Kratz, Mario , PhD
Inflammatory dendritic cells in adipose tissue inflammation and insulin resistance
General Research Subject: Obesity
Focus: Obesity, Integrated Physiology\Insulin Resistance, Insulin Action\Insulin Resistance
Type of Grant: Clinical Translational Research
Project Start Date: July 1, 2009
Project End Date: June 30, 2012
Recent studies in mice have shown that insulin resistance, glucose intolerance, and type II diabetes are the result of an inflammation in fat tissue. In obese mice, preventing inflammation of fat tissue was found to prevent type II diabetes, suggesting that it is not excess body fat mass per se but the inflammation of this fat that causes metabolic disease in obese individuals.
Few studies have as yet looked at the relationship between fat tissue inflammation and metabolic health in humans. We have performed two pilot studies in normal weight and obese men and women, and have identified new types of cells in fat tissue. One of resembles so-called 'inflammatory dendritic cell' which have been identified in other tissues, e.g. chronically inflamed skin in patients with psoriasis. Therefore, we think that the cells we have identified in fat tissue may play a role in the inflammation of fat tissue and the development of type II diabetes in obese individuals.
To test this hypothesis, we will collect intra-abdominal and subcutaneous fat tissue from very obese as well as leaner individuals undergoing surgery. We will measure whether the cells we found in fat tissue do in fact contribute to inflammation. We will also test whether higher numbers of these cells are present in the fat of obese people and people with metabolic disease such as insulin resistance. Understanding how fat inflammation is related to insulin resistance might help us find new strategies to prevent or treat type II diabetes.
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?
We will be studying the mechanisms by which obesity is linked to insulin resistance and type 2 diabetes mellitus. In healthy individuals, insulin promotes the uptake of glucose (sugar) from the blood into the cells of the body. It is well known that most obese individuals are insulin resistant to some degree, i.e. the insulin is not as effective in mediating this uptake of sugar into cells. What is not as well understood is how being obese leads to insulin resistance, and why some obese people are insulin resistant while others are not.
One hypothesis is that in some people, fat tissue all over the body gets inflamed, a process we call 'adipose tissue inflammation'. Adipose tissue inflammation refers to the fact that the fat tissue contains not only the cells that usually make up this tissue (fat cells, blood vessels etc.), but also a large number of immune cells that are activated and seem to act as if they were fighting an infection. It is believed that this adipose tissue inflammation might be what ultimately causes the insulin resistance in obesity. The main goal of this project is to characterize the immune cells present in the fat tissues of normal weight, obese, and morbidly obese individuals, and to establish laboratory methods that will allow us to study why these cells are present in adipose tissue.
In order to effectively treat, prevent, or even cure a disease, we need to understand the disease mechanisms well. Experiments in mouse models of obesity suggest that obese mice without adipose tissue inflammation are insulin sensitive and are not prone to developing type 2 diabetes mellitus. It will therefore be important to study if adipose tissue inflammation is similarly important in humans, and which factors are involved in causing the infiltration of immune cells into fat tissue.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?
It has been only relatively recently discovered that large numbers of immune cells are present in the fat tissue of insulin resistant individuals. The vast majority of this work has been done in mouse models of obesity. Thus far, we know very little about whether or not these findings apply to humans. Our project is one of the first to study adipose tissue inflammation in men and women who are lean, obese, or morbidly obese, ranging in metabolic health from insulin sensitive to insulin resistant, and from glucose tolerant to diabetic. Learning more about the link between obesity and type 2 diabetes mellitus is of crucial importance to enable us and other researchers around the world to devise new prevention and treatment strategies, for example by testing new drugs that are more effective or have fewer side effects.
Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?
As many others, I have witnessed the numerous long-term health consequences this condition can have in several friends and family members. While it is always challenging to face a severe sickness or death of a loved-one, I find it particularly frustrating in the face of the fact that I strongly believe that type 2 diabetes could be completely prevented in the majority of cases. Already, we do know that preventing body weight gain is tremendously effective in lowering the risk of diabetes. However, the worldwide epidemic of obesity shows clearly that it is a challenge for many individuals to sustain a healthy body weight in an environment often characterized by a lack of physical activity and a ubiquitous availability of highly palatable, energy dense foods. As we see a dramatic rise in obesity not just among adults, but even children and teenagers, it will become critical to understand the mechanisms by which obesity leads to associated diseases such as type 2 diabetes.
Over the last year, we have completed two small pilot studies on the relationship between adipose tissue inflammation and insulin resistance in lean and obese men and women, with very promising results. This award by the American Diabetes Association will enable us to continue and expand this work immediately.
In what direction do you see the future of diabetes research going?
I can see two parallel developments. One is what is often referred to as 'individualized medicine', i.e. a treatment strategy that is tailored to an individual patient based on his or her genes and environmental exposures. While we are clearly not there yet, I believe that new high-throughput methods and dramatic reductions in the costs of technology in the research laboratory will enable us to move in that direction. Nevertheless, such therapies will be expensive, and I therefore strongly believe that preventive strategies for the major diseases such as diabetes mellitus will be urgently needed as well. Such preventive measures could be implemented on a population level, and would be associated with improvements in the health and well being of a large number of individuals, as well as potentially dramatic cost savings for our health care system. It is our belief that this project funded by the American Diabetes Association will make a long-term contribution to improve our approaches in both the treatment and prevention of type 2 diabetes.
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