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The primary cause of Type 2 diabetes is insulin resistance, the loss of the ability to respond normally to insulin, followed by the gradual destruction of the insulin secreting beta cells. Predisposition to diabetes is inherited and it is much more likely to occur in those who are obese but there is much more to be learned about this disease.

What are the genetic foundations of insulin resistance? Why is glucose so toxic to beta cells and what are the mechanisms involved in beta cell destruction? What are the limitations of the beta cell regenerative capacity? Why does obesity cause insulin resistance?

 
 

A better understanding of these factors and how they interact over time to cause beta cell failure and permanent diabetes will lead to novel prevention strategies and new treatments. Present treatments for type 2 diabetes remain unsatisfactory for a variety of reasons, and as the incidence of this disease continues to rise, concomitant with the prevalence of obesity, improved therapy is greatly needed.

The Genetics of Diabetes
Today, scientists know little more than that there is an inherited component to the risk of getting diabetes and on the subsequent development of complications. It appears that diabetes is caused by the combined action of many weakly acting genetic causes. Clearly, variations in these genes must explain the predisposition to diabetes but the identification of the predisposing genes has, until now, been an insurmountable challenge.

The Human Genome Project has provided a basic map of over 90% of the DNA comprising human chromosomes. This map enables scientists to better understand the genetic basis for our differences. In most cases, very few differences are found when comparing the same gene between two different individuals. When there are differences, they tend to affect only one or a few of the basic building blocks of genes, called nucleotides. Nevertheless, since we have so many genes, these few differences per gene add up to many thousands of variations in total.

Dr. David Altshuler, one of the world leaders in the quest to identify all of the common variations in genes, has amassed a huge number of these gene variations. Taking a genomic approach, he will compare the spectrum of these variants in very large numbers of individuals for which substantial medical information is available. From this, he will determine which genes are critical for the development of diabetes and its complications.

This information, alone, cannot tell us much about the role of individual genes. However, new technologies (such as DNA chips) can be used determine where and when specific genes are expressed. Sophisticated computers analysis (bioinformatics) makes it possible to examine biological data on a large scale and to gather information about the specific changes that underlie the vast genetic diversity of the human population. With this information, coupled with the knowledge of the susceptibility or resistance to disease of many individuals, it will be possible to make specific predictions about how complex gene combinations, called genotypes, are related to health or disease. At the heart of this program is an understanding, not only of what goes wrong in disease, but also of the capacity of the human gene pool to withstand and avoid disease.

This genetic analysis is based on statistics, comparing the variations present in individuals' genes with the presence or absence of metabolic conditions such as diabetes. Only now can this be applied on a genome-wide level and across an entire population. Yet, similar analyses of candidate genes in large families have allowed scientists to make educated guesses about which particular genes might predispose some individuals to diabetes. By forming and testing hypotheses in this way, Dr. Habener's laboratory recently linked some cases of type 2 diabetes to mutations in the regulatory gene, IDX-1. Functional analysis of this gene demonstrated that it plays a role in beta cell development and insulin gene activation. A genomic approach will yield information on many more genes that are linked to diabetes, which will require subsequent functional analysis similar to that which Dr. Habener's laboratory has done for IDX-1. Many of these genes will undoubtedly play a role in the production of or the response to insulin.

Once we know how the combination of individual genes relates to disease, we will know who is at risk and we can advise those individuals on disease prevention. We will know who is likely to succumb to complications of diabetes and thus who needs to pay extra special attention to controlling blood sugar levels. We would like to use genetics to predict drug response, and target medications to those who will benefit most. By completing the full loop - from the patient, to the genotype, and then back to the patient - will we develop insights of direct benefit to the patient.

Promoting beta cell growth and regeneration in vivo and in cell culture
Once the individual genes that regulate beta cell development, insulin production, and the response to insulin are identified and their function understood, it will be possible to design drugs to target and manipulate them. Only then will it be possible to restore insulin production, the number of insulin producing cells, and insulin sensitivity in diabetic patients, enabling their bodies to respond to and tightly control blood sugar levels in the same way as a healthy person.

Dr. Melissa Thomas is working towards this goal. She studies the regulation of the insulin gene and of additional genes important for forming new beta cells and has recently discovered a novel co-activator of the insulin gene, Bridge-1, that may function to boost insulin production in beta cells in the pancreas. She has identified new functions for signaling by Hedgehog proteins, which were previously known to be important regulators in development, demonstrating that they regulate production both of insulin and of IDX-1, a master regulator of beta cell development. Understanding how these regulatory proteins control insulin gene activity and the development of new beta cells is critical for designing new drugs to activate insulin production in response to rising blood sugar levels.

Dr. Thomas also characterizes functional defects in pancreatic beta cells in transgenic mouse models that mimic diabetes in humans. By examining altered patterns of gene expression in animal models of diabetes, she is working to identify important signals that lead to beta cell failure with the goal of restoring beta cell function in patients with diabetes.

How do "diabetes" genes act to cause insulin resistance and cell failure?
A great deal of information is available describing the regulation of energy metabolism in man, and the ways in which nutrient utilization is disturbed in the setting of insulin deficiency, prediabetic insulin resistance, and obesity. The two primary sources of energy in the body are carbohydrate (glucose) and fat; sources that are available at all times circulating in the blood stream. After a meal, any calories not immediately needed for energy are removed from the blood stream and stored, ready to be summoned for utilization during the interval between meals. The ability to store carbohydrate is limited, and heavily dependent on effective insulin action, whereas the capacity for fat storage is unlimited.

Individuals with diabetes often have increased or decreased sensitivity to the effects of insulin, particularly uptake and utilization of glucose by muscle and fat. In individuals with type 1 diabetes, heightened insulin sensitivity can lead to poor control of their disease and low blood sugar. In those with type 2 diabetes, decreased sensitivity ("insulin resistance") frequently contributes not only to the development of diabetes itself, but may also contribute to the development of diabetic complications. It is therefore important to understand how insulin acts at the cellular and molecular level, and to learn how this action is altered in diabetics. Only with such an understanding can we know exactly how to intervene, with the goal of reversing the course of the disease or preventing it entirely.

Dr. Joseph Avruch has devoted his career to understanding the molecular components of the signaling cascade necessary for an effective insulin response within the cell. Binding of insulin to its receptor initiates a series of interactions among proteins and other molecules present within cells. These interactions convey the information that insulin is present. Muscle and fat cells respond to this information in several ways: by absorbing glucose and fat from the blood and storing them, by growing or dividing, and by secreting other hormones involved in controlling metabolism. Pancreatic beta cells also require many of these effects of insulin for optimal development and function of the pancreatic beta cell.

Dr. Bogan is studying the mechanism by which muscle and fat cells to absorb glucose from the blood. After insulin stimulation, these cells move specialized glucose transporting proteins to their surfaces. These glucose transporting proteins allow glucose to enter the cell from the bloodstream, and to be metabolized or stored by the cells. Previous research to determine what specific proteins convey the insulin signal to cause movement of the glucose transporting proteins has employed conventional biochemical techniques, based on binding of one protein to another. This approach has resulted in some understanding of how insulin causes glucose utilization. However, it is sometimes difficult to identify the next protein in the cascade downstream of the insulin receptor. Another difficulty is that even once a new protein is identified, it may turn out to be involved in one of insulin's many actions other than glucose uptake.

Dr. Bogan has developed a completely new method to study movement of glucose transporting proteins to and from the cell surface, and to specifically identify proteins involved in insulin-stimulated glucose uptake and utilization. The power of this method is that it identifies proteins based on their function, rather than by relying on conventional protein interaction techniques. With this new technology, he has already discovered two new proteins that elucidate previously unidentified and unexpected mechanism through which the glucose transporting proteins function.

Further application of this new technology will identify many additional proteins involved in insulin's ability to stimulate glucose utilization, and will greatly accelerate our understanding of this important process and will identify potential targets for new drugs which could modulate the sensitivity/resistance to insulin.

How does expanded adipose tissue cause insulin resistance?
In type 2 diabetes, the failure of insulin to regulate fatty acid release from fat cells results in elevated levels of circulating fat in the blood stream. In addition, the concentration of circulating fat is directly related to amount of fat tissue and, as the levels of circulating fat increase, glucose utilization is diminished.

The combination of these two factors is significant since the overwhelming majority of those with type 2 diabetes are overweight or obese. Furthermore, at least partly because glucose uptake into cells is impaired in diabetes, fat metabolism is both increased and abnormal. For example, when fat is the sole energy source, toxic metabolites known as ketone bodies are produced when fat is utilized for energy. In addition, the liver reacts to the high levels of circulating fat by converting excessive amounts of it to cholesterol.

Dr. Tod Gulick's work is focused on learning how fat metabolism is normally regulated and determining strategies to restore it to normal in diabetes. In particular he is focusing on the mechanism by which fat is either converted to energy or stored. That this mechanism may have gone awry in individuals with diabetes is highlighted by the fact that several currently used drugs for type 2 diabetes interact with proteins controlling the fate of fat absorbed from the blood.
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