Hoehn, Kyle , Ph.D.
The role of the mitochondrial permeability transition pore in insulin resistance
General Research Subject: Insulin Resistance Pre Diabetes
Focus: Insulin Action\Insulin Resistance, Insulin Action\Signal Transduction, Insulin Action\Transgenic Models
Type of Grant: Junior Faculty
Project Start Date: January 1, 2011
Project End Date: December 31, 2013
Type 2 diabetes (T2D) is a metabolic disease characterized by poor removal of sugar from the blood. High blood sugar causes a number of problems that can lead to limb amputations, blindness, and cardiovascular disease. Risk factors for T2D include poor diet, physical inactivity, obesity, stress, and inflammation. These pathological insults antagonize insulin's ability to reduce blood sugar levels. Current treatments for diabetics improve insulin action and increase lifespan but do not effectively reverse diabetes. New treatment options are needed. A major barrier to the development of new treatments is that we still do not understand what changes cause the body to stop responding to insulin (aka insulin resistance).
This project has identified a new target linked to the development of insulin resistance. This target is a mitochondrial protein that when inhibited protects against the development of insulin resistance in cultured muscle cells and mice. The goal of this study is to investigate the role of this new target in insulin action and insulin resistance. Our rationale is that it will provide new molecular insight into how insulin resistance and diabetes develop and will reveal new avenues for the prevention and treatment of T2D.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
This project investigates the origin of type 2 diabetes. Aging, obesity, and inflammation are well known risk factors for diabetes, however it is unclear how these diverse physiological conditions drive the disease at the cellular and molecular levels. We have recently identified that all of these insults share a common dysfunction that is linked to oxidative stress and altered regulation of a mitochondrial pore. Using pharmacology and mouse genetics to block pore opening we can improve insulin sensitivity in cultured cells and mice. This work advances our understanding of diabetes etiology and we hope that targeting this pore will be an effective new strategy for the prevention and treatment of type 2 diabetes in humans.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
The most widely prescribed anti-diabetes treatments including metformin and rosiglitazone were not developed through rational drug design and their mechanism of action is still debated. Although these and other anti-diabetes treatments extend diabetic patient lifespan, they do not reverse the disease nor are they a cure for type 2 diabetes. Our work has recently identified a mitochondrial pore as a new druggable target. Inhibition of this pore, either alone or in combination with current anti-diabetes drugs, will hopefully provide new treatment options for type 2 diabetes in humans.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Diabetes can lead to horrible co-morbidities including blindness, limb amputations, kidney disease, and stroke. I sympathize with the diabetic condition because, like many Americans, I have family and friends that are struggling with type 2 diabetes. Therefore it is very important for me to be involved in diabetes research. The ADA Junior Faculty Award will make a huge difference for my research team and allow us to aggressively investigate new avenues for diabetes treatment and prevention.
In what direction do you see the future of diabetes research going?
The future of diabetes research must include a better understanding of how the disease originates and how altered glucose and fat metabolism affects whole body physiology. The former will require a critical assessment of cellular and molecular mechanisms of insulin resistance and the latter can only be achieved by systems biology assessments of insulin-sensitive tissues under both normal and diseased conditions. These fields are starting to come together to generate a global picture of diabetes at the molecular, cellular, and physiological levels and in the near future we will be in a better position to rationally develop new approaches for the treatment of this disease.
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