Molecular Genetics of Diabetes Mellitus 
Graeme I. Bell, Ph.D. — Investigator 
Dr. Bell is also Professor of Biochemistry and Molecular Biology, Medicine, and Genetics at the University 
of Chicago. He received his B.S. degree in zoology and M.S. degree in biology from the University of 
Calgary, Canada. He earned his Ph.D. degree in biochemistry and biophysics from the University of 
California, San Francisco, where he also did his postdoctoral research. Before moving to the University of 
Chicago, Dr. Bell served as Senior Scientist at the Chiron Corporation. Dr. Bell has received a number of 
awards for his work, including the Outstanding Scientific Achievement Award from the American Diabetes 
Association, the Rolf Luft Award from the Swedish Medical Society, and the Distinguished Alumni Award 
from the University of Calgary. 
DIABETES mellitus is a disorder of carbohy- 
drate metabolism characterized by elevated 
blood glucose levels. In the United States, an esti- 
mated 6 million persons are known to have dia- 
betes, and there are probably an equal number 
with unrecognized disease. About 10 percent of 
persons over age 65 have diabetes, and the com- 
plications of the cardiovascular, kidney, visual, 
and nervous systems are major causes of morbid- 
ity and mortality. 
Clinically diabetes is a heterogeneous dis- 
order. One form, insulin-dependent diabetes 
mellitus, primarily affects children and adoles- 
cents. It results from immunological destruction 
of the insulin-producing cells of the pancreas; 
because of the absolute deficiency of insulin, pa- 
tients require insulin therapy for survival. The 
more common form of diabetes, non-insulin- 
dependent diabetes mellitus (NIDDM), includes 
about 90 percent of diabetic patients. This form 
results from reduced insulin levels in some pa- 
tients and a relative deficiency in others and is 
due to abnormal functioning of the insulin- 
producing cells or decreased responsiveness of 
tissues to insulin. In these patients the blood glu- 
cose levels can usually be controlled by diet or by 
drugs that can be taken orally to improve insulin 
secretion and action. 
As with other common diseases of middle age 
such as cardiovascular disease and hypertension, 
genetic factors contribute to the development of 
NIDDM. Our goal is to identify the genes that in- 
crease the risk of developing diabetes and to de- 
termine how, together with environmental and 
life-style factors, they result in the elevated blood 
glucose levels that define this disorder. 
We have taken an approach that combines ge- 
netics and molecular biology. Our working hy- 
pothesis is that a relatively small number of po- 
tentially identifiable major genes increase the 
risk of developing diabetes and that the individ- 
ual's overall genetic background, together with 
environmental and life-style factors, influences 
the phenotypic expression of the major suscepti- 
bility genes. 
In our genetic studies, we are studying diabetes- 
prone families in which NIDDM has an early age- 
at-onset and a clear autosomal dominant mode of 
inheritance. In one such family we have identi- 
fied a DNA marker on the long arm of human 
chromosome 20 that is tightly linked to the 
diabetes-susceptibility gene. We are presently 
trying to isolate this gene and to identify the mu- 
tation that impairs its normal function and leads 
to failure of the insulin-secreting pancreatic ^- 
cells. The identification of this gene may suggest 
others whose mutation could also cause NIDDM. 
Drawing on our understanding of the patho- 
physiology of NIDDM, we are also cloning and 
characterizing genes that might reasonably con- 
tribute to diabetes susceptibility. Since the pan- 
creatic /3-cell plays an important role in the patho- 
genesis of all forms of diabetes mellitus, we are 
particularly interested in studying the genes that 
are responsible for its unique physiological char- 
acteristics. These include genes encoding hor- 
mones such as insulin and islet amyloid polypep- 
tide (a newly discovered hormone-like peptide 
of uncertain function), ion channels, and recep- 
tors for hormones and other agents that regulate 
insulin secretion. In addition to cloning and 
characterizing genes expressed in /3-cells, we are 
also identifying DNA polymorphisms in these 
genes to facilitate genetic studies of their contri- 
bution to development of NIDDM. Furthermore, 
we are studying the effects of hyperglycemia and 
other altered metabolic states on their expression 
in order to determine if changes in the levels of 
the proteins encoded by these genes can provide 
a molecular explanation for the failure of the 
cell to secrete appropriate amounts of insulin in 
response to glucose in patients with NIDDM. 
Recent studies of the receptor for the polypep- 
tide hormone somatostatin are beginning to shed 
new light into the mechanism by which this hor- 
mone inhibits insulin secretion. In addition, they 
are leading us into the area of neurobiology and 
hormonal regulation of neuronal function. So- 
matostatin is a cyclic 1 4-amino acid polypeptide 
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