D.C., and Beaudet, A.L. 1992. An initiation co- 
don mutation in CD 18 in association with the 
moderate phenotype of leukocyte adhesion defi- 
ciency. /B/o/ Chem 267:714-718. 
Smith, C.W., Entman, M.L., Lane, C.L., Beaudet, 
A.L., Ty, T.I., Youker, K., Hawkins, H.K., and An- 
derson, D.C. 1991. Adherence of neutrophils to 
canine cardiac myocytes in vitro is dependent on 
intercellular adhesion molecule- 1. / Clin Invest 
88:1216-1223. 
MOLECULAR GENETICS OF DIABETES MELLITUS 
Graeme I. Bell, Ph.D., Investigator 
Dr. Bell's laboratory is studying the molecular ge- 
netics of diabetes mellitus. The major interest is in 
the form that primarily affects aging individuals: 
non-insulin-dependent, or type 2, diabetes mellitus 
(NIDDM). 
Genetics of Non-Insulin-Dependent 
Diabetes Mellitus 
About 10% of adults in the United States are af- 
fected by NIDDM. The disorder is characterized by 
high blood glucose levels, which can result, if un- 
treated, in cardiovascular disease, kidney failure, 
blindness, nerve damage, and early death. In con- 
trast to patients with the less common insulin- 
dependent, or type 1, diabetes mellitus, who re- 
quire daily insulin injections for survival, patients 
with NIDDM are able to produce insulin, but the 
amounts secreted by their pancreas are inappropri- 
ately low relative to their blood glucose levels. 
Both genetic and nongenetic factors contribute to 
the development of NIDDM. However, the genetics 
of NIDDM is complex, and the mode of inheritance 
of NIDDM does not correspond to that of a simple 
dominant or recessive disorder. Moreover, there are 
likely to be a number of different genes whose mu- 
tation increases the risk of developing NIDDM. 
Identification of these genes is the goal of this labo- 
ratory. An understanding of the molecular basis of 
diabetes will lead to new and better forms of therapy 
and will facilitate the identification of presympto- 
matic genetically susceptible individuals, thereby 
allowing intervention programs to be initiated. 
Because of the late onset of NIDDM, usually in 
middle age, the patients' parents are often not avail- 
able for study, and the patients' children are too 
young to display symptoms of diabetes. Thus it is 
difficult to obtain large multigenerational pedigrees 
suitable for genetic studies. However, Dr. Stefan S. 
Fajans (University of Michigan) has described a 
slowly progressing form of diabetes occurring in 
some children, adolescents, and young adults that 
has a prominent familial character. This form, called 
maturity-onset diabetes of the young, or MODY, is 
highly penetrant and has an autosomal-dominant in- 
heritance. It is therefore a good model for investi- 
gating the natural history of NIDDM. In all other 
respects, except for the age at onset, the clinical 
features of MODY are similar to those found in the 
more common late-onset form of NIDDM. 
The largest and most thoroughly studied family 
with MODY is the R-W pedigree, a Michigan family 
of German origin. Their NIDDM is characterized by 
a delayed and subnormal insulin secretory response 
to glucose, suggesting that the primary defect 
responsible for the disease manifests itself in the 
insulin-secreting /3 cell of the pancreas. In collabora- 
tion with Dr. Fajans and Dr. Richard Spielman (Uni- 
versity of Pennsylvania), Dr. Bell and his colleagues 
reported that the gene responsible for diabetes in 
the R-W family is on the long arm of chromosome 
20. They have now narrowed its location to a region 
of ~10 million bp, and studies are under way to 
isolate it and identify the mutation that impairs its 
function. It will then be possible to study how ge- 
netic variation in this gene contributes to the devel- 
opment of the more common late-onset form(s) of 
NIDDM. 
The past year saw the report of a second locus 
responsible for the development of MODY. Dr. Phi- 
lippe Froguel (Centre d'Etude du Polymorphisme 
Humaine, Paris) reported close linkage of DNA poly- 
morphisms in the glucokinase gene on chromosome 
7 with early-onset NIDDM in a group of French fami- 
lies. In collaboration with Dr. Froguel, Dr. Bell and 
his colleagues have identified mutations in 18 of 32 
French families with MODY. Dr. Bell and his col- 
leagues have also identified mutations in the glu- 
cokinase gene in British, Swedish, Japanese, and 
African-American patients with NIDDM, indicating 
that they are not restricted to a particular ethnic or 
154 
