from the biobank, the scientists proceeded to identify the molecular “dimmer switch” and probe its workings. This work was described in a paper (“Isocitrate-to-SENP1 signaling amplifies insulin secretion and rescues dysfunctional β cells”) that appeared September 21 in the Journal of Clinical Investigation.

“ICDc-dependent generation of NADPH and subsequent glutathione (GSH) reduction contribute to the amplification of insulin exocytosis via sentrin/SUMO-specific protease-1 (SENP1),” wrote the authors. “In human T2D and an in vitro model of human islet dysfunction, the glucose-dependent amplification of exocytosis was impaired and could be rescued by introduction of signaling intermediates from this pathway.”

Next, the scientists extended their study from cell cultures to transgenic animals, experimented with islet-specific Senp1 deletion in mice. This deletion, the scientists found, caused impaired glucose tolerance by reducing the amplification of insulin exocytosis.

Together, the cell culture and animal model studies made it possible for the scientists to identify a pathway linking glucose metabolism to the amplification of insulin secretion. In addition, the scientists demonstrated that restoration of the pathway rescues β cell function in type 2 diabetes.

Although the ability to restore and fix the dimmer switch in islet cells has been shown only in cell cultures and transgenic animals, the molecular-level possibilities invite further investigation. The current study’s findings could, eventually, lead to translational work that would explore dimmer repair as a clinical strategy. According to Dr. MacDonald, “Understanding the islet cells in the pancreas that make insulin, how they work—and how they can fail—could lead to new ways to treat the disease, delaying or even preventing diabetes.”

In their paper, the scientists considered various diabetes scenarios that could result in a faulty dimmer switch: reduced mitochondrial function, leading to lowered isocitrate export and cytosolic NADPH production; oxidative stress and redirection of NADPH, GSH, and GRX1 into a protective function; or direct oxidative inactivation of SENP1. “That dysfunction in β cells from donors with T2D can be circumvented by reintroduction of isocitrate-to-SENP1 pathway intermediates,” the authors noted, “suggests that the exocytotic mechanism remains intact and could be harnessed for alternative therapeutic approaches to increase insulin secretion in T2D.”

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