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Research at Mass General
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. The fundamental questions our laboratory is addressing are:
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.
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.
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, Joel 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.
Melissa Thomas is working toward promoting beta cell growth and regeneration in vivo and in cell culture. 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.
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. 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.
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.
Diabetes Research Center
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