Puigserver, Pere , PhD
New components of the insulin signaling pathway and metabolic action: implications for diabetes
General Research Subject: Type 2 Diabetes
Focus: Insulin Action, Insulin Action\Metabolism, Insulin Action\Signal Transduction, Integrated Physiology, Integrated Physiology\Insulin Resistance
Type of Grant: Mentor Based Postdoctoral Fellowship
Project Start Date: July 1, 2012
Project End Date: June 30, 2016
One of the main causes of the clinical manifestations of type 2 diabetes is insulin resistance or the inability of insulin to accomplish metabolic function in response to ingestion of meals. For example, insulin resistance in diabetic patients leads to lower rates of glucose clearance after eating and inability to suppress production of glucose in fed and fasting conditions. Thus, because insulin does not work properly controlling these metabolic processes, blood glucose levels are elevated resulting in hyperglycemia, a main driver of the disease of type 2 diabetes.
In this context, our laboratory has recently identified a new gene that encodes for a kinase --group of proteins that transmit the insulin signal in tissues- termed Clk2 which activity is increased in response to insulin levels after a meal. Increases of Clk2 activity mimic the action of insulin in the liver and is able to suppress production of glucose and augment rates of glucose --derived from the meal- to fatty acids, a process called lipogenesis. Importantly, Clk2 activity is lower in mouse models of insulin resistance. In this application, we propose a series of four interrelated projects focused to understand (1) how Clk2 is controlled in response to insulin and why its activity decreases in insulin resistance and diabetic states; (2) Clk2 function mediating insulin action/resistance in skeletal muscle; (3) adipose tissue and (4) liver. The outcomes of this grant application will identify Clk2 as a potential drug target to treat diabetic patients.
Mentor:Pere Puigserver, PhD Postdoctoral Fellow:Mitsuhisa Tabata, 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?
Defects in the activation of components of the insulin signaling/transcriptional cascade (causing insulin resistance) play a crucial role in the pathology of type 2 diabetes. In fact, insulin resistance causes hyperglycemia and lipid dysregulation in diabetic patients. The overall objective of this grant is to determine how defects in a specific component of the insulin signaling pathway, a kinase called Clk2, contributes to insulin metabolic action and progression of diabetes. This research is based on initial work from our laboratory in which we identified Clk2 as a downstream component of insulin signaling linked to transcriptional control of glucose and lipid metabolic genes. Using biochemical and genetic approaches in mouse models of obesity/diabetes we will investigate the role of this kinase in insulin metabolic action and diabetes. Since Clk2 is an enzyme with kinase activity, we propose that drugs that modulate kinase activity could be potentially used to treat type 2 diabetes.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
The outcomes of these studies will provide important new insights into the treatment of diabetes. Critically, these insights into the regulation of Clk2 during progression of diabetes will be the basis for the development of drugs that specifically target the kinase activity of Clk2. Importantly, this ADA mentor-based fellowship award will train young scientists in the field of diabetes and make sure they remain in diabetes research in their career.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Type 2 diabetes is a current epidemic in the US and worldwide. This is due, at least in part, to increases of obesity that is a very high risk for type 2 diabetes. Progression of diabetes is a leading cause of several pathologies including renal diseases and non-traumatic loss of limb. Although important components of the insulin pathway have been identified and are defective in type 2 diabetes, there is an important lack of therapeutic targets within this pathway that could be used to treat diabetic patients. Thus, the necessity to identify new targets and drugs to treat diabetes becomes an important personal reason to focus our efforts in diabetes research. This ADA mentor-based fellowship award will support a postdoctoral fellow who will focus his/her efforts to identify new targets that reinstall insulin sensitivity in diabetes.
In what direction do you see the future of diabetes research going?
In my view there are two areas in which future diabetes research should maintain the effort: 1) One of the major factors that contributes to hyperglycemia is uncontrolled hepatic glucose output, but there is a lack of specific drugs that target specific components and/or regulators of this pathway. 2) Obesity, a bioenergetic disorder, is a major risk factor for type 2 diabetes. Therefore, identification of druggable targets that increase energy expenditure could be used to increase insulin sensitivity in obese/diabetic patients.
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