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.Sc. degree in zoology and M.Sc. degree in biology from the University of 
Calgary, Canada. He earned his Ph.D. degree in biochemistry and biophysics from the University of Cali- 
fornia, 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 and the Rolf Luft Award from the Swedish Medical Society. 
DIABETES mellitus is a disorder of carbohy- 
drate metabolism characterized by elevated 
blood glucose levels. It affects individuals of all 
ethnic groups. In the United States, an estimated 
6 million persons are known to have diabetes, 
and there is probably an equal number with un- 
recognized disease. About 10 percent of persons 
over age 65 have diabetes, and the complications 
of the cardiovascular, kidney, visual, and nervous 
systems are major causes of morbidity 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, 
which results from reduced insulin levels in 
some patients and a relative deficiency in others, 
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 such as athero- 
sclerosis and hypertension, genetic factors con- 
tribute to the development of NIDDM. Our long- 
term goal is to identify the genes for diabetes 
susceptibility and to determine how, together 
with environmental and life-style factors, they re- 
sult in the elevated blood glucose levels that de- 
fine this disorder. 
We have taken an approach that applies genet- 
ics and molecular biology. Our working hypothe- 
sis is that a relatively small number of potentially 
identifiable major genes increase the risk of devel- 
oping diabetes and that the individual's overall 
genetic background, together with environmen- 
tal and life-style factors, influences the expres- 
sion of the major susceptibility genes. 
In our genetic studies we are examining the 
segregation of DNA polymorphisms in diabetes- 
prone families. We have recently identified a 
DNA marker on the long arm of human chromo- 
some 20 that cosegregates with NIDDM in a 
larger multigenerational family with a form of 
NIDDM termed maturity-onset diabetes of the 
young (MODY). The diabetes in this family is 
characterized by low serum insulin levels, an age 
of onset of less than 25 years, and an autosomal 
dominant mode of inheritance. The isolation of 
this MODY-susceptibility gene and identification 
of the mutation that impairs its function may pro- 
vide important clues to causes of other forms of 
NIDDM. In addition, it will also be possible to 
assess the contribution of this locus to the overall 
prevalence of diabetes mellitus. Since the 
MODY-susceptibility gene on chromosome 20 is 
unlikely to account for genetic susceptibility to 
NIDDM in all individuals, we are continuing to 
search for other markers that cosegregate with 
NIDDM, using large families in which the dia- 
betes is not linked to the marker on chromosome 
20. These genetic studies should lead to the iden- 
tification of additional diabetes-susceptibility 
genes. 
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. These include 
genes encoding proteins that are expressed in the 
insulin-producing cell, including insulin, islet 
amyloid polypeptide (a newly discovered hor- 
mone-like peptide of uncertain function), and 
the and Ca^"*" channels that are involved in in- 
sulin secretion. We are also studying the genes for 
proteins responsible for uptake and metabolism 
of glucose, since the insulin-producing cells of 
NIDDM patients have lost the ability to secrete 
insulin in response to increasing circulating glu- 
cose levels. Other candidate genes encode pro- 
teins expressed in the insulin-responsive target 
cell, including the insulin receptor and the mem- 
brane proteins involved in glucose uptake. In ad- 
dition, we have considered genes encoding 
serum proteins that are instrumental in the trans- 
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