News & Research

    Penn State College of Medicine, Hershey, Pennsylvania

Diabetes, stroke and the blood-brain barrier

General Research Subject: Type 2 Diabetes

Focus: Clinical Therapeutics/New Technology\Pharmacologic Treatment of Diabetes or its Complications, Immunology, Signal Transduction (Non-Insulin Action)\Cytokines and Apoptosis

Type of Grant: Basic Science

Project Start Date: January 1, 2011

Project End Date: December 31, 2013

Diabetes Type: Type 2 diabetes

Research Description

The overall objective of this proposal is to determine the role peripheral leukocytes play in the impaired stroke recovery observed in the diabetic db/db mouse as compared to its non-diabetic db/+ littermate.  To date, an estimated 20 million Americans live with Type II diabetes and an additional 54 million with pre-Type II diabetes are yet to be diagnosed.  This is alarming, considering diabetes is an independent risk factor for stroke and the diabetic population has a 2-4 times higher risk of experiencing stroke and a 2.8 fold greater risk of mortality.  Stroke is the third leading cause of death and the leading cause of disability in the United States, thus a dramatic increase is predicted within the next 25 years. A common denominator in an array of diabetic complications including wound healing, retinopathy, nephropathy, and stroke recovery is a compromised leukocyte-mediated immune response. Preliminary studies suggest that the blood-brain barrier (BBB) which regulates contact between the circulation and the brain is more readily breached following stroke in the diabetic (db/db) mouse compared to its non-diabetic (db/+) littermate resulting in a more deleterious outcome. This study will determine whether or not the BBB breakdown results from the release of the proteinase MMP-9 that degrades the BBB; if this is due to the excessive adherence of neutrophils and/or macrophages to the BBB in the diabetic brain following stroke, and whether reagents that either inhibit leukocyte adherence or block MMP-9 activity will block the BBB breakdown and improve stroke recovery.

Research Profile

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

The focus of this project is to investigate why the diabetic patient has a poorer prognosis following a stroke than the general population. There are an estimated 21 million Americans living with diabetes, of which 90-95% have Type II diabetes, and an additional 54 million with pre-Type II diabetes yet to be diagnosed. This is alarming, as it is well-established that the diabetic population has a 2 to 4 times greater risk of experiencing ischemic stroke and 2.8 times greater risk of mortality compared to the non-diabetic patient. Stroke is the third leading cause of death and the major cause of disability in the United States and the occurrence of strokes, which stands at 5.2 million annually in the United States, is predicted to increase dramatically within the next 25 years as the numbers of diabetic patients increase. Currently, the only available treatment to improve stroke outcome uses a recombinant tissue plasminogen activator (TPA) to reinstate reperfusion, however, the drug must be administered within a three-hour window and there is growing evidence that suggests diabetic patients do not benefit from this treatment. Our preliminary data suggests that the blood-brain barrier (BBB), which protects the brain from harmful agents in the circulation, is more susceptible to being breached in the diabetic patient following a stroke. This breakdown in the barrier results in circulating cells gaining access to brain and causing greater cell death and consequent loss of faculties and further delay in recovery. The objectives of this proposal are determine the underlying mechanism(s) that lead to the breakdown of the BBB and the increased susceptibility of the diabetic and to evaluate various agents that will prevent breakdown and promote recovery.

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

The first part of my response would be to reiterate the statistics presented above and I would particularly emphasize the increased mortality and morbidity that is experienced by the diabetic patient following a stroke. Our understanding of the link between atherosclerosis and the increased frequency of heart attacks and strokes in the diabetic population is fairly well established and thus most diabetics in the Western world receive a standard cocktail of drugs, which in addition to lowering blood glucose levels, also reduces blood pressure and LDL levels. However, essentially nothing is known that explains why diabetes exacerbates the recovery from stroke and consequently no specific treatments have been identified that are tailored to promote stroke recovery in the diabetic patient. The objectives of this proposal are to determine what specific elements of the diabetic condition are responsible for causing the increased cell damage and slower recovery seen in the diabetic brain following a stroke. Then, having identified these elements, we intend to develop interventions that will reverse these conditions and promote a more rapid and complete recovery. Gaining insights into the deleterious actions of diabetes will also provide invaluable information into the mechanism(s) of cell loss that occur following a stroke and the responses that are triggered to promote healing and recovery. Thus in the event that the patient might experience a stroke, we may be able to intercede with a treatment that lessen the extent of the disabilities that are incurred and speeds up a return to normal life.

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 been engaged in diabetes research since arriving in the USA in December of 1979 as a Post Doctoral fellow in the Diabetes Branch of NIDDK, NIH. Over this time I have been fortunate to receive support from the ADA on several occasions. They have supported Mentor -based fellowships and the fellows they have supported continue to be involved in scientific research. Indeed, my last fellow, Dr Kumari continues to work with me and will be actively engaged in the current proposal. ADA support also enabled me to undergo my successful transition into stroke research and to obtained the necessary preliminary data to obtain my current NIDDK support. The current proposal represents a change in focus from the major thrust of the lab and we hope that, if successful, it to will lead to increased NIH funding to continue this line of research. Regarding my personal motivation for engaging in diabetes research and the reason I started my career at the NIH was pure coincidence. The physician who diagnosed the onset of my Type I diabetes in 1977 was Dr Harry Keen, an outstanding British diabetologist. He had 'friends' doing research in the USA and thought that diabetes research was about to take off and that my career would benefit from a USA experience. How right he was -the two year fellowship has lasted 30 years and although the focus of my research has changed from insulin action to studying the complication of diabetes, my enthusiasm remains the same and given the dramatic increase in the numbers of diabetics world-wide, the need for research is ever more relevant.

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

Things are moving so quickly in the field of Type I diabetes, that it is difficult to predict what constitutes the future, however, the potential for the development of inoculations to prevent some forms of Type 1 is now viable and exciting possibility. I do anticipate that the closed loop system for regulated insulin delivery will become a practical reality within the next 5 years but its utility in managing glucose homeostasis in children will remain questionable. The future for the artificial pancreatic beta cell seems less clear than five years ago. With respect to Type II diabetes, an appreciation of the role(s) the CNS gut interactions play with their array of hormones and neuropeptides play in overall energy metabolism, food intake, obesity and satiety will become of increasing interest and importance, particularly with the increase in the many gastric bypass variations that are evolving. One thing that is not going away for either Type I &II patients are the complications, which although lessened by tighter control still contribute dramatically to loss of sight, limbs and kidneys and represent a contributing factor to heart attacks and strokes that beset the diabetic patient. A common denominator that interrelates all the diabetic complications would appear to be a compromised immune response. The ability to treat these complications in future will require that we intercede in the underlying alterations in the diabetic inflammatory system that cause the release of cytotoxic cytokines and proteases that  in turn promote the inappropriate inflammatory cell interactions within the respective tissues.