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Vol. 55, Issue 1, 105-132, March 2003
Diabetes Section, National Institute on Aging, National Institutes
of Health, Baltimore, Maryland
I. Introduction
II. Insulin Synthesis and Secretion
A. Stimulus Secretion Coupling/the Metabolism of Glucose
1. The Basic Mechanism of Glucose-Induced Insulin
Secretion.
2. Mitochondria
Calcium Effects and Metabolism.
B. Components of the Insulin Secretory Pathway
1. Ion Channels.
a. The Potassium Channels.
b. The Voltage-Dependent Ca2+ Channels.
2. Second Messengers.
a. G-Protein-Coupled Receptor Systems.
i. Adenylyl Cyclase System.
ii. Calcium/Phosphatidylinositol System.
b. G-Protein-Coupled Receptors on the 
-Cell
i. Gut Hormone Receptors.
ii. Muscarinic Receptors.
iii. Adrenergic Receptors.
iv. Purinergic Receptors.
C. Insulin Synthesis
1. Transcriptional and translational regulation.
2. Endoplasmic Reticulum, Insulin Secretory Vesicles and
Transportation, and Exocytosis.
III. Pharmaceutical Agents Active in the Treatment of Disorders of
Glucose Homeostasis
A. Insulinotropic Agents
B. Thiazolidinediones
C. Agents Used in the Treatment of Hyperinsulinemia
D. The Potential Agents and Targets for Future Treatment of
Diabetes
1. Agonists at the Glucagon-Like Peptide-1
Receptor.
2. Agonists at the Purinergic 2 Receptor.
3. Imidazolines.
IV. Drugs Administered in the Treatment of Disorders Other Than
Diabetes That Have Effects on Pancreatic Insulin Secretion and
-Cell Function
A. Drugs Implicated in Post-Transplant Diabetes Mellitus
1. Calcineurin Inhibitors.
2. Antiproliferative Agents.
B. Quinolines
C. Somatostatin Receptor Agonists
D. Drugs Used Mainly to Treat Hypertension
E. Methylxanthines
F. Phosphodiesterase Inhibitors
G. Diamidines
H. Colchicine
I. Acetylcholine and Cholinesterase Inhibitors
J. Miscellaneous
1. Anesthetics.
2. Oral Contraceptives.
3. Anti-Psychotic Drugs.
4. Glucosamine.
Acknowledgments
References
Blood glucose levels are sensed and controlled by the release of
hormones from the islets of Langerhans in the pancreas. The -cell,
the insulin-secreting cell in the islet, can detect subtle increases in
circulating glucose levels and a cascade of molecular events spanning
the initial depolarization of the -cell membrane culminates in
exocytosis and optimal insulin secretion. Here we review these
processes in the context of pharmacological agents that have been shown
to directly interact with any stage of insulin secretion. Drugs that
modulate insulin secretion do so by opening the KATP
channels, by interacting with cell-surface receptors, by altering
second-messenger responses, by disrupting the -cell cytoskeletal
framework, by influencing the molecular reactions at the stages of
transcription and translation of insulin, and/or by perturbing
exocytosis of the insulin secretory vesicles. Drugs acting primarily at
the KATP channels are the sulfonylureas, the benzoic acid
derivatives, the imidazolines, and the quinolines, which are channel
openers, and finally diazoxide, which closes these channels.
Methylxanthines also work at the cell membrane level by antagonizing
the purinergic receptors and thus increase insulin secretion. Other
drugs have effects at multiple levels, such as the calcineurin
inhibitors and somatostatin. Some drugs used extensively in research,
e.g., colchicine, which is used to study vesicular transport, have no
effect at the pharmacological doses used in clinical practice. We also
briefly discuss those drugs that have been shown to disrupt -cell
function in a clinical setting but for which there is scant information
on their mechanism of action.
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