Cytokine Resistance Contributes to Pathology of Type 2 Diabetes

A new study by University of Illinois researchers describes how an impaired anti-inflammatory response plays a role in the pathology of type 2 diabetes.

Published in the Journal of Immunology, the study focused on a number of cytokines, protein signals that bind to specific receptors on cells and set off a cascade of biochemical reactions within the cell.

Interleukins, interferons, tumour necrosis factors, and some growth factors are among the cytokines that direct many aspects of the immune response say the researchers.

Previous studies had shown that that macrophages in diabetic and obese (diabese) mice secrete more pro-inflammatory and less anti-inflammatory cytokines than those of non-diabese mice.

In the new study, led by pathology professor and department head Gregory Freund, the researchers demonstrated that human monocytes cultured under type 2 diabetic conditions had impaired interleukin-4 signalling, an important player in the immune response in that it steers macrophages toward the production of other anti-inflammatory cytokines.

Boffins say when IL-4 binds to its receptor on a target cell, it sets off one of two cascades of intracellular events, the first of which signal transduction pathways, the Jak-STAT pathway. But the scientists were more interested in knowing about the second pathway, called the insulin receptor substrate 2 / phosphatidylinositol-3 kinase (IRS-2/PI3K), which was more of a mystery.

“One of the actions of diabetes is to create intracellular insulin resistance. Some of the cytokines that work on cells share the same pathways as the insulin receptor,” Freund said.

The study showed that the IRS-2 signalling arm of the interleukin-4 pathway directed the up-regulation of a key anti-inflammatory molecule in primary macrophages, and that the pathway was disrupted in type 2 diabetic conditions.

It also found that the loss of IL-4 function in diabese mice caused chronic over-expression of an important suppressor of cytokine signalling (SOCS) protein, which aborts the cascade of events that normally leads to insulin uptake and/or cytokine signalling in a balanced inflammatory response.

According to Freund, the study supports earlier findings that inflammation is a key part of the pathology of diabetes.

The researchers say that pro-inflammatory cytokines are elevated in type 2 diabetes, but the anti-inflammatory mechanisms are also impaired, leading to a multitude of major and minor health issues in the diabese.

“They get a cold. They get injured. Something happens. And it’s worse in those people with obesity or diabetes and lasts longer than it does in others. Why? The imbalance may be the elevation in pro-inflammation. But it probably also includes a loss of anti-inflammatory function,” Freund said.

Source-ANI
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