racial group. To date, 20 different mutations have 
been identified in the glucokinase gene, and muta- 
tions in this gene represent the most common cause 
of NIDDM so far identified. 
Glucokinase is expressed in the insulin-secreting 
18 cells of the pancreas and in cells of the liver. It 
catalyzes the transfer of phosphate from ATP to glu- 
cose and plays an important role in regulating and 
integrating glucose metabolism in both tissues. In 
pancreatic /3 cells, glucokinase is believed to be the 
"glucose sensor" that modulates insulin secretion 
in response to changes in plasma glucose concentra- 
tion. Dr. Bell has suggested that mutations in this 
gene may cause diabetes by a gene dosage mecha- 
nism. The presence of a mutation in one of two al- 
leles of the glucokinase gene results in a decrease in 
the levels of glucokinase activity in pancreatic 18 
cells. As a consequence, the threshold for glucose- 
stimulated insulin secretion is increased and higher 
levels of glucose are required to trigger secretion. 
Such decreased /3-cell sensitivity to glucose can ac- 
count for many of the clinical features of this type of 
NIDDM. The identification of diabetes-causing mu- 
tations in the glucokinase gene suggests that NIDDM 
may be primarily a disorder of glucose metabolism. 
This observation also suggests that other glycolytic 
enzymes, especially those that control rate-limiting 
steps in glucose metabolism, are candidates for con- 
tributing to the development of this clinically het- 
erogeneous disorder. 
Molecular Biology of Diabetes Mellitus 
In addition to using genetic strategies for identify- 
ing diabetes susceptibility genes, Dr. Bell and his 
colleagues, with support from a grant from the Na- 
tional Institutes of Health, have continued to clone 
and characterize cDNAs/genes encoding proteins 
whose mutation or altered regulation may contrib- 
ute to diabetes or its characteristic metabolic de- 
rangements. These clones can be used as molecular 
probes for genetic studies and for physiological stud- 
ies examining the effects of diabetes on cellular pro- 
cesses. A major effort is under way in Dr. Bell's labo- 
ratory to isolate cDNAs encoding proteins that 
regulate insulin secretion by the pancreatic /3 cell. 
The group has isolated cDNAs encoding the sub- 
unit of the neuroendocrine-type voltage-dependent 
calcium channel and has shown that glucose re- 
presses this gene's expression, which suggests that 
its decreased expression may contribute, at least in 
part, to (8-cell failure in NIDDM. 
In addition, cDNAs encoding a third subtype of 
the inositol trisphosphate receptor, as well as a fam- 
ily of somatostatin receptors, have been isolated and 
characterized from pancreatic islet cDNA libraries. 
The inositol trisphosphate receptor functions in the 
mobilization of intracellular calcium, thereby facil- 
itating insulin secretion. In contrast, the somato- 
statin receptors mediate somatostatin inhibition of 
insulin secretion. These studies represent the first 
steps toward deciphering the molecular mecha- 
nisms regulating insulin secretion. 
Dr. Bell's multidisciplinary approach is providing 
a better understanding of the causes of diabetes mel- 
litus. This will facilitate the development of new 
therapeutic approaches based on recognition that 
the disease has not one cause but many. 
Other Projects 
Dr. Bell, in collaboration with Rex Haydon (a 
graduate student in the Department of Anthropol- 
ogy, University of Chicago) and Dr. Jane Buikstra 
(University of Chicago), is isolating DNA from tis- 
sues of Chiribaya mummies (a.d. 1000-1300) from 
the west coast of South America. Their studies have 
shown that DNA of sufficient quality can be isolated 
from bone and mummified flesh from these archeo- 
logical samples and that specific sequences can be 
amplified using the polymerase chain reaction. 
They propose to use molecular biology to recon- 
struct population structure and migrational events 
of these ancient peoples. 
Dr. Bell is also Professor of Biochemistry and 
Molecular Biology and of Medicine at the Univer- 
sity of Chicago. 
Articles 
Bell, G. 1992. Struttura molecolare dei trasportatori 
di glucosio [in Italian]. / trasportatori del gluco- 
sio, IL DIABETE, Marzo 1992, pp 6-8. 
Burant, C.F., Sivitz, W.I., Fukumoto, H., Kayano, 
T., Nagamatsu, S., Seino, S., Pessin, J.E., and Bell, 
G.I. 1991. Mammalian glucose transporters: 
structure and molecular regulation. Recent Prog 
Horm Res 47:349-388. 
Burant, C.F., Takeda, J., Brot-Laroche, E., Bell, G.I., 
and Davidson, N.O. 1992. Fructose transporter in 
human spermatozoa and small intestine is GLUT5. 
fBiol Chem 267:14523-14526. 
Cox, N.J., Xiang, K.S., Fajans, S.S., and Bell, G.I. 
1992. Mapping diabetes-susceptibility genes: les- 
sons learned from the search for a DNA marker for 
MODY. Diabetes A\ A0\-4Q>7 . 
Davidson, N.O., Hausman, A.M.L., Ifkovits, C.A., 
Buse, J.B., Gould, G.W., Burant, C.F., and Bell, 
G.I. 1992. Human intestinal glucose transporter 
GENETICS 155 
