The Production and Actions of Insulin and 
Other Islet Hormones 
Donald F. Steiner, M.D. — Senior Investigator 
Dr. Steiner is also A. N. Pritzker Distinguished Service Professor of Biochemistry and Molecular Biology 
and of Medicine at the University of Chicago Pritzker School of Medicine. He received his M.D. degree at 
the University of Chicago. His interest in insulin developed during postdoctoral training with R. H. Wil- 
liams at the University of Washington School of Medicine. After joining the faculty at Chicago, he studied 
insulin action in the liver and, later, insulin biosynthesis. This work led to his discovery of proinsulin 
and preproinsulin. Dr. Steiner has received many awards, including the Lilly and Gairdner Awards, and 
several honorary degrees. 
THE production and regulated release of insu- 
lin is essential for normal growth and the uti- 
lization of food. A deficiency of insulin, or de- 
fects in its action, can lead to diabetes, a disease 
characterized by high blood sugar and a variety of 
possible complications, including blindness, 
heart disease, stroke, and increased susceptibility 
to certain infections. Diabetes affects 2-3 per- 
cent of the population of the developed 
countries. 
Control of diabetes can be achieved through 
various combinations of diet, oral hypoglycemic 
agents, and/or insulin injections, depending on 
type and severity. Such therapies, however, are 
often less than fully satisfactory; they may only 
retard the progress of complications. Abetter un- 
derstanding of insulin biosynthesis, its regulated 
release into the bloodstream, and its action on 
receptors to regulate metabolism and growth is 
vitally important to the development of new ap- 
proaches to the therapy of this disease. 
Insulin is made in the islets of Langerhans — 
small clusters of cells in the pancreas. Islet cells 
also secrete other hormones that appear to regu- 
late digestion or nutrient metabolism. These in- 
clude glucagon, somatostatin, amylin, and pancre- 
atic polypeptide. The islet hormones, like many 
other regulatory peptides in the body, are derived 
from larger precursor molecules (proteins) called 
preprohormones. These precursors contain addi- 
tional portions that serve as markers to guide them 
along special intracellular pathways, where they 
are concentrated into storage vesicles and pro- 
cessed into their smaller, biologically active 
forms. These are then secreted into the blood- 
stream in varying proportions to meet physiologi- 
cal needs. One goal of our research is to learn 
more about how prohormones like proinsulin are 
sorted from other proteins, concentrated into se- 
cretory granules, and processed into active hor- 
mones by specialized protein-splitting enzymes. 
Insulin secretion from /3-ceIls in response to ele- 
vated plasma glucose is a complex electrochemical 
process resembling the transmission of nerve im- 
pulses or the contraaion of the heart. In the insulin- 
producing (S-cells, a specialized sensor mechanism 
couples the metabolism of glucose to ion channels 
in the plasma membrane. Upon depolarization of 
the membrane, these channels allow the selective 
entry of calcium into the cell, triggering the release 
of secretory granule contents. 
Certain oral hypoglycemic agents used to treat 
diabetes — the sulfonylureas — appear to stimulate 
insulin secretion by inhibiting a specialized potas- 
sium channel in the (S-cell membrane, which then 
initiates electrical depolarization of the cell. We 
are trying to learn more about the structure of this 
and other important ion channels to understand 
both their normal functions and their possible 
malfunction in some forms of diabetes. 
We are also studying mutations that affect 
(pro)insulin structure. Some of these mutations, 
occurring in families with mild diabetes, give rise 
to abnormal insulin molecules with greatly re- 
duced biological activity, as reflected in reduced 
binding to insulin receptors. Certain other muta- 
tions in the insulin gene primarily affect the con- 
version of proinsulin to insulin, leading to other 
familial disorders known as hyperproinsulinemias. 
Insulin acts on tissues by binding to a large, 
complex receptor protein on the surface of cells. 
This activates a tyrosine kinase that alters many 
intracellular processes through a cascade of 
phosphorylations. Binding of insulin to the re- 
ceptor also leads to its uptake and degradation in 
the liver and other tissues. This process, known as 
receptor-mediated endocytosis, may also play a 
role in the generation of some biological re- 
sponses to insulin and in mediating the rapid re- 
moval of insulin from the circulation. By studying 
defective or modified precursor, hormone, and/ 
or receptor molecules, we hope to learn more 
about normal islet hormone production and ac- 
tion and about derangements in these processes 
that can lead to diabetes or other diseases. 
Our current areas of investigation include the 
following: 
• mechanisms of intracellular sorting and pro- 
teolytic processing of hormone precursors, 
• mechanisms regulating insulin secretion, 
• mutant human insulin or insulin receptor 
genes and their functional significance, 
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