Diabetes is not one disease, but several. In each type of diabetes a different pathophysiology leads to the high glucose. In the most common form, non-insulin dependent diabetes mellitus (NIDDM), individuals often produce an adequate amount of insulin--the hormone that directs glucose metabolism--but their tissues are less responsive to insulin's actions. Conversely, in insulin-dependent diabetes (IDDM), individuals lose their ability to produce insulin at a young age and subsequently lose control of their blood-sugar levels.

   Doctors have been able to treat diabetes with insulin and with medicines that increase insulin secretion or potentiate its effect. Because of the variety of genetic and environmental factors that are thought to be responsible, however, they have not been able to cure diabetes nor to predict easily who is at risk. Although many clinicians are studying diabetes, a surprising number of powerful discoveries have emerged from the laboratory of Howard Hughes Medical Institute (HHMI) Investigator Graeme Bell, who is not a physician but instead holds a doctorate in biochemistry and biophysics. Bell's focus on the genetics of diabetes, along with occasional forays into related aspects of neurobiology (see the table on page 4), have yielded over 300 publications. He chose to concentrate on families with a high incidence of diabetes, seeking to delineate which genetic defects are responsible for high blood sugar and how genetic markers may predict the development of high blood sugar, as well as an individual's response to treatment.

   Born in Canada, Bell was initially educated at the University of Calgary, where he earned his bachelor's degree in 1968 and a master of science degree in 1971. After moving from Canada to California, Bell spent six years at the University of California, San Francisco (UCSF), where he received his Ph.D. in Biochemistry in 1977. Over the following years he rose to Assistant Adjunct Professor in the Department of Biochemistry and Biophysics and also worked as a senior scientist for the Chiron Corporation. In 1986 Bell moved to the University of Chicago to become an Associate Professor in Biochemistry and Molecular Biology and an Associate Investigator with the HHMI. His appointment was broadened and elevated in the following years as he reached full professorship and HHMI Investigator status in 1990. In 1994 Bell was named Louis Block Professor in the Departments of Biochemistry & Molecular Biology, Medicine and Human Genetics at the University of Chicago. He currently directs a laboratory with nearly a dozen post-doctoral fellows.

  How did your work gravitate towards diabetes?

   Bell: It started at UCSF following our cloning of the human insulin cDNA and gene in the late 70s and early 80s. The question I asked was, "Could some cases of diabetes be due to mutations or polymorphism in the insulin gene?" I met John Karam, a clinician who is still at UCSF, and we started working together on this problem. John taught me about diabetes and provided patient samples for our studies. This was the beginning, and my interest in diabetes has continued to grow. When I moved to Chiron, I dabbled with diabetes-related problems, although the work didn't follow in a systematic way. My research in this area really took off when I moved to the University of Chicago, because of the large number of investigator here who are studying various aspects of diabetes. Our initial studies focused on candidate genes, including the insulin receptor and glucose transporters.
   We also began genetic studies of families with diabetes, initially in collaboration with Steve Fajans of the University of Michigan, who for many years had been studying a family with an autosomal dominant form of diabetes that he called Maturity-Onset Diabetes of the Young (MODY). We were able to localize the gene responsible for diabetes in this family to chromosome 20, and did so in August of 1990. It took us another six years before we identified this diabetes gene as the liver-enriched transcription factor, hepatocyte nuclear factor 4a. We now know that diabetes can result from mutations not only in this transcription factor but also in other transcription factors expressed in the insulin-secreting pancreatic b-cells as well as the glycolytic enzyme glucokinase.
   More recently we have begun to search for the genes that contribute to the development of NIDDM and IDDM. With regard to NIDDM, our working hypothesis has been that a comparatively small number of major genes underlie diabetes. This has been confirmed in Mexican Americans, a population in which our studies have localized the major gene responsible for NIDDM in this population to the distal end of the long arm of chromosome 2. This particular gene, which we call NIDDM1, plays a less-important role in other racial and ethnic groups. We suspect, although we haven't proved it yet, that there will be other major genes in other groups. By studying the genetics of diabetes in different populations, we hope to be able to identify all the genes that contribute to the development of diabetes.

  Do you think that knowledge of the genetics of diabetes will lead to new treatments?

   Bell: I'm hopeful that this will be the case. I believe that one day physicians will be able to tailor their treatment of diabetes depending on the nature of the underlying molecular defect, or defects. I also believe that the information gained from genetic studies of diabetes will indicate key pathways involved in the control of blood glucose levels, and that this will lead to the development of new drugs for treating this disease. Finally, the most common forms of diabetes involve both genetic and poorly understood environmental factors. If we understand the genetic factors involved, this will allow us to begin to search for the important environmental or lifestyle factors that convert genetic risk to overt disease. Susceptible individuals may then be able to modify their lifestyle accordingly and thereby reduce their risk of developing diabetes in much the same manner that reducing cholesterol levels reduces the risk of heart disease.

  Which types of diabetes do you think can be curtailed by identifying and modifying environmental or lifestyle factors?

   Bell: I believe that the prevalence of the two most common forms of the disease, insulin-dependent and non-insulin-dependent, which together account for more than 95% of all cases, could be reduced if we had a better understanding of the environmental and lifestyle factors that contribute to the development of diabetes in genetically susceptible individuals.
   We're not interested in curing diabetes, because "curing" implies that someone has the disease already. Our goal is eventually to prevent diabetes from developing in the first place. That's what we're striving for. continued