Basaraba, Randall , Ph.D.
Pathogenesis of tuberculosis in guinea pigs with diabetes mellitus
General Research Subject: Both Type 1 And Type 2 Diabetes
Focus: Clinical Therapeutics/New Technology\Pharmacologic Treatment of Diabetes or its Complications, Immunology, Obesity\Animal Models
Type of Grant: Basic Science
Project Start Date: January 1, 2011
Project End Date: December 31, 2013
Diabetes Type: Type 1 diabetes
People with diabetes mellitus (DM) are at higher risk of contracting tuberculosis (TB) than non-diabetics. Diabetics are at greater risk of dying due to poor responses to treatment of both TB and DM but the reason is unknown. The increasing concern over why TB is more severe in diabetics is that the poor treatment response threatens attempts to control the global spread of TB.
In order to understand why diabetics are more susceptible to TB, both diseases have to be created at the same time and studied in laboratory animals. Not all animals are suitable models of human DM and TB but guinea pigs (GPs) are the exception because experiment DM and TB in GPs resembles the diseases in humans. Both type 1 and type 2 DM will be created in GPs infected with Mycobacterium tuberculosis (Mtb), the bacterium that causes human TB. Our hypothesis is that TB is more severe in diabetics because both diseases result in the generation of excess oxygen free radicals that causes more severe tissue damage relative to non-diabetic animals.
Our research will: (1) validate the GP model of TB and type 1 and type 2 diabetes (2) measure free radicals in diabetic and non-diabetic GPs with TB (3) determine if antioxidant drugs reverse the tissue damage and improve the effectiveness of anti-bacterial drugs used to treat TB. This research will help us better understand the interaction between DB and TB so that better treatments for both TB and DM can be developed.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
It has been known for many years that patients with diabetes have a higher risk of becoming infected with a variety of bacteria including Mycobacterium tuberculosis, the causative agent of tuberculosis in people. Recent studies have confirmed that diabetics are more susceptible to M. tuberculosis infection compared to non-diabetics and that the incidence of these two diseases in the same patient is increasing at an alarming rate in many parts of the world. Tuberculosis in diabetic patients is a complex disease that not only complicates the ability to control blood glucose levels but lessens the response to treatment of tuberculosis. The reason patients with diabetes are more susceptible to tuberculosis and other bacteria and why these infections are more difficult to treat is unknown.
In order to develop more effective prevention and treatment strategies, experimental M. tuberculosis infections first have to be reproduced in animals with diabetes. The problem is that while mice and rats are the most widely accepted animal model of diabetes, they are a less desirable model for tuberculosis. Our research is aimed at developing the model of M. tuberculosis infection in diabetic guinea pigs which more closely resembles the naturally occurring disease in humans. Our research will be the first to establish tuberculosis in guinea pigs with either type 1 or type 2 diabetes. We will show that tuberculosis is more severe in diabetic compared to non-diabetic guinea pigs. Next we will determine if the increased severity of tuberculosis is due to a defect in the cellular immune response needed to control the infection. We will then use this new model to test a variety of novel treatment strategies designed to treat tuberculosis and diabetes concurrently.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
Our research will not only help us better understand the basic mechanisms of diabetes and tuberculosis but will enable us to better understand why diabetics are in general more susceptible to bacterial infections compared to non-diabetics. When new diseases or disease combinations like diabetes and tuberculosis emerge, it forces us to study the diseases using non-traditional models and methods. Studying diseases or disease combinations using new approaches often leads to discoveries that were not possible using traditional models. The new information that we gain from studying M. tuberculosis infection in diabetic guinea pigs will be directly applicable to the treatment and prevention of other bacterial infections that commonly complicate diabetes. Because some animals respond differently to M. tuberculosis infection compared humans, experimental infections may not accurately reflect the clinical disease that occurs in people.
By using animal models that more closely mimic the naturally occurring human disease, we will avoid costly mistakes or misleading results that can delay the discovery of urgently needed improvements in diagnosis, prevention and treatment. To further speed up the discovery of new treatments, our research focuses on the off label use of currently available drugs that can be combined to more effectively treat tuberculosis in patients with diabetes. By using drugs Food and Drug Administration (FDA) approved drugs, we will speed up the process of moving experimental treatments to clinical use in humans. At the same time, new, experimental treatments for future use can also be tested in our new animal model.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
Diabetes is an extremely important disease in that it is responsible for the chronic illness and death of millions of people every year. Diabetes is not limited to developed countries like the United States but affects people of all socioeconomic backgrounds all over the world. The tragedy of diabetes in developing countries is that not only do patients often lack high quality health care necessary to assist them in the diagnosis and management of their diabetes but they are more likely to be exposed to deadly bacterial infections like tuberculosis. When this double burden of disease occurs in parts of the world where patients lack basic healthcare, a delay in the diagnosis and treatment of their infections can seriously threaten their chance for survival.
To become involved in diabetes research means that I personally have the opportunity to improve the treatment of millions of diabetic patients all over the world. It is our hope that results from these studies will have an immediate impact on the treatment of patients with diabetes and tuberculosis but more importantly, our approach can also be used by other scientists to accelerate the rate of new drug discovery in other laboratories. In addition, this award allows me to continue to support and train a team of undergraduate and graduate students that will become the next generation of research scientists. Collectively, this research will help us and other researchers gain a better understanding of basic disease mechanisms as well as improving the diagnosis, treatment and prevention of tuberculosis and other bacterial infections in diabetics which have the greatest impact in developing countries.
In what direction do you see the future of diabetes research going?
Bacterial and fungal infections account for many serious complications of many patients with diabetes. While it is important to control blood glucose levels and the adverse side effects of hyperglycemia, it is also important to prevent the infections that contribute to the complications of diabetes. The possibility exists that the current vaccines used to lessen the severity of bacterial infections like tuberculosis, especially in children, are less effective in patients with diabetes. I see the future of diabetes research aimed at developing novel vaccines that are specifically designed to prevent opportunistic infections in diabetic patients. The same strategy used to discover novel bacterial antigens that can be used as vaccines can also be applied to the development of improved diagnostic assays for complicating bacterial infections.
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