Jack Youngren, Ph.D.
The first step in the progression towards development of type 2 diabetes mellitus occurs when a resistance to the effects of the hormone insulin develops in various tissues of the body. Dr. Youngren’s research is focused on exploring the causes underlying this initial derangement in the body’s ability to regulate blood sugar levels. Beyond its contribution to the progression toward diabetes, tissue insulin resistance is significant in that this condition also contributes to the development of the cluster of diseases that occur in diabetic and pre-diabetic individuals, such as high blood pressure and heart disease. Despite the serious health risks associated with insulin resistance, it exists in the absence of any overt symptoms and is therefore rarely if ever diagnosed.
Dr. Youngren’s work investigates the initial events that cause muscle cells to lose their ability to take up sugar from the blood in response to insulin. It is clear that lifestyle is a major contributor to these cellular changes, as obesity, diets high in fats and refined sugars, and physical inactivity all directly contribute to insulin resistance. In recent publications, Dr. Youngren has demonstrated that the first step in the cell’s response to insulin, the activation of the insulin receptor, is affected by dietary factors, regular physical exercise, and accumulation or loss of excess body fat.
Most recently, Dr. Youngren has been studying individuals with “invisible” insulin resistance, or those who are of normal weight and who have not yet progressed to symptomatic impairments in glucose tolerance, but who are nevertheless at risk for development of cardiovascular and metabolic diseases. This research has documented that even in these individuals of normal body weight, small differences in fat accumulation, particularly within the abdominal cavity and in muscle cells, contribute to their altered metabolic status. As with overweight individuals, fat accumulation in lean subjects can induce an inflammatory environment in the body that alter the normal biochemical process that control insulin action and glucose regulation.
The finding that even normal weight individuals are negatively affected by an accumulation of lipids within their muscle cells has fueled laboratory investigations into the impact of cellular lipids on normal biological function. Dr. Youngren’s group is studying the causes and consequences of lipid accumulation within muscle cells in order to determine the defects in fat metabolism that lead to lipid accumulation, and the mechanisms whereby intracellular lipids directly inhibit the insulin signaling pathway.
ho are resistant to insulin are at significant risk to progress to impaired glucose tolerance (which can be diagnosed by the elevations in blood glucose levels following meals) and, eventually, type 2 diabetes. Insulin resistance also contributes to the development of the cluster of diseases that occur in diabetic and pre-diabetic individuals, such as high blood pressure and heart disease. Recent evidence has also linked insulin resistance to the development of several forms of cancer and perhaps Alzheimer’s disease. Because insulin resistant subjects are at heightened risk for a variety of diseases, but are “invisible” in a clinical setting due to both the lack of symptoms and the poor understanding of the factors that contribute to this condition, I have focused my research on clarifying the initial events causing cells to lose their ability to respond to insulin and increase their uptake of sugar from the blood. A central question in my work has been to examine the role that our lifestyle plays in inducing these defects in cells, and the potential for changes in our lifestyle to reverse insulin resistance and prevent the development of type 2 diabetes.
Insulin resistance is related to two types of factors, genetic and lifestyle. While the genetic factors are not well understood, it is well known that obesity, diets high in fats and refined sugars, and physical inactivity all directly contribute to insulin resistance. Focusing on the first step in the cell’s response to insulin, the activation of the insulin receptor, I have demonstrated that the function of this cell surface protein is affected by dietary factors, regular physical exercise, and accumulation or loss of excess body fat.
Currently, I am contributing to a clinical study at UCSF that will test the ability of a regular exercise program to decrease the risk of diabetes and cardiovascular disease and reverse the insulin resistance in this “invisible, pre-diabetic” group of subjects.
In addition, work in my laboratory is currently underway to understand the mechanisms whereby obesity can lead to insulin resistance in muscle tissue. We have grown muscle cells from obese subjects in the laboratory to understand the changes that excess body fat can induce in muscle. We are also studying how an impaired ability to burn fats as a fuel source can develop with excess caloric intake, and how this may lead to an accumulation of fat within muscle and produce the insulin resistance seen in obese subjects. In these studies we are exploring new targets where drugs could increase the fat burning capacity of muscle, reduce fat production and improve insulin action.