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β-cell insulin secretion |
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Insulin secretion from the pancreatic β-cell
Since the current advances in the treatment of both type 1 and 2 diabetes still cannot prevent diabetes or is devoid of significant side-effects, the search continues for more effective therapies. In order to develop these compounds we must gain further insights in the mechanism of both insulin signaling and β-cell function. My PhD thesis focused on β-cell function and the role of uncoupling protein-2 (UCP2) in the regulation of β-cell function. This section will discuss some of the general concepts of glucose-stimulated insulin secretion (GSIS). The “insulin secretion and metabolism” page will discuss glucose metabolism in the pancreatic β-cell and the relevance to GSIS.
In vivo insulin secretion is biphasic with a first phase burst in insulin secretion occurring within the first 10 minutes and a second phase that reaches plateau very quickly as seen in mice or can show a progressively slow increase in insulin secretion reaching a plateau in 2-3 hours as seen in rats and humans (Gerich, 2002). Defects in both first and second phase insulin secretion, especially first phase, may be the earliest detectable defect in individuals destined to develop type 2 diabetes (Gerich, 2002).
In isolated β-cells or other in vitro studies, the first phase burst in insulin release arises from the readily releasable pool of insulin granules at the plasma membrane whereas second phase insulin secretion is thought to arise from newly synthesized insulin granules (Henquin et al., 2002;Rutter & Tsuboi, 2004;Barg et al., 2002;Rorsman et al., 2000). The mechanism of nutrient controlled insulin release from insulin granules is still not completely understood. The general scheme controlling insulin release goes as follows: glucose enters the b-cell and is metabolized increasing the ATP/ADP ratio, which inhibits ATP-sensitive potassium channels (KATP channels) on the plasma membrane leading to membrane depolarization and activation of voltage-dependent Ca2+ channels (VDCC). The influx of Ca2+ stimulates insulin granule fusion with the plasma membrane and insulin release (Figure 1). These steps control both first and second phase of insulin secretion with second phase insulin release involving additional steps of insulin biosynthesis, packaging into granules and transport to the plasma membrane for release (Henquin et al., 2002;Barg et al., 2002;Rorsman et al., 2000).
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