News & Research

    University of Maryland Baltimore, Baltimore, Maryland

Phosphorylation of Ser24 in IRS-1 by IRAK-1 promotes insulin resistance in mice

General Research Subject: Insulin Resistance Pre Diabetes

Focus: Insulin Action, Insulin Action\Insulin Resistance, Insulin Action\Transgenic Models, Signal Transduction (Non-Insulin Action)

Type of Grant: Basic Science

Project Start Date: January 1, 2013

Project End Date: December 31, 2015

Research Description

Inflammation is one cause of insulin resistance in diabetes and obesity. Insulin resistance is a major underlying contributor to diabetes. However, specific molecular mechanisms for insulin resistance remain to be determined. We have identified one inflammatory signaling molecule called IL-1 receptor associated kinase-1 (IRAK-1) that we have implicated as a potential contributor to insulin resistance. In preliminary data, we show that the major insulin signaling molecule insulin receptor substrate-1 (IRS-1) is a substrate for IRAK-1. This raises the possibility that phosphorylation of IRS-1 by IRAK-1 contributes to insulin resistance.

To test this hypothesis, we will characterize mice missing the gene for IRAK-1 (IRAK-1 k/o mice). We will use state of the art methods to evaluate insulin sensitivity/resistance and glucose tolerance in IRAK-1 k/o mice and compare the results to normal control mice. We will also evaluate tissues from the IRAK-1 k/o mice to determine whether IRS-1 phosphorylation is altered in skeletal muscle, liver, and fat of IRAK-1 k/o mice when compared with normal control mice using a special antibody we developed that can detect phosphorylation of IRS-1 caused by IRAK-1. These studies will provide novel insights into mechanisms for proinflammatory signaling to contribute to insulin resistance that may be translatable to treatments for diabetes.

Research Profile

What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and curing diabetes?

Our project investigates mechanisms for inflammation to contribute to insulin resistance in diabetes. Inflammation is one cause of insulin resistance in diabetes and obesity. Insulin resistance is a major underlying contributor to diabetes. However, specific molecular mechanisms for insulin resistance remain to be determined. We have identified one inflammatory signaling molecule called IL-1 receptor associated kinase-1 (IRAK-1) that we have implicated as a potential contributor to insulin resistance. In preliminary data, we show that the major insulin signaling molecule insulin receptor substrate-1 (IRS-1) is a substrate for IRAK-1. This raises the possibility that phosphorylation of IRS-1 by IRAK-1 contributes to insulin resistance.

To test this hypothesis, we will characterize mice missing the gene for IRAK-1 (IRAK-1 k/o mice). We will use state of the art methods to evaluate insulin sensitivity/resistance and glucose tolerance in IRAK-1 k/o mice and compare the results to normal control mice. We will also evaluate tissues from the IRAK-1 k/o mice to determine whether IRS-1 phosphorylation is altered in skeletal muscle, liver, and fat of IRAK-1 k/o mice when compared with normal control mice using a special antibody we developed that can detect phosphorylation of IRS-1 caused by IRAK-1. These studies will provide novel insights into mechanisms for proinflammatory signaling to contribute to insulin resistance that may be translatable to treatments for diabetes.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?

These studies will provide novel insights into mechanisms for proinflammatory signaling to contribute to insulin resistance that may be translatable to future treatments for diabetes.

Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your efforts?

I initially became interested in diabetes research through my biomedical engineering studies on the mathematical modeling of regulation of insulin mediated glucose uptake. During my post-doctoral training, I had the opportunity to learn and apply experimental techniques to test some of the hypotheses generated by my previous theoretical work. This involved molecular biology, cell biology, animal physiology, and human clinical investigation. My interests have broadened to include studying abnormalities in insulin action that are related to diabetes, obesity, and hypertension. My interest in the field has been sustained by the realization that diabetes, obesity, hypertension, and related diseases are a major cause of morbidity and mortality in the U.S. and other parts of the world. Productive research related to diabetes is likely to have a major impact on human health in the long run.

The financial support provided by this ADA clinical research award is absolutely crucial to carrying out my work on understanding insulin action and insulin resistance. I have devoted my 25 year career to conducting diabetes research and I hope to continue this for the rest of my life.

In what direction do you see the future of diabetes research going?

The future of diabetes research is likely to involve understanding on a molecular level the processes involved in both insulin action and insulin secretion. In addition, genetic studies that identify abnormal genes involved in the development of diabetes will be important. As the molecular genetics of diabetes are elucidated, gene therapy may play an important role in treating and preventing diabetes. Another important area for future research will be prevention of disease and health maintenance in the areas of functional foods and nutritional supplements.