Physiology and pathophysiology of insulin secretion
Physiology and pathophysiology of insulin secretion. H Rasmussen , K C Zawalich , S Ganesan , R Calle and W S Zawalich Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut 06510. Abstract Mechanisms by which various classes of extracellular signals regulate insulin secret...
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Published in | Diabetes care Vol. 13; no. 6; pp. 655 - 666 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Diabetes Association
01.06.1990
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Subjects | |
Online Access | Get full text |
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Summary: | Physiology and pathophysiology of insulin secretion.
H Rasmussen ,
K C Zawalich ,
S Ganesan ,
R Calle and
W S Zawalich
Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut 06510.
Abstract
Mechanisms by which various classes of extracellular signals regulate insulin secretion are discussed regarding their cellular
and molecular actions. Under physiological circumstances, the small postprandial changes in plasma glucose concentrations
(approximately 4.4-6.6 mM) primarily serve as a conditioned modifier of insulin secretion and dramatically alter the responsiveness
of islets to a combination of neurohormonal agonists. These agonists have two functions. Cholecystokinin (CCK) and acetylcholine
activate the hydrolysis of polyphosphoinositides, and gastric inhibitory polypeptide (GIP) and glucagonlike peptide 1 activate
adenylate cyclase. These two functional classes of neurohumoral agonists act synergistically to enhance insulin secretion
when plasma glucose is greater than 6.0 mM but not when it is less than or equal to 4 mM. On the other hand, an increase in
plasma glucose concentration to 8-10 mM induces an increase in insulin secretory rate in the absence of any of the neurohormonal
agonists. Remarkably, high glucose leads to an increase in the same intracellular signals, as does a combination of acetylcholine
and GIP. On the basis of these data, a model of how insulin secretion is regulated under physiological circumstances is proposed.
This model emphasizes that the regulation of insulin secretion occurs in three stages: cephalic, early enteric, and later
enteric. In this view, the crucial event occurring during the first two phases is the agonist-induced, translocation of protein
kinase C (PKC) to the plasma membrane under conditions in which an increase in Ca2+ influx does not occur. PKC is now in a
cellular location and a Ca2(+)-sensitive conformation such that an increase in Ca2+ influx rate occurring during the third
phase leads to its immediate activation and an enhanced rate of insulin secretion. Furthermore, under physiological circumstances,
an optimal insulin secretory response is dependent on a correct temporal pattern of signals arising from neural and enteric
sources. If this pattern is deranged, an abnormal pattern of insulin secretion is observed. An important new insight is provided
by the observation that agonists (e.g., CCK or acetylcholine) that act to stimulate the hydrolysis of phosphatidylinositides,
when acting for a short period (10-20 min), induce an enhanced responsiveness of islets to glucose, i.e., proemial sensitization.
However, when acting unopposed for several hours, these agonists will induce a time-dependent suppression of responsiveness
to glucose and other agonists. The latter observation implies that optimal insulin secretion is dependent on periodic rather
than a continuous exposure to the correct pattern of extracellular signals. |
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Bibliography: | ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 ObjectType-Review-3 content type line 23 ObjectType-Feature-3 ObjectType-Review-1 |
ISSN: | 0149-5992 1935-5548 |
DOI: | 10.2337/diacare.13.6.655 |