News & Research

    Washington University in St. Louis, St. Loius, Missouri

Lipogenic signaling and diabetes

General Research Subject: Obesity,Type 2 Diabetes

Focus: Complications, Integrated Physiology

Type of Grant: Basic Science

Project Start Date: January 1, 2012

Project End Date: December 31, 2014

Diabetes Type: Type 2 diabetes

Research Profile

A quarter to a half of all Americans have the metabolic syndrome, prediabetes, or diabetes. More than half of Americans are overweight or obese. These individuals are at substantially increased risk for complications that include vascular diseases and fatty liver. Excess fat is associated with the development of these complications, but not everyone who is obese develops metabolic disease. The observation that some individuals can be quite obese yet apparently healthy raises the possibility that excess fat can be diverted to produce beneficial signals for preserving or protecting the function of organs affected by diabetes. Recent observations suggest that the enzyme fatty acid synthase (FAS), which normally synthesizes fats, can be involved in the generation of lipid signals that could improve the function of organs including the liver and blood vessels that are frequently damaged in people with diabetes. By studying the cellular pathways required to transmit signals from FAS, this project has the potential to identify new targets for the development of pharmacological or nutritional therapies to improve the quality of life for people with diabetes.

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

Metabolic syndrome, obesity, and diabetes predispose to nonalcoholic fatty liver disease, which is so strongly associated with cardiovascular complications that many of these individuals die from vascular disease before the development of advanced liver disease. This project will pursue the mission of the ADA by increasing our understanding of how lipids are synthesized and transported inside cells to generate signals that maintain health. We have shown that FAS (fatty-acid synthase), which makes fats, produces signals that alter cell function in ways that cannot be impacted by the simple addition of palmitate, the fat that is made by FAS. This finding suggests that all fats are not the same. We have extended this work by demonstrating that FAS exists in distinct pools in the cell that are differentially affected by phosphorylation, a modification that frequently occurs due to the action of insulin. Achieving the proposed aims of this project would establish the concept that FAS transmits physiological signals in key organs like liver and blood vessels. Given the strong association between fatty liver and vascular dysfunction, characterization of a novel system of lipid transport will provide attractive new targets for driving lipids toward beneficial signaling in the setting of 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?

Worldwide there are 1.5 billion overweight people, of which a half billion are obese. Being overweight increases all-cause mortality. Increased adiposity leads to diabetes, which is associated with premature death from many causes. 25-40% of Americans have the metabolic syndrome, diabetes or prediabetic. Obesity is prevalent in young Americans and even modest increases in BMI during adolescence increase risk for obesity-related disease in adulthood. Treatment options are limited. Residual risk of premature death in diabetes is high despite appropriate current therapies, recently developed new modalities to treat diabetes are of unclear benefit in terms of preventing death, and intensive glucose lowering in advanced type 2 diabetes actually increases 5-year mortality. Obesity and diabetes are immense problems. Developing new therapies is hindered by a limited understanding of how lipids move inside of cells to impact risk of disease. This project has the potential to help people with diabetes by aiding in the development of new therapies that could reduce the incidence of metabolic syndrome and diabetes, and potentially reduce the risk of death due to diabetes. By understanding how fat metabolism, which is disrupted in diabetes, damages blood vessels, we hope to be able to provide leads for new therapies that may eventually help everyone with diabetes.

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

I was inspired to pursue a career in diabetes research by a high school English teacher. She took particular interest in me and provided direction and advice that was invaluable. Tragically, she died due to diabetes complications before I graduated from high school. However, I was one of the graduation speakers and paid tribute to her efforts. This award allows us to try to develop therapies to improve the quality of life for inspiring people like my high school English teacher.

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

Research will move toward the development of new treatment modalities that focus not only on blood glucose but also other aspects of metabolism that are affected by diabetes such as abnormal lipid signaling.