Abstract
β-cells of the pancreatic islets are highly specialized and high-throughput units for the production of insulin, the key hormone for maintenance of glucose homeostasis. Elevation of extracellular glucose and/or GLP-1 levels triggers a rapid upregulation of insulin biosynthesis through the activation of post-transcriptional mechanisms. RNA-binding proteins are emerging as key factors in the regulation of these mechanisms as well as in other aspects of β-cell function and glucose homeostasis at large, and thus may be implicated in the pathogenesis of diabetes. Here we review current research in the field, with a major emphasis on RNA-binding proteins that control biosynthesis of insulin and other components of the insulin secretory granules by modulating the stability and translation of their mRNAs.
Highlights
The hallmark of the pancreatic islet β-cell is its ability to synthesize and secrete large quantities of insulin, which maintains metabolic homeostasis by lowering glycemia
Insulin is synthesized as a single-chain precursor termed preproinsulin, composed of an N-terminal signal sequence, the B chain, the connecting C-peptide, and the A chain, which is covalently linked to the B chain via disulfide bridges
Proinsulin is sorted at the trans-Golgi network into immature secretory granules (SGs); subsequent removal of the intervening C-peptide by protein convertases during the maturation of SGs leads to the generation of insulin [1]
Summary
The hallmark of the pancreatic islet β-cell is its ability to synthesize and secrete large quantities of insulin, which maintains metabolic homeostasis by lowering glycemia. Each β-cell contains on average $ 5 Â 103 SGs [2], of which only 1–2% undergo regulated exocytosis in response to elevation of glycemia [3] Other stimuli, such as incretins, further potentiate the release of insulin induced by hyperglycemia. Glucose-triggered SG exocytosis is coupled to a concomitant rapid increase in the biosynthesis of insulin and other components necessary for SG assembly [5]. This is especially relevant in view of the evidence that newly-synthesized SGs undergo preferential exocytosis [6,7,8]. Detailed knowledge of the molecular machinery responsible for preproinsulin mRNA stability and translation is of paramount importance for understanding the physiology of β-cells and their inability to meet insulin demands in type 2 diabetes
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