Molecular Genetics of Diabetes Mellitus 
port of triglycerides and cholesterol and thus im- 
plicated in the development of cardiovascular 
disease, since there are data suggesting that dia- 
betes and cardiovascular disease may have com- 
mon genetic antecedents. 
Genetic variation associated with these candi- 
date genes is being examined in groups of dia- 
betic and nondiabetic subjects, as well as in fami- 
lies, to assess the contribution of these genes to 
the development of NIDDM. The results of the 
studies to date suggest that there is variation in 
the genes for the insulin receptor and for apoli- 
poproteins Al and B that influences the pheno- 
typic expression of a major susceptibility gene. 
Our isolation of the genes for membrane pro- 
teins involved in the transport of glucose across 
the plasma membrane, in addition to providing 
markers for our genetic studies, has revealed un- 
expected functional complexity that could have 
important implications for the treatment of dia- 
betes. These studies indicate that facilitative glu- 
cose transport is not the property of a single pro- 
tein but rather involves a family of at least five 
structurally related proteins. These proteins have 
distinct patterns of tissue distribution and differ- 
ent kinetic properties and are independently reg- 
ulated. These features allow the precise disposal 
of dietary glucose under varying physiological 
conditions. 
Data from our laboratory and others indicate 
that decreased levels of two of these glucose 
transport proteins may contribute to the develop- 
ment of the diabetic state. In adipose tissue there 
are reduced amounts of the glucose transport 
protein GLUT4, which is responsible for insulin- 
stimulated glucose uptake by this tissue. The re- 
duced amounts of GLUT4 provide a molecular 
explanation for the decreased ability of adipose 
tissue of diabetic and obese individuals to take up 
glucose. Because adipose tissue participates in 
the disposal of dietary glucose after a meal, the 
decreased expression of this protein may contrib- 
ute to high circulating glucose levels. The levels 
of GLUT2, the glucose transport protein of insu- 
lin-producing cells, are also decreased in dia- 
betes. Since GLUT2 may comprise part of the glu- 
cose-sensing mechanism that regulates insulin 
secretion, decreased levels of this protein may be 
responsible for the abnormal functioning of the 
insulin-producing cells of diabetic individuals. A 
better understanding of the regulation of expres- 
sion of GLUT2 and GLUT4 may facilitate the de- 
velopment of novel therapeutic strategies for the 
treatment of diabetes. 
34 
