Mechanisms of the amplifying pathway of insulin secretion in the β cell

Abstract

Pancreatic islet β cells secrete insulin in response to nutrient secretagogues, like glucose, dependent on calcium influx and nutrient metabolism. One of the most intriguing qualities of β cells is their ability to use metabolism to amplify the amount of secreted insulin independent of further alterations in intracellular calcium. Many years studying this amplifying process have shaped our current understanding of β cell stimulus-secretion coupling; yet, the exact mechanisms of amplification have been elusive. Recent studies utilizing metabolomics, computational modeling, and animal models have progressed our understanding of the metabolic amplifying pathway of insulin secretion from the β cell. New approaches will be discussed which offer in-roads to a more complete model of β cell function. The development of β cell therapeutics may be aided by such a model, facilitating the targeting of aspects of the metabolic amplifying pathway which are unique to the β cell.

Swimming training reduces glucose‐amplifying pathway and cholinergic responses in islets from lean‐ and MSG‐obese rats

“…Pancreatic beta cells synthesize and secrete insulin through two primary mechanisms, known as triggering and amplifying pathways . In the triggering pathway, the glucose‐stimulated insulin secretion (GSIS) depends on the closing of the ATP‐sensitive K + (K ATP ) channels, while the amplifying pathways are based on the increased sensitivity of insulin granules to the given triggering calcium influx, as well as metabolic signals generated by the glucose metabolism . Both pathways are involved in the biphasic insulin secretion where the signals of each pathway interact in order to guarantee the glucose homeostasis.…”

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In the triggering pathway, the glucose-stimulated insulin secretion (GSIS) depends on the closing of the ATP-sensitive K + (K ATP ) channels, 3,5-7 while the amplifying pathways are based on the increased sensitivity of insulin granules to the given triggering calcium influx, as well as metabolic signals generated by the glucose metabolism. 3,[8][9][10] Both pathways are involved in the biphasic insulin secretion where Abstract Here, we investigate the effects of exercise training on glucose-and cholinergic-induced insulin secretion in pancreatic islets from obese and lean rats. Male Wistar rats were treated with monosodium glutamate (MSG) for the first 5 days of life, while control (CON) rats received saline.

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Glucose as a Major Antioxidant: When, What for and Why It Fails?

“…More recently, with the use of metabolomics approach it was shown that insulin release is controlled by direct implication of PPP [87]. According to a recent review, among the most important amplifiers/regulators of insulin secretion by β-cells are high levels of NADPH and glutathione [88]. So, insulin release is taking place in conditions of "metabolic welfare" and oxidative stress may reduce the ability of β-cells to release insulin [89].…”

“…One may argue, that there are many other mechanisms of regulation of insulin and glucagon that can either enhance or inhibit respective secretion, including paracrine δ-cells secreting somatostatin [92,93], effects of glucagon-like peptide-1 (GLP-1) [94], glucose-dependent insulinotropic peptide (GIP) [95], leptin/adiponectin axis [96], autonomic nervous system [97,98] etc. However, the effects of all these regulators are integrated at the level of α-and β-cells and their metabolism resulting shifts of redox potential [87,88,90].…”

Chromomycin A2potently inhibits glucose-stimulated insulin secretion from pancreatic β cells

“…In the screen we stimulated the cells using the diazoxide paradigm to drive both the triggering and metabolic amplifying pathways of insulin secretion (30,31) to provide a platform to later assign the actions of hit compounds to triggering and/or amplification and give maximal dynamic range in the assay. From the screen, we selected natural product fractions that appeared non-toxic after an overnight treatment but still potently inhibited glucose-stimulated insulin secretion.…”