News & Research

    University of Michigan, Ann Arbor, Michigan

Maintenance of insulin signaling sensitivity by sestrin2-mediated feedback loop

General Research Subject: Insulin Resistance Pre Diabetes

Focus: Insulin Action, Insulin Action\Insulin Resistance, Insulin Action\Signal Transduction, Obesity, Obesity\Animal Models

Type of Grant: Basic Science

Project Start Date: January 1, 2013

Project End Date: December 31, 2015

Research Description

With the development of modern society, type 2 diabetes which is well-known for its association with obesity, aging and lack of exercise has become a major health problem of people in the United States and the world. However, the molecular mechanisms underlying insulin resistance, a precursor and basis of type 2 diabetes, are not well understood. Therefore, a better understanding of the causes of insulin resistance and identification of potential therapeutic strategies would have a significant impact on human health.

In this proposal, the group will focus on a protein named Sestrin2, which our body synthesizes upon hypernutrition and obesity. Their current results indicate that Sestrin2 has a critical role in slowing down the hypernutrition-caused development of insulin resistance, therefore halting type 2 diabetic progression. They will further study (i) how Sestrin2 synthesis is promoted in response to obesity, (ii) whether artificial supplementation of Sestrin2 protein can be used to suppress insulin resistance thereby preventing type 2 diabetes development, and (iii) how Sestrin2 suppresses diabetic progression during obesity. The results of the proposed research are expected to facilitate the development of clinically relevant and innovative treatment methods for diabetes by utilizing the beneficial activity of the Sestrin2.

Research Profile

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

This project focuses on a new protein family named Sestrins. Sestrins were originally discovered as proteins that accumulate in cells upon diverse environmental stresses. Our recent studies show that Sestrins have important metabolic functions in controlling lipid homeostasis, blood glucose level and insulin signal transduction, and that Sestrin deficiencies can cause acceleration of diabetic progression upon dietary or genetic obesity. Our goal is to understand how Sestrin-family proteins, including Sestrin2, operate to attenuate obesity-induced diabetic progression.

The results from the proposed study would have an important positive impact because they will provide us a more comprehensive understanding of the molecular network associated with insulin resistance and metabolic syndrome and of a novel rationale for treatment and prevention of obesity-associated type 2 diabetes using beneficial metabolic activities of Sestrin2 and other Sestrins.

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

We anticipate that the proposed work will show the beneficial effects of Sestrin2 against obesity-prompted diabetic progression. The basic knowledge gained from the proposed studies will determine how we can naturally induce a Sestrin-family protein and whether manipulation of the mammalian Sestrin family can have therapeutic applications. We predict that future development of Sestrin inducers or mimetics can lead to a new therapeutic strategy to prevent, attenuate or cure insulin resistance and type 2 diabetes in humans.

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

My research program focuses on Sestrin proteins that regulate several important metabolic pathways. While studying Sestrins¡¯ biological functions, I realized that further research on Sestrins may enable us to develop innovative therapeutic methods for type 2 diabetes. As we have just generated several genetic models that can be used for the investigation of Sestrins¡¯ anti-diabetic roles, we would now be able to examine how Sestrins can attenuate diabetic progression during obesity, aging and lack of exercise, with the support from the ADA basic science award.

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

With the development of modern society, type 2 diabetes associated with aging and obesity has become a major health problem of people in the United States and the world. Thus, more future research should be conducted to identify molecular mechanism of how different environment or lifestyle can affect development of obesity and diabetes. As a protein family regulated by diverse stresses, Sestrins may provide an unknown link on how diverse environmental factors can affect obesity-associated pathological progression of diabetes.