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Archive - 08 - 2013
August 25, 2013 (Newswise — BIRMINGHAM, Ala.) – The same protein tells beta cells in the pancreas to stop making insulin and then to self-destruct as diabetes worsens, according to a University of Alabama at Birmingham (UAB) study published online today in the journal Nature Medicine.
Specifically, the research revealed that a protein called TXNIP controls the ability of beta cells to make insulin, the hormone that regulates blood-sugar levels.
"We spent years confirming that TXNIP drives beta-cell death in both Type 1 and Type 2 diabetes," said Anath Shalev, M.D., director of the UAB Comprehensive Diabetes Center and senior author of the paper. "We were astounded to find that its action also contributes to a second major diabetic mechanism — the decrease seen in insulin production by beta cells — by a mechanism never before seen."
During their research, Shalev and colleagues discovered that high TXNIP triggers beta cells to make a specific snippet of genetic material called microRNA-204.
Genetic instructions are encoded in DNA chains and converted into ribonucleic acids (RNA) that direct the building of the proteins that comprise bodily structures and signals. A large portion of human genetic material, however, does not encode proteins and once was considered "junk DNA." RNA snippets called microRNAs are built based on this junk DNA, but instead of converting its messages into proteins, they silence targeted genes. This provides yet another level of regulation and a tool to turn genes on or off.
The study found that microRNA-204, in response to the TXNIP signal, interferes with MAFA, a transcription factor known to turn on the insulin gene. This is not the first instance of a microRNA influencing a transcription factor, but is a first for a factor critical to the expression of the human insulin gene. Taken together, the evidence argues for the existence of a previously unknown TXNIP/miR-204/MAFA pathway that dials down insulin production and drives diabetic disease. After demonstrating that TXNIP ramps up production of miR-204 in a microarray analysis, the team confirmed the finding in beta cells, pancreatic islets of diabetic or TXNIP-deficient mice and human islets.
Based on these findings, the team redoubled its effort in 2013 to identify a new class of drugs that can regulate TXNIP levels to increase insulin production by beta cells and extend their lifespan. In partnership with the Southern Research Institute and Alabama Drug Discovery Alliance, the researchers screened a library of 300,000 small molecules and the search has yielded lead molecules. The team expects to begin medicinal chemistry and preliminary mouse studies on the best candidates soon, with a goal of identifying a clinical compound and launching the first human clinical trials at UAB.
In early tests, the lead molecule normalizes TXNIP expression levels that have grown too high in response to elevated blood sugar without causing detrimental effects, Shalev said. Her team has also launched an effort to search for experimental compounds that interfere with microRNA-204 instead of TXNIP, opening the door for the design of novel RNA therapeutics.
Excessive expression of the gene for TXNIP — or thioredoxin-interacting protein — has emerged as one of the most destructive forces in diabetes because it unleashes waves of highly reactive molecules — free radicals — that tell beta cells to self-destruct. Cells evolved to use oxidation to switch on cellular processes such as healing.
Disease-related oxidation, however, can create reactive particles that destroy cell components in a process called oxidative stress. By shutting down antioxidant thioredoxin, TXNIP contributes to oxidative stress; pancreatic beta cells are especially susceptible to oxidative stress and more likely to undergo programmed cell death in response to it.
Shalev favors the theory that any excessive demand on beta cells to produce insulin to counteract elevated blood sugar eventually stresses the beta cells, which become less able to make enough insulin to meet demand. This leads to an increase in blood sugar and greater levels of TXNIP production that result in even less insulin production and beta cell death.
In 2002, a team led by Shalev published a study showing that – in the face of rising glucose levels – the gene for TXNIP undergoes an 11-fold increase in expression in human pancreatic islets. A 2008 paper by the team revealed that deleting the gene for TXNIP in mice protected them against Type 1 and Type 2 diabetes and too much TXNIP-signaling shuts down the signaling pathway that keeps beta cells alive.
All that said, the mechanism revealed in this study has nothing to do with TXNIP's relationship with thioredoxin or its contribution to oxidative stress. This is the first study to suggest that TXNIP, along with being a regulator of cellular oxidation state, also regulates gene expression through a microRNA-based mechanism.
"Beyond the potential implications for diabetes drug design, our finding fundamentally alters the current understanding of the relationships between TXNIP, microRNAs, gene expression and insulin production," Shalev said. "The field may once again have to rethink its concepts of gene regulation, including that of insulin."
In Shalev's lab, post-doctoral fellow Guanlan Xu, Ph.D. and research associates Junqin Chen, Ph.D., and Gu Jing, Ph.D., were also authors of the study, which was funded by the American Diabetes Association (7-12-BS-167), the National Institute of Diabetes, Digestive and Kidney Diseases (R01DK-078752) and the Juvenile Diabetes Research Foundation/JNJSI (40-2011-1).
Known for its innovative and interdisciplinary approach to education at both the graduate and undergraduate levels, the University of Alabama at Birmingham is the state of Alabama's largest employer and an internationally renowned research university and academic health center; its professional schools and specialty patient-care programs are consistently ranked among the nation's top 50. Find more information at www.uab.edu and www.uabmedicine.org.
August 23, 2013 (Newswise) — Researchers at the University of Adelaide have discovered that the way the gut "tastes" sweet food may be defective in sufferers of type 2 diabetes, leading to problems with glucose uptake. This is the first time that abnormal control of so-called "sweet taste receptors" in the human intestine has been described by researchers. The work could have implications for a range of health and nutrition problems experienced by diabetes patients. Dr Richard Young, Senior Postdoctoral Researcher in the University of Adelaide's Nerve-Gut Research Laboratory, says taste buds aren't the only way the body detects sweetness. "When we talk about 'sweet taste', most people think of tasting sweet food on our tongue, but scientists have discovered that sweet taste receptors are present in a number of sites in the human body. We're now just beginning to understand the importance of the sweet taste receptors in the human intestine and what this means for sufferers of type 2 diabetes," Dr Young says. In his study, Dr Young compared healthy adults with type 2 diabetic adults. He found that the control of sweet taste receptors in the intestine of the healthy adults enabled their bodies to effectively regulate glucose intake 30 minutes after exposure to glucose. However, abnormalities in the diabetic adults resulted in more rapid glucose uptake. "When sweet taste receptors in the intestine detect glucose, they trigger a response that may regulate the way glucose is absorbed by the intestine. Our studies show that in diabetes patients, the glucose is absorbed more rapidly and in greater quantities than in healthy adults," Dr Young says. "This shows that diabetes is not just a disorder of the pancreas and of insulin - the gut plays a bigger role than researchers have previously considered. This is because the body's own management of glucose uptake may rely on the actions of sweet taste receptors, and these appear to be abnormally controlled in people with type 2 diabetes." Dr Young says more research is needed to better understand these mechanisms in the gut. "So far, we've seen what happens in people 30 minutes after glucose is delivered to the intestine, but we also need to study what happens over the entire period of digestion. There are also questions about whether or not the body responds differently to artificial sweeteners compared with natural glucose," he says. "By gaining a better understanding of how these mechanisms in the gut work, we hope that eventually this will assist to better manage or treat diabetes in the future." This study has been funded by the National Health and Medical Research Council (NHMRC) and Diabetes Australia. The results have been published online ahead of print in the international journal Diabetes.