A new protein is discovered, which will become the target for the treatment of diabetes

At a fundamental level, diabetes is a disease caused by stress. Microscopic stress, causing inflammation and blocking the production of insulin pancreas, and systemic stress due to the loss of a hormone that regulates blood sugar. Scientists at the University of California in San Francisco (UCSF) discovered a molecule that plays a key role in increasing stress in the earliest stages of diabetes, the protein TXNIP (thioredoxin-interacting protein). This molecule stimulates the development of an inflammatory process leading to the death of pancreatic cells that produce insulin.

The results of the study are published in the journal Cell Metabolism in parallel with the work of scientists at the University of Washington in St. Louis (Washington University in St. Louis).

This study can be called a roadmap for the development of new drugs, the mechanism of action of which will be the blocking of TXNIP effects and the prevention or suspension, thus, of the development of the protein-enhanced inflammatory process. Scientists working in this area believe that this strategy can benefit patients at the earliest stage of the disease, when diabetes is only beginning to develop or should develop in the near future (this period is called a "honeymoon").

Numerous clinical studies have shown that changes in diet and other approaches can delay the onset of diabetes in some people and even prevent its development in others. The main purpose of this study is to find a way to extend the "honeymoon" indefinitely, explains its leader Feroz Papa, MD, PhD, associate professor of medicine at UCSF and a researcher at the UCSF Diabetes Center and the California Institute of Quantitative biosciences (California Institute for Quantitative Biosciences).

The basis of diabetes is a disruption of the function of specialized cells of the pancreas - beta cells, hormone producing insulin, regulating blood sugar. One beta cell can synthesize one million insulin molecules per minute. This means that about a billion beta cells of a healthy pancreas create more insulin molecules per year than grains of sand on any beach and in any desert in the world. If the beta cells die, the pancreas can not produce enough insulin, and the body can not maintain proper blood sugar levels. This is exactly what happens with diabetes.

Studies conducted in recent years have allowed Dr. Pope and his colleagues to conclude that the stress of the endoplasmic reticulum (ER) is at the root of the destruction of beta cells and diabetes.

The endoplasmic reticulum is present in any cell, and its membrane-covered structures are clearly visible under a microscope. In all cells, ER plays an important role, helping to process and coagulate proteins synthesized by them. But for the beta-cells this structure is of particular importance due to their specialized function - the secretion of insulin.

Accumulation in the endoplasmic reticulum (ER) to irreparably high levels of inverted proteins causes the inactivation of intracellular signaling pathways called the unfolded protein response (UPR), the goal of which is the inclusion of an apoptosis program. Scientists have determined that the TXNIP protein is an important node in this "terminal reaction to non-folded proteins." The TXNIP protein is rapidly induced by IRE1α, a bifunctional kinase / endoribonuclease (RNase) of the endoplasmic reticulum. The hyperactive protein IRE1α enhances the stability of TXNIP matrix RNAs by reducing the level of miR-17 miRNA miRNA destabilizing TXNIP. In turn, an elevated level of the TXNIP protein activates the inflamasome NLRP3, causing the cleavage of procaspase-1 and the secretion of interleukin 1β (IL-1β). In Akita mice, the removal of the txnip gene reduces pancreatic β-cell death in stress ER and suppresses diabetes caused by inappropriate coagulation of proinsulin . Finally, inhibitors of the small RNase IRE1α molecule inhibit the synthesis of TXNIP by blocking the secretion of IL-1β. Thus, the IRE1α-TXNIP pathway is used in terminal response to non-folded proteins to stimulate aseptic inflammation and programmed cell death and may be the target for developing effective drugs for the treatment of cellular degenerative diseases.

If you accept a beta-cell for a miniature factory, ER can be called a shipping warehouse - the place where the final product is beautifully packaged, supplied with address labels and sent to the destination.

The endoplasmic reticulum of healthy cells is similar to a well-organized warehouse: goods are processed quickly, packaged and sent. And ER in a state of stress resembles ruins with loose unpackaged cargo everywhere. The longer this continues, the more everything falls into decay, and the body solves this problem radically: it burns the factory to the ground almost and closes the warehouse.

In scientific terms, the cell initiates what is known as a "reaction to unfolded proteins" in ER. This process activates inflammation, mediated by interleukin-1 protein (IL-1), and eventually includes an apoptosis program-programmed cell death.

On a body-wide scale, such a loss is not so terrible: having about a billion beta cells in the pancreas, most people can afford the luxury of losing a small amount of them. The problem is that a very large number of people burn too many "warehouses".

"The pancreas does not have such a large reserve - if these cells begin to die, the remaining ones have to work" for two, "explains Dr. Papa. At a certain point of fracture, the balance is broken and diabetes develops.

Recognizing the importance of the inflammatory process in the development of diabetes, several pharmaceutical companies are already conducting clinical trials of new drugs, the target of which is the protein interleukin-1.

In his work, Dr. Papa and his colleagues emphasize the role of the currently underappreciated key participant in this process - the TXNIP protein - as a new drug target: TXNIP is involved in initiating the destructive stress of ER, the reaction to inverted proteins, inflammation and cell death.

The researchers found that at the beginning of this process, the IRE1 protein induces TXNIP, which directly leads to the synthesis of IL-1 and inflammation. Removing TXNIP from the equation protects cells from death. Indeed, when mice without TXNIP are crossed with animals prone to developing diabetes, the offspring are completely immune from this disease, since their insulin-producing beta-cells are able to survive.

According to Dr. Papa, the inhibition of TXNIP in humans can protect their beta cells, possibly by delaying the onset of diabetes - an idea that now needs to be developed and, ultimately, tested in clinical trials.

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