News & Research

Michigan State University Ann Arbor, Michigan

New therapeutic targets in diabetic neuropathy

General Research Subject: Both Type 1 And Type 2 Diabetes

Focus: Clinical Therapeutics/New Technology\Pharmacologic Treatment of Diabetes or its Complications, Complications\Neuropathy, Obesity\Animal Models

Type of Grant: Basic Science

Project Start Date: January 1, 2009

Project End Date: June 30, 2012

Research Description

Funded by the Order of the Amaranth

The cells that line blood vessels are first in line for injury when blood glucose and oxidized LDL increase in diabetic patients.  Injury to these cells causes broader damage to the tissue the blood vessels are feeding by leaking and by decreasing the availability of oxygen.  This proposal aims to define the mechanisms of injury to the blood vessel cells and to explore the potential for fenofibrate to block these mechanisms.  Increased glucose overloads the energy-producing component of a cell, the mitochondria.  As mitochondrial function decreases, a state known as oxidative stress occurs.  Enzyme systems are activated to protect the mitochondria including NAD(P)H oxidase that attempts to remove the load on the mitochondria.  Oxidized LDL also activate NAD(P)H oxidase.  These injuries will be defined in cultured blood vessel cells and in diabetic mice.  Fenofibrate is used in type 2 diabetes to correct poor blood lipids.  Recently, fenofibrate was found to produce a broader range of effects.  This proposal will test the hypothesis that fenofibrate will directly prevent oxidative stress and mitochondrial dysfunction as well as alleviate diabetes.  Understanding these mechanisms will permit improvement to therapies to prevent not only hyperglycemia, but also the complications of diabetes including neuropathy.

Reseacher Profile

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

I am interested in understanding the mechanisms that lead to sensory nerve injury in diabetic patients.  This type of nerve injury is the most common complication of diabetes and can lead to chronic pain, or to the need for limb amputation.  My project is designed to investigate how increased levels of glucose and/or blood lipids in diabetes cause injury to sensory nerves.  Both type 1 and type 2 diabetic patients experience high blood glucose, but the additional importance of blood lipids in diabetic nerve injury is becoming increasingly recognized.  Type 2 diabetes is commonly associated with increased blood lipids, but the incidence of type 1 patients with elevated blood lipids is increasing.  The project also will evaluate a potentially beneficial drug, fenofibrate.  Fenofibrate is already used clinically to improve blood lipid levels, but we contend that it may be more broadly applicable to directly prevent nerve injury in diabetic patients.  In this regard, if our hypothesis is correct, fenofibrate may be effective in both type 1 and type 2 diabetes to prevent sensory nerve damage.    

If a person with diabetes were to ask you how your project will help them in the future, how would you respond? 

As we dissect the mechanisms that lead to nerve injury in diabetes, we can better design therapeutic interventions.  This is critically important for diabetic nerve disease since this is the most common complication of diabetes, but there are no approved treatments other than tight glycemia control.  The studies also will help us to understand which patients are at risk for developing nerve disease and how they could prevent the progression by altering their diet or by using a new drug treatment.

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

The incidence of diabetes is growing at a significant rate and it is critically important to prevent complications to improve the quality of life for diabetic patients.  I have a broad experience of working in neurodegenerative diseases and the role of oxidative stress.  My preliminary work in diabetes has established that mechanisms leading to oxidative stress are the key to the development of complications.  My diabetes research efforts have grown from a side project assisting other researchers to a strong desire to build an independent research project in this area.  This is the result of compelling findings using the experimental systems available- microvascular endothelial cells, primary sensory neuron cultures, and mouse models of both type 1 and type 2 diabetes.  I believe we can both understand and treat diabetes complications and that this is a worthy research goal.  This award is the essential next step for me to begin to establish an independent research program.  It will establish my status as a researcher and will permit me to produce important data on mechanisms of nerve injury and protection.  I will gain insight into the use and validation of a mouse model of diabetic nerve disease and I intend to further establish methods for the assessment of nerve disease in these mice.

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

Diabetes research will remain an important field of endeavor, since our long-established knowledge of nutrition and exercise has not prevented the current diabetes epidemic.  We have demonstrated that oxidative stress is central to the development of complications, although an effective treatment is not yet determined.  In order to prevent or reverse complications, we need to further characterize the mechanisms that produce oxidative stress, as well as understand more fully the roles of oxidative stress in the susceptible cell types.  It is increasingly clear that single antioxidant therapy is ineffective because of the essential balance of regulatory systems.