Study shows how exercise protects pancreas in diabetics

Substance secreted by muscles in response to physical activity protects insulin-producing cells in experiments that simulate type 1 diabetes autoimmune attack.

By Karina Toledo

Agência FAPESP – A study conducted at the University of Campinas (UNICAMP) in São Paulo State, Brazil, has shown that interleukin 6 (IL-6), a substance secreted by muscles in response to physical exercise, increases the survival of the pancreatic cells that produce insulin in a type 1 diabetes model.

The findings are described in a paper published in The FASEB Journal and selected for the Research Highlights section of Nature Reviews Endocrinology.

“Besides reinforcing the importance of physical activity in the control of diabetes, the discovery paves the way to the development of drugs that simulate the action of IL-6 in the pancreas,” said Claudio Cesar Zoppi, a researcher at the Endocrine Pancreas & Metabolism Laboratory of UNICAMP’s Department of Structural & Functional Biology, and one of the article’s authors.

Type 1 diabetes is caused by autoimmune attack on insulin-producing beta cells. As the cells die, insulin production becomes insufficient to control blood sugar levels, Zoppi explained.

Recent studies had already shown that exercise training improves both survival and beta-cell functioning in patients with both type 1 and type 2 diabetes (in which insulin production is high but certain cells resist its action).

The scientific literature also shows that exercise not only makes the environment in the pancreas more favorable to cell survival, by reducing levels of blood sugar, inflammation and triglycerides, for example, but also induces direct adaptations in beta cells.

“The question we set out to answer in the study was what molecular and intracellular mechanisms are altered in beta cells by exercise and how this signal reaches the pancreas,” Zoppi said.

In search of the answers, several experiments were performed during postdoctoral research by Flávia Maria Moura de Paula, supported by a scholarship from FAPESP and supervised by Antonio Carlos Boschero, a professor at UNICAMP. Boschero and Zoppi are also affiliated with the Obesity and Comorbidities Research Center (OCRC), one of FAPESP’s Research, Innovation and Dissemination Centers (RIDCs).

In one of the models, healthy mice were submitted to a two-month endurance exercise training program of low intensity and long duration. After this period, the researchers took samples from pancreatic islets, regions of the pancreas that contain its endocrine (hormone-producing) cells, including the beta cells that produce insulin.

“The next step was in vitro simulation of an autoimmune attack on beta cells, which is what happens in type 1 diabetes. To do this, we incubated the mouse islets with proinflammatory cytokines interferon-gamma and interleukin 1-beta, the same as defense cell secretions,” Zoppi said.

Islet mortality was 50% lower for trained mice than for the sedentary mice in the control group. Moreover, the researchers observed that trained mice produced less nitric oxide and cleaved caspase-3 protein, both of which signal to cells that it is time to begin apoptosis (programmed cell death).

“But pancreatic islets contain other cell types, including alpha and delta cells. We had to show the effect of exercise specifically on beta cells,” Zoppi said. This step involved in vitro experiments with two lines of beta cells: rat INS-1E and mouse MIN-6. The exercise stimulus was pharmacologically simulated, Zoppi explained.

“We incubated a muscle cell line with a drug known to induce the same adaptations as those promoted by endurance exercise. Next, we incubated the beta cell lines solely with culture medium from these pharmacologically ‘trained’ muscle cells. In another experiment, beta cell lines were incubated with serum from animals submitted to endurance training. In sum, we were able to simulate the cellular environment of a trained animal,” Zoppi said.

The results were similar to those observed in the experiment with islets. The mortality of “trained” INS-1E cell mortality was 50% lower than in the control situation.

“It remained to discover which molecule made the link between muscle and beta cells. We thought IL-6 would be a possible candidate since muscle contraction stimulates the release of large amounts of this cytokine,” he said.

According to Zoppi, recent research shows the importance of IL-6 signaling between tissues, especially those involved in blood sugar control. For example, IL-6 sends signals from muscles to organs such as the liver and hypothalamus.

To test their hypothesis, the researchers repeated the initial experiments, observing that when a pharmacological inhibitor of IL-6 was added to the culture medium, the protective effects of exercise were abolished.

To reinforce the results, the group used “knockout” mice, which had been genetically modified not to express IL-6. They were submitted to training. After two months, islets from the sedentary control animals were treated in the same way as before, with serum from trained IL-6 knockout mice.

“We repeated the same experiment, and in this case physical exercise didn’t have any protective effect on beta cells,” Zoppi said.

New drugs

De Paula is currently performing experiments with islets from human donors at Brussels Free University’s Laboratory of Experimental Medicine in Belgium, with the aim of trying to repeat the results observed in mice, and the UNICAMP group is planning a study to prospect for molecules capable of activating the same IL-6 signaling pathway in the pancreas.

“I believe we won’t be able to use IL-6 directly for treatment because it acts in several ways and can be anti-inflammatory or proinflammatory, depending on the context. Perhaps we’ll find an analogue with therapeutic effects,” Zoppi said.

The research is being conducted within the ambit of the Thematic Project “Molecular mechanisms involved in the dysfunction and death of pancreatic beta cells in Diabetes Mellitus: strategies for the prevention of islet dysfunction and for islet mass recuperation in different cellular and animal models,” coordinated by Boschero.