Ahima, Rexford , MD, PhD
Role of IPMK in metformin-mediated metabolism
General Research Subject: Type 2 Diabetes
Focus: Integrated Physiology, Integrated Physiology\Insulin Resistance, Integrated Physiology\Liver, Signal Transduction (Non-Insulin Action), Signal Transduction (Non-Insulin Action)\Phosphatases-Kinases
Type of Grant: Basic Science
Project Start Date: July 1, 2013
Project End Date: June 30, 2016
Mammals have developed mechanisms to maximize the use of nutrients and store excess calories mainly in the form of fat. Obesity is characterized by excessive fat accumulation in adipose tissue, liver, muscle and other organs. This results in insulin resistance which predisposes to diabetes when the beta cells of the pancreas fail to produce enough insulin. Our preliminary studies show that an enzyme, inositol polyphosphate multikinase (IPMK), is involved in glucose sensing in cells. Importantly, IPMK activity in liver is associated with the action of metformin, one of the most popular drugs for treatment of type 2 diabetes. Metformin enhances insulin action in liver and decreases blood glucose; however, the underlying mechanisms are unclear. To elucidate the action of IPMK, we are proposing to specifically disrupt the enzyme in liver and examine how this affects glucose and lipid metabolism in mice fed a high-fat (Western diet). We will also investigate whether IPMK plays a critical role in the molecular actions of metformin. These studies will increase our knowledge of cellular metabolism, and lead to the development of new drugs for diabetes.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
My project covers the treatment of type 2 diabetes.
My project will investigate the molecular mechanisms underlying the effects of metformin on insulin action in liver and other organs. We will determine whether an enzyme IPMK mediates the insulin sensitizing action of metformin.
If a person with diabetes were to ask you how your project will help them in the future,
how would you respond?
Type 2 diabetes accounts for 95% of cases of diabetes. Although insulin resistance from obesity is a major contributing factor in type 2 diabetes, and metformin has been shown to improve insulin sensitivity, the molecular mechanisms are not well understood. The project will provide new insights into how metformin and related drugs act in the liver to improve insulin action, lower blood sugar, and prevent diabetes complications.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
I have several family members with diabetes, hence I am highly motivated to find new cures for the disease.
My current research funded by the National Institutes of Health is focused mainly on the actions of fat secreted hormones (adipokines) on feeding and metabolism. This award from the ADA will allow me to expand my research toward understanding the molecular mechanisms of diabetes, the most common disease associated with obesity.
In what direction do you see the future of diabetes research going?
The current classification of diabetes as type 1 or type 2 does not address the myriad molecular mechanisms involved in insulin production and secretion, and insulin action in the liver, muscle and fat. Future diabetes research will lead to a rational classification of various types of diabetes based on molecular defects, which could lead to better preventive and treatment strategies.
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