Transcription Factor Links Chronic Inflammation to Diabetes

A recent publication described the identification of a metabolic link between insulin resistance and inflammation, results obtained as part of a program to identify new targets for treatment of type 2 diabetes.

Investigators from the University of Pittsburgh School of Medicine (PA, USA) worked primarily with macrophages growing in tissue culture. They determined cytokine profiles for these cells and identified the interluekin-1 (IL-1)beta gene as a potential target of the FoxO1 (Forkhead Box 01) protein, a key transcription factor that mediates insulin action on gene expression. They studied the mechanism by which FoxO1 mediated insulin-dependent regulation of IL-1beta expression in cultured macrophages. They also correlated FoxO1 activity in peritoneal macrophages with IL-1beta production profiles in mice with low-grade inflammation or insulin resistance.

Results published in the August 3, 2009, online edition of the journal Diabetes revealed that FoxO1 selectively promoted IL-1beta production in cultured macrophages. This effect correlated with the ability of FoxO1 to bind and enhance IL-1beta promoter activity. Mutations of the FoxO1 binding site within the IL-1beta promoter abolished FoxO1 induction of IL-1beta expression. Macrophages from insulin-resistant obese mice or lipopolysaccharide (LPS)-inflicted mice were associated with increased FoxO1 production.

In unstimulated macrophages, FoxO1 remained inert with benign effects on IL-1beta expression. However, in response to inflammatory stimuli, FoxO1 activity was augmented due to an impaired ability of insulin to phosphorylate FoxO1 and promote its nuclear exclusion.

"The findings suggest that when there is a lack of insulin or when cells such as macrophages are resistant to its presence, there are no brakes on FoxO1's stimulation of IL-1Beta and its further interference with insulin signaling,” explained senior author Dr. Henry Dong, assistant professor of pediatrics at the University of Pittsburgh School of Medicine. "That might explain why chronic inflammation often is coupled with obesity and type 2 diabetes. Also, a drug that acts on FoxO1 might be able to better control blood sugar. But it is not yet clear if there is a cause-and-effect relationship between chronic exposure to low-grade inflammation and the onset of insulin resistance. Other studies have shown that in patients who have inflammation and diabetes, insulin-sensitizing drugs seem to reduce inflammation while anti-inflammatory therapies improve sensitivity to insulin.”

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University of Pittsburgh School of Medicine