Insulin and the Islets of Langerhans 
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 Robert 
Williams at the University of Washington School of Medicine. After joining the faculty at the University of 
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 honors, including the Lilly and 
Gairdner Awards, the Wolf Prize in Medicine, and several honorary degrees. 
INSULIN is essential for normal growth and uti- 
lization of food. Diabetes, a disease due to 
insulin deficiency or defects in its action, is char- 
acterized by high blood sugar and such complica- 
tions as blindness, heart disease, stroke, and in- 
creased susceptibility to infections. It affects 2-3 
percent of people in developed countries. 
Diabetes can be controlled through various 
combinations of diet, oral hypoglycemic agents, 
and/or insulin injections, depending on the type 
and severity of the disease. Such therapies, how- 
ever, are often less than fully satisfactory because 
they may only retard the development of compli- 
cations. A better understanding of how insulin is 
formed and secreted in a regulated manner into 
the bloodstream and how it acts on tissue recep- 
tors to control metabolism and growth are vitally 
important to the development of new therapeutic 
approaches. 
Insulin is only made in the islets of Langerhans 
— small clusters of cells dispersed throughout 
the pancreas. Specialized islet cells also secrete 
other hormones that influence metabolism, in- 
cluding glucagon, somatostatin, amylin (or islet 
amyloid polypeptide), and pancreatic polypep- 
tide. The islet hormones, like other regulatory 
peptides in the body, are derived from larger pro- 
teins called prepro hormones. 
These precursors contain additional portions 
that may guide them along special intracellular 
pathways, where they are concentrated into stor- 
age vesicles and processed into their biologically 
active forms. The contents of these vesicles are 
then released into the bloodstream in varying 
proportions to meet physiological requirements. 
One goal of our research is to learn more about 
how newly formed prohormones are separated 
from other proteins in the cell, concentrated into 
secretory granules, and processed into active hor- 
mones by highly specialized enzymes before be- 
ing secreted. 
Insulin secretion from |8-cells in response to 
elevated plasma glucose is a complex electro- 
chemical process resembling the transmission of 
nerve impulses or the contractions of the heart. 
In the insulin-producing |8-cells, a specialized 
sensor mechanism couples the metabolism of 
glucose to ion channels in the plasma membrane. 
These channels, upon membrane depolarization, 
allow the selective entry of calcium into the cell, 
triggering the release of secretory granule con- 
tents. Certain oral hypoglycemic agents used to 
treat diabetes — the sulfonylurea drugs — appear 
to stimulate insulin secretion by inhibiting a spe- 
cialized potassium channel in the ;8-cell mem- 
brane, which then initiates electrical depolariza- 
tion of the cell. We are trying to learn more about 
the structure of this and other important ion 
channels in insulin-producing cells to under- 
stand both their normal functions and their possi- 
ble malfunction in some forms of diabetes. 
We also are studying mutations that affect insu- 
lin or proinsulin structure. Some of these occur 
in families and are associated with mild diabetes 
as a result of the synthesis of abnormal insulin 
molecules with greatly reduced biological activ- 
ity. Other mutations in the insulin gene primarily 
affect the conversion of proinsulin into insulin, 
leading to elevated proinsulin in the circulation. 
Insulin acts on tissues by binding to a large and 
complex protein receptor that is present on the 
surface of most cells, activating a tyrosine kinase 
that alters many intracellular processes through a 
cascade of intracellular phosphorylations. Insu- 
lin binding to the receptor also leads to the up- 
take and degradation of the hormone in the liver 
and other tissues. This process, known as recep- 
tor-mediated endocytosis, plays an important 
role by rapidly removing insulin from the circu- 
lation. By studying inherited defects in proinsu- 
lin and insulin receptor molecules, we are learn- 
ing more about the normal processes of islet 
hormone production and action and how their 
derangement can lead to disease. 
Prohormone-converting Enzymes 
We have recently identified two cDNAs, which 
we call PC2 and PC3, in neuroendocrine cells. 
These encode proteases having catalytic domains 
similar to that of Kex2, a yeast prohormone- 
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