At its most fundamental level, diabetes is a disease characterized by stress—microscopic stress that causes inflammation and the loss of insulin production in the pancreas, and system-wide stress due to the loss of that blood-sugar-regulating hormone.
Now, researchers led by scientists at the University of California, San Francisco (UCSF) have uncovered a new key player in amplifying this stress in the earliest stages of diabetes: a molecule called thioredoxin-interacting protein (TXNIP). The molecule, they've discovered, is central to the inflammatory process that leads to the death of the cells in the human pancreas that produce insulin.
"This molecule does something remarkable -- it takes stress and makes it worse," said the senior author of the study, UCSF's Feroz Papa, MD, PhD, an associate professor of medicine at UCSF and a member of the UCSF Diabetes Center and the California Institute for Quantitative Biosciences (QB3).
The study is published this week in the journal Cell Metabolism, with a parallel study by researchers at Washington University in St. Louis. Both studies were funded by the Juvenile Diabetes Research Foundation (JDRF).
The work provides a roadmap for finding new drugs that could target and shut down the action of TXNIP, thus preventing or stalling the inflammatory processes it amplifies. Researchers in the field believe that this strategy could benefit people in the early days of the disease, when diabetes is first developing or is soon to develop—a time referred to as the "honeymoon" period.
Clinical studies have already shown that dietary changes and other approaches can extend the honeymoon period in some people and prevent diabetes in others. The overarching goal of Papa's research, he said, is to find a way to extend this honeymoon period indefinitely.
Diabetes and the Loss of Beta Cells
Diabetes is a major health concern in the United States, affecting an estimated 8.3 percent of the U.S. population—some 25.8 million Americans—and costing U.S. taxpayers more than $200 billion annually. In California alone, an estimated 4 million people (one out of every seven adults) has type 2 diabetes, and millions more are at risk of developing it. These numbers are poised to explode in the next half century if more is not done to prevent the disease.
At the heart of diabetes is the specialized hormone-producing beta cells, which dot the human pancreas and produce the insulin that helps regulate a person's blood sugar.
These beta cells are like tiny biological factories that churn out insulin. A single beta cell might make a million molecules of insulin a minute. That means the billion or so beta cells in the average healthy pancreas will make more copies of insulin every year than there are grains of sand on every beach and in every desert in the world.
They are part of a delicate balance, however, and if the beta cells are lost, the pancreas may not be able to produce enough insulin and the body may not be able maintain proper blood sugar levels. That's exactly what happens in diabetes.
Stress to the Cells
Papa and his colleagues have found in recent years that underlying beta cell destruction and diabetes is stress within a part of the cell known as the endoplasmic reticulum (ER).
All cells have these structures, and the enveloped folds of the ER are easily spotted under a microscope. They play a crucial role in all human cells by helping to process and fold proteins the cells produce. But for beta cells, this structure is critical to their specialized function of secreting insulin.
If one thinks of a beta cell as a little factory, the ER would be like the shipping warehouse -- the packaging place where the end products are nicely wrapped, tagged with address labels, and sent to their final destination.