Author(s): Doyle ME, Egan JM
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Abstract Blood glucose levels are sensed and controlled by the release of hormones from the islets of Langerhans in the pancreas. The beta-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 beta-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 K(ATP) channels, by interacting with cell-surface receptors, by altering second-messenger responses, by disrupting the beta-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 K(ATP) 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 beta-cell function in a clinical setting but for which there is scant information on their mechanism of action.
This article was published in Pharmacol Rev
and referenced in Journal of Diabetes & Metabolism