How much do we really know about the causes of diabetes?

In the popular media, the story is simple. People eat too much and exercise too little. They gain weight. They get diabetes.

That’s cold comfort to those struggling to stave off type 2 diabetes when they see their good intentions frustrated between the fatigue of low blood sugar and the cravings of surging insulin that can’t get into the cells to release the energy they need to exercise and fight back.

Add to that the intriguing mystery of the metabolically healthy obese who somehow compensate so they never develop diabetes. When you take a closer look—at the cellular and genetic level—what becomes clear is that the story is not so simple.

The more researchers learn about diabetes, the more they understand the complexity of just how much more we need to know.

The constellation of factors that could be influencing the development of diabetes was the topic of two research meetings at UAB and the 74th Scientific Sessions of the American Diabetes Association last month in San Francisco.

Beta cells were the focus of the first meeting at UAB. Researchers from 18 institutions came to exchange ideas about how they develop and are differentiated, how they die and why, and how the process is modulated. The second meeting in late May was UAB’s 5th Annual Diabetes Research Day, which covered topics ranging from the genetics of susceptibility to oxidative stress and how insulin resistance and obesity factor into the equation

Those attending had a great deal to discuss, including the findings of several recent studies that have added a variety of new suspects to the list of factors that may be involved.

To get her perspective on current hot topics of conversation between diabetes researchers, we spoke with Anath Shalev, MD, director of the UAB Comprehensive Diabetes Center, at the Scientific Sessions of the American Diabetes Association where 18 UAB researchers were presenting their work.

“There is no one single cause of diabetes. It is so multifactoral. Is a person’s individual genetic makeup susceptible or not? What triggers their susceptible genes? How do their beta cells, fat cells, muscle cells and other tissues response to insulin?” Shalev said.

When the process begins, a variety of proteins, enzymes, hormones, epigenetic changes and other factors build on each other. After the first domino falls, another and another and another factor starts changing. What begins as a small whirlwind builds on itself till it becomes a powerful tornado attacking multiple body systems.

“It’s circular. We’ve had success in developing therapies to counter the effects of diabetes, but it’s still not optimal. We have no means of addressing the causes of these changes. What we need is to identify pathways and how we can interrupt them. If we can find a point where we can break that loop to stop it from progressing, it could make a real difference” Shalev said.

A host of new targets have been identified over the past couple of years as researchers track the footprints of the disease at the cellular, metabolic and genetic level and are rewriting much of what we thought we new about diabetes.

The University of Cincinnati found that even fat cells themselves begin to change as the PKC-zeta gene that normally regulates inflammation becomes a pro-inflammatory agent that causes fat cells to secrete a substance than increases insulin resistance. Changes in an enzyme called HDAC9 also seems to lead to body fat dysfunction.

“For years, the immune system was the primary focus, but now we know a lot more is involved,” Shalev said. “Our lab identified thioredoxin-interacting protein (TXNIP) as a potential target. It is normally involved in the cellular redox state, and it’s the most dramatically up-regulated gene in response to glucose, which suggested that it might play an important role. We found that TXNIP expression is increased in the islets of mice with diabetes and that overexpression induces beta cell death in both type 1 and type 2 diabetes. It plays a critical role linking glucose toxicity to beta cell death.”

The study also determined that in response to the TXNIP signal, microRNA-204 interferes with MAFA, a transcription factor known to turn on the insulin gene. UAB researchers also found that TXNIP induces expression of Islet Amyloid Polypeptide (IAPP), which leads to the development of fibrils that are associated with the loss of beta cells.

“A highlight of the ADA Scientific Session this year was that Gu Jing, PhD, a post doctorate fellow from our lab, received an ADA Young Investigator Travel Grant Award for his work in this area. The abstract was entitled “Islet Amyloid Polypeptide Expression Is Regulated by Thioredoxin-Interacting Protein: Role of miR-124 and FoxA2.”

Seventeen other UAB researchers also presented their work in diabetes in areas ranging from the role of iPA2beta in beta cell inflammation to the molecular response to exercise and the effects city design can have on opportunities to get that exercise. Topics also included the healthy obese, the role of macrophages, and how muscle-specific TRIB3 overexpression produces weight gain and insulin resistance in mice.

The work of Alabama researchers was well represented and well received. Local scientists also had the opportunity to talk with their peers from across the country about progress in other area of inquiry into diabetes.

Research from the University of Pennsylvania suggests that sleep deprivation, particularly in older patients, may negatively influence glucose metabolism.

“We’re seeing the effects more in disruptions of circadian rhythm. Some genes have the same effect all the time, and others tend to be more active in waking or sleeping cycles. This could be a factor in how shift workers respond to some situations,” Shalev said.

The human microbiome is also making news, with differences in gut flora linked to diabetes and obesity.

“It is a chicken and egg situation at this point,” Shalev said. “We don’t know yet whether the differences cause the problem, or are a result of the problem. If there are organisms that have a causative or protective effect, we would need to identify them and then learn how to use them.”

Diabetes is a battle on a very broad front, but one by one, researchers are finding its vulnerabilities and developing new strategies to fight back. Alabama’s diabetes researchers are at the vanguard of that fight.

“There are so many factors involved. No one person can deal with it all. It takes a team. That’s why UAB’s Comprehensive Diabetes Center is such an asset. It brings people together to address the many, many angles, share ideas and approach the problem from different perspectives.”