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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.
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.
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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