Bajaj, Mandeep , MD
Effect of Exenatide on Hepatic and Myocardial Fat in Type 2 Diabetes
General Research Subject: Type 2 Diabetes
Focus: Clinical Diabetes, Clinical Therapeutics/New Technology\Treatment of Insulin Resistance, Integrated Physiology
Type of Grant: Clinical Translational Research
Project Start Date: January 1, 2010
Project End Date: December 31, 2012
In this grant proposal we would like to study the effect of exenatide on fat in the liver and heart in type 2 diabetes. One of the primary defects in type 2 diabetes is the inability of insulin to work on the liver due to excessive fat. Exenatide treatment in type 2 diabetes improves glucose in type 2 diabetes-it is also associated with weight loss. We suggest that combining exenatide with pioglitazone improves glucose better by reducing liver fat and insulin action in liver. We also propose to study the effect of exenatide and pioglitazone, a diabetes tmedication, on fat in the heart and heart function. These studies will provide important information about the effects of anti-diabetes medications on the liver and the heart.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
Ectopic or tissue fat is a feature of type 2 diabetes with excessive fat deposition in the liver, skeletal muscle and heart. Increased myocardial fat is associated with impairment in myocardial systolic and diastolic function and increased risk of heart failure in type 2 diabetes. Fatty liver is considered to occur commonly in type 2 diabetes mellitus. Obesity, insulin resistance, and increased concentrations of plasma fatty acids are considered to increase the risk for fatty liver, and each of these metabolic factors is also characteristic of type 2 DM.
In some individuals, fatty liver can lead to steatohepatitis and progress further to end-stage liver disease; nevertheless, even for those in whom there is not progression to inflammation and fibrosis in the liver, fatty liver influences severity of hepatic insulin resistance and glucose intolerance in type 2 DM. We propose to study the effect of exenatide and thiazolidinediones on myocardial fat/LV function as well as hepatic glucose and lipid metabolism in patients with type 2 diabetes. These studies will provide important information regarding the role of anti-diabetes treatment in preventing and/or treating Non-Alcoholic Fatty Liver Disease as well as cardiovascular complications of type 2 diabetes related to myocardial fat.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
There is an increased risk of heart failure in patients with type 2 diabetes and may be related to increased fat in the heart muscle. Another site of fat deposition in type 2 diabetes is the liver. One of the primary defects in type 2 diabetes is the inability of insulin to work on the liver due to excessive fat. We know that either weight loss or anti-diabetes treatment with certain diabetes medications such as pioglitazone reduces liver fat. Exenatide treatment in type 2 diabetes improves glucose in type 2 diabetes-it is also associated with weight loss. We will investigate the effect of anti-diabetes treatment on fat in the liver and heart and its associated metabolic and cardiovascular complications.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Since I was a young child I watched my father work in his laboratory trying to find the answers to questions about diabetes and its complications. It was then that I decided to devote my career to diabetes research and find new and better ways to prevent and treat this disease. I became very interested in understanding the mechanism by which insulin functions to maintain normal glucose levels and the relationship between obesity and insulin resistance. This award represents a significant encouragement to my research efforts and career.
In what direction do you see the future of diabetes research going?
Diabetes research in the future will focus on the genetics and molecular biology of insulin resistance and insulin secretion abnormalities in type 2 diabetes. It will also have a focus on the molecular mechanisms linking obesity, insulin resistance and cardiovascular disease. Discovering new drugs for the prevention of diabetes would be another important direction for diabetes research.
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