Diabetes linked to arsenic

“Arsenic is everywhere,” says Dr. Donna Zhang, a professor in the Department of Pharmacology and Toxicology at the University of Arizona. “It’s a big environmental contaminant that causes many diseases.” Dr. Zhang is one of the leading experts on the subject. Her lab studies the mechanism by which arsenic promotes disease. “We know there is a link between exposure to arsenic and diseases such as cancer and type II diabetes, but the mechanism is not well understood,” she says. “Our work focuses on revealing that mechanism. If we can do that, then we can find a way to prevent or slow down the disease.”

Arsenic occurs naturally in many areas of the world, often in the water supply. Very low levels are not a risk, but concentrations above 10 micrograms per liter are unsafe for humans, according to the World Health Organization. Chronic exposure to arsenic at these levels increases the likelihood of a person developing numerous serious diseases, including cancer and type II diabetes.

An estimated 200 million people are exposed to unsafe levels of arsenic in the environment. Dangerous levels have been detected in regions across the world, including in Bangladesh, Taiwan, China, Thailand, Brazil, and parts of the United States.

Dr. Matthew Dodson, a post-doctoral research associate, has been working in Dr. Zhang’s lab for four years, leading experiments using mouse models to examine how chronic exposure to arsenic causes genetic changes and how those changes are linked to disease development. “It’s my goal to find ways to treat or help people that get diseases,” he says.

The unseen danger

Type II diabetes is the most common form of diabetes. It is a metabolic disease-causing elevation of blood sugar and leading to serious health problems. It affects many organs in the body, potentially leading to heart or kidney problems, nerve damage, or vision loss. “Often people who have been exposed to arsenic in the environment are unaware of the fact and they may also be unaware that they are already in the early stages of developing a disease,” says Dr. Dodson. “That’s one reason why it is so important to determine the mechanism by which arsenic exposure leads to the development of the disease.”

Dr. Dodson already knew that autophagy plays an important role. Autophagy is the process by which cells recycle their old parts to rebuild themselves. Damaged and long-lived proteins that aren’t needed are degraded to make new ones. Dr. Dodson set out to look at how arsenic blocks this process.
The team looked at the role of prolonged changes in a set of RNA molecules called the Nrf2 transcriptome. Nrf2 is a master regulator of redox, protein, and metabolic homeostasis. In a normal cell, it is activated intermittently. In a cancer cell or a cell where autophagy is not working properly, Nrf2 is activated for extended periods or continuously. The latter is what happens when a person is exposed to arsenic over a long period of time. When autophagy stops working, Nrf2 is not activated in the normal way, and this, in turn, promotes disease.

As the effects that arsenic has on cells are comparable to the effects of high-fat diets, the experimental model examined not only the role of Nrf2 in promoting arsenic-linked diabetes but also the role of diet. Dr. Dodson compared high-fat diets and exposure to high levels of arsenic in four groups of mice: one group was given a normal diet with no exposure to arsenic, the second received a normal diet with high exposure to arsenic, the third received a high-fat diet with no exposure to arsenic, and the fourth received a high-fat diet with high exposure to arsenic. In half the mice in each group, Nrf2 had been inactivated. “We wanted to get an initial assessment of overall transcriptomic changes across these different groups,” says Dr. Dodson.

A massive data set

This is where QIAGEN Genomic Services came in. “Dr. Zhang’s team had a vision for the project. Our experts talked it through with them and suggested using our new UPX transcriptome service because it is a great tool for screening a lot of samples and our Unique Molecular Identifiers allow us to assess gene expression with a high level of accuracy,” says Jon Olson, QIAGEN’s sales manager.” The team at QIAGEN extracted, purified and stabilized the RNA from the biological samples using the new UPX transcriptome service, and analyzed the data.

“They had precious samples and had not worked with us before, so it was a bit of a leap of faith,” says Olson. “But we have a good group of Field Application Specialists at QIAGEN. They spoke to Dr. Zhang and her team to identify the best approach and our team turned around the sample in six weeks.”

The leap of faith paid off. Dr. Zhang, Dr. Dodson and the team were delighted with the results and the preliminary data. “QIAGEN was also happy to accommodate their request to analyze a higher number of samples than was originally planned so that they could gather the data needed for publication.”

“The process of working with QIAGEN and submitting samples was very easy,” says Dr. Zhang. “That’s in contrast to the analysis we needed, which was very complicated as we included the influence of diet on arsenic poisoning. It was a complex model and there was a lot of data to tease out. We required significant bioinformatics capabilities and QIAGEN was able to provide this.”