Diabetes Driven by Inflammation

A growing body of data show that type 2 diabetes is at least in part rooted in inflammation, said Edgar Engleman, MD, a professor of pathology and medicine at Stanford University.

For years now, scientists have known that inflammatory macrophages accumulate in subcutaneous and visceral fat and are causally related to insulin resistance, Engleman said during a presentation on adiposity and inflammation at the American College of Rheumatology (ACR)/Association of Rheumatology Health Professionals Annual Meeting (ACR/ARHP) Annual Meeting 2017. The higher a person’s body mass index, the more pro-inflammatory macrophages they have in their adipose tissue, he said.

Inflammation involves many immune cell types, Engleman said. About 7 years ago, his lab and others began to research the role of the adaptive arm of the immune system, such as T-cells and B-cells, in insulin resistance in mice.

The team looked at the role of T-cells in adipose, which they believed to be the principle site of chronic inflammation, he said. In non-obese mice, the team found relatively high activity of T-cells compared to inflammatory cells, Engleman said. Under the condition of obesity that reversed, he explained.

In obese mice, the number of inflammation-causing macrophages increased, Engleman said.

“The T-cells and macrophages effect one another, though we don’t yet know exactly what initiates it,” he said.

The research showed that in the insulin resistant mice, T-cells were not being replaced, they were being joined by inflammatory CD-4 and CD-8 cells.

When insulin-resistant mice were put on a 9-week program and treated with anti-CD-3 antibodies, researchers saw the normalization of glucose metabolism and the return of regulatory T-cells to full levels, Engleman said.

“The anti-CD3 antibodies had very little effect on weight but did impact inflammation,” he said.

The researchers also investigated B-cells in inflammation and found them to have an equally key role, he said.

Mice engineered to live without B-cells were put on a high-fat diet. Researchers found this made the animals more likely to develop insulin resistance, Engleman said. In a study, which the team published in Nature in 2009, Engleman’s team looked broadly at the effect of using anti-CD3 antigens, expressed on all T-cells, in individuals with insulin resistance. Treatment with anti-CD3 antibodies normalized glucose metabolism but had very little effect on weight, Edelman said.

The good news, said Engleman, “is that all these effects being studied in great detail are reversible.”

“People with full-blown, type 2 diabetes and morbid obesity undergo gastric bypass surgery and the diabetes literally goes away after the surgery,” Edelman said. “We don’t yet know the mechanistic explanation, but I suggest the effect on the immune system is probably profound.”

Reference

Engleman E. Adiposity, Inflammation, and Metabolic Syndrome. Presented at: 2017 ACR/ARHP Annual Meeting; November 3-8, 2017; San Diego.