News & Research

    Harvard University, Boston, Massachusetts

Inflammatory mechanisms underlying insulin resistance and associated pathologies

General Research Subject: Type 2 Diabetes

Focus: Integrated Physiology\Insulin Resistance

Type of Grant: Mentor Based Postdoctoral Fellowship

Project Start Date: July 1, 2008

Project End Date: June 30, 2012

Research Description

Obesity, insulin resistance and type 2 diabetes pose a major threat to public health globally. As the incidence of these problems increase dramatically, the number of individuals at great risk for developing additional problems such as liver or heart disease also increase at alarming rates. Despite this overwhelming burden on health, the mechanisms causing these conditions especially remains unclear, thus, leaving these common diseases without adequate treatments.

Our previous and ongoing studies focus on the involvement of stress and inflammatory mechanisms leading to insulin resistance and type 2 diabetes. We have identified several important pathways, such as an enzyme named JNK and a group of proteins that bind fatty acids as critical players in insulin resistance and diabetes. Recently, we also discovered that faulty function in one of cells organelles can give rise to inflammatory and stress signals and chemical or genetic repair of this organelle can treat diabetes. These studies carry the potential to provide important insights into the mechanisms of obesity and diabetes and might help defining novel therapeutic strategies. Through these projects, and support from ADA, we also aim to train more outstanding scientists that will engage in diabetes research and treatment in the future.

Reseacher Profile

Mentor: Gokhan Hotamisligil, MD, PhD   Postdoctoral Fellow: Ling Yang, MD, PhD

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

Obesity is the major cause for type-2 diabetes, characterized by insulin resistance and glucose intolerance. Obesity triggers a cluster of closely related clinical conditions, including insulin resistance, cardiovascular disease, type 2 diabetes, neurodegenerative disease, asthma and several cancers. This broad cluster of problems emerges from an interface of metabolic and inflammatory stresses that combine to mount a full-scale systemic attack on energy, lipid, and glucose homeostasis. The ER (endoplasmic reticulum), an organelle response for synthesis secretory protein for cell, demonstrates significant stress in obesity and insulin resistance. Previous studies in our group demonstrated that the metabolic and inflammatory stresses of obesity disrupt the homeostasis of the ER, which in turn results in suppression of insulin action.

However, the physiological assaults that cause the obesity-induced ER stress remain unclear. Oxidative stress generally occurs when the production of reactive oxygen species (ROS) overwhelms the intracellular microenvironments. An excess amount of ROS, such as NO, is produced in inflammatory diseases including obesity and diabetics. Our research will focus on examining the hypothesis that NO-induced oxidative stress is one of the potential physiological assaults that cause the obesity-induced ER stress, particularly through modification of the ER chaperone proteins by NO. Moreover, we're interested in processes that can either be involved in the turnover of long-lived proteins and whole organelles in a general fashion or can specifically target distinct organelles, thereby eliminating supernumerary or damaged organelles. Autophagy is one such process which we will investigate in the context of endoplasmic reticulum function and metabolic homeostasis. Information obtained in this research will lead to novel prevention strategies as well as treatment for both obesity and diabetes.

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

The causal relationship between obesity and diabetes has been well recognized but the molecular mechanism underline this connection remains unclear. Our research aims to identify the molecular components that link obesity to diabetes at the cellular level and confirm their significance in a physiologically relative context. Insights from these studies will help develop both drugs that intervene in the process of obesity leading to diabetes and better treatments for diabetes and its associated complications.

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

Obesity and type 2 diabetes represent a serious threat to the health of the population of almost every country in the world. In the United States, only about a third of adults are considered to be of 'normal' weight. Obesity is associated with an array of additional heath problems with the most devastating of which may be type 2 diabetes. At the turn of this century, 171 million individuals were estimated to have diabetes, and this is expected to increase to 366 million by 2030. The reletatioship between obesity and diabetes emerged as a very critical question for me toward unvealing the mechanisms underline obesity-induced diabetes. This award will give me the opptunity to work on answering this important question and to explore the molecular and genetic based new approaches for treatment of diabetes.

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

Future research will focus on understanding the molecular details of diabetes and its connection to other disorders within metabolic syndrome. Combined with information from nutrition and epidemiological studies, this approach will eventually lead to the identification of the key factors that cause diabetes and provide the foundation for the efforts in reversing the rising trend of this disorder.