New protein discovered to be a target for diabetes treatment

At a fundamental level, diabetes is a disease caused by stress. Microscopic stress, which causes inflammation and blocks the pancreas from producing insulin, and systemic stress, due to the loss of the hormone that regulates blood sugar. Scientists at the University of California, San Francisco (UCSF) have discovered a molecule that plays a key role in amplifying stress in the earliest stages of diabetes: TXNIP (thioredoxin-interacting protein). This molecule stimulates inflammation, leading to the death of insulin-producing cells in the pancreas.

The results of the study were published in the journal Cell Metabolism, in parallel with the work of scientists from Washington University in St. Louis.

The study could be seen as a roadmap for developing new drugs that work by blocking the effects of TXNIP and thereby preventing or halting the inflammation it promotes. Scientists working in the field believe that this strategy could benefit patients early in the disease, when diabetes is just beginning to develop or is about to develop (a period known as the “honeymoon period”).

Numerous clinical studies have shown that dietary changes and other approaches can delay the onset of diabetes in some people and even prevent it in others. The main goal of this study is to find a way to extend the honeymoon period indefinitely, says study leader Feroz Papa, MD, PhD, an associate professor of medicine at UCSF and a research scientist at the UCSF Diabetes Center and the California Institute for Quantitative Biosciences.

Diabetes is caused by a malfunction of specialized cells in the pancreas called beta cells, which produce the hormone insulin, which regulates blood sugar levels. A single beta cell can synthesize a million insulin molecules per minute. This means that about a billion beta cells in a healthy pancreas create more insulin molecules per year than there are grains of sand on any beach or in any desert in the world. If the beta cells die, the pancreas is unable to produce enough insulin, and the body cannot maintain proper blood sugar levels. This is exactly what happens in diabetes.

Research conducted in recent years has led Dr. Papa and his colleagues to conclude that endoplasmic reticulum (ER) stress underlies beta cell destruction and diabetes.

The endoplasmic reticulum is present in every cell, and its membrane-covered structures are easily visible under a microscope. In all cells, the ER plays a vital role, helping to process and fold the proteins they synthesize. But for beta cells, this structure is of particular importance due to their specialized function: secreting insulin.

Accumulation of unfolded proteins in the endoplasmic reticulum (ER) to irreparably high levels causes hyperactivation of intracellular signaling pathways called the unfolded protein response (UPR), the purpose of which is to switch on the apoptotic program. Scientists have found that the protein TXNIP is an important node in this “terminal unfolded protein response”. The protein TXNIP is rapidly induced by IRE1α, a bifunctional kinase/endoplasmic reticulum endoribonuclease (RNase). Hyperactive IRE1α increases the stability of TXNIP messenger RNAs by reducing the levels of the TXNIP-destabilizing microRNA miR-17. In turn, elevated TXNIP protein levels activate the NLRP3 inflammasome, causing procaspase-1 cleavage and interleukin 1β (IL-1β) secretion. In Akita mice, txnip gene deletion reduces pancreatic β-cell death during ER stress and suppresses proinsulin misfolding-induced diabetes. Finally, small molecule RNase inhibitors IRE1α suppress TXNIP synthesis, blocking IL-1β secretion. Thus, the IRE1α-TXNIP pathway is used in the terminal response to unfolded proteins to stimulate aseptic inflammation and programmed cell death and may be a target for the development of effective drugs for the treatment of cellular degenerative diseases.

If you think of the beta cell as a miniature factory, the ER could be thought of as a shipping warehouse – a place where the final product is beautifully packaged, labeled, and shipped to its destination.

The endoplasmic reticulum of healthy cells is like a well-organized warehouse: goods are processed, packaged, and shipped quickly. But the ER under stress resembles a ruin with unpackaged goods lying around. The longer this goes on, the more everything falls into disrepair, and the body solves the problem radically: it practically burns down the factory and closes the warehouse.

In scientific terms, the cell initiates what is known as the “unfolded protein response” in the ER. This process activates inflammation mediated by the protein interleukin-1 (IL-1), and ultimately switches on a program of apoptosis – programmed cell death.

On a body-wide scale, this loss isn't that bad: With about a billion beta cells in the pancreas, most people can afford the luxury of losing a small number. The problem is that too many people burn through too much storage.

"The pancreas doesn't have that much reserve - if these cells start to die, the remaining ones have to work 'for two,'" explains Dr. Papa. At some point, the balance is upset and diabetes develops.

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

In their work, Dr. Papa and his colleagues highlight the role of a hitherto underappreciated key player in this process, the protein TXNIP, as a new drug target: TXNIP is involved in the initiation of destructive ER stress, the response to unfolded proteins, inflammation, and cell death.

The scientists 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 the cells from death. Indeed, when TXNIP-deficient mice are crossed with animals prone to developing diabetes, the offspring are completely protected from the disease, since their insulin-producing beta cells are given the opportunity to survive.

Dr. Papa believes that inhibiting TXNIP in people could protect their beta cells, possibly delaying the onset of diabetes – an idea that now needs to be developed further and eventually tested in clinical trials.

[ 1 ], [ 2 ], [ 3 ], [ 4 ], [ 5 ], [ 6 ], [ 7 ], [ 8 ], [ 9 ]