This page is provided by the Beta Cell Biology Consortium - (2004-2007) Beta Cell Biology Consortium prof. aza prof. aza

Insulin – from secretion to action Insulin is a pillar of treatment for those with Type 1 diabetes. Insulin acts as a messenger to instruct the body's cells to absorb glucose, in effect reducing blood glucose levels. We present here some facts about insulin synthesis and secretion in insulin-producing beta cells and its effect on the body. Conversely, we also touch on the topic of what happens when there is an insufficient supply of insulin. prof. aza

Introduction One of the greatest medical events was the discovery of insulin. The importance of insulin is juxtaposed with that of glucose, our body’s basic unit of fuel. Both are required for life. In order to regulate glucose metabolism, insulin circulates through blood vessels to deliver its message by means of a ‘handshake’ with its cognate cell surface receptor. For those with diabetes mellitus, the body is either unable to produce insulin, or unable to produce it in sufficient amounts, and is therefore powerless in maintaining proper levels of blood glucose. prof. aza

a better understanding of Even though insulin is a life saver, it does not cure the disease. Insulin injections themselves are not without risk. Improvements in the treatment of diabetes will come from a better understanding of how insulin is made in the pancreas and released into the bloodstream, and how it promotes uptake of circulating glucose by tissues including muscle and fat. prof. aza

Panel 1. Insulin Synthesis - prof. aza

Panel 1. Insulin Synthesis - Insulin production involved intermediate steps. Initially, preproinsulin is the inactive that is secreted into the endoplasmic reticulum. Post-translational processing clips the N-terminal signal sequence and forms the disulfide bridges. Lastly, the polypeptide is clipped at two positions to release the intervening chain C. This and active insulin are finally packaged into secretory granules for storage prof. aza

islets of Langerhans Insulin is a hormone that is exclusively produced by pancreatic beta cells. Beta cells are located in the pancreas in clusters known as the islets of Langerhans. Insulin is a small protein and is produced as part of a larger protein to ensure it folds properly. In the protein assembly of insulin, the messenger RNA transcript is translated into an inactive protein called preproinsulin (see panel 1). Preproinsulin contains an amino-terminal signal sequence that is required in order for the precursor hormone to pass through the membrane of the endoplasmic reticulum (ER) for post-translational processing. prof. aza

active insulin The post-translational processing clips away those portions not needed for the bioactive hormone. Upon entering the ER, the preproinsulin signal sequence, now useless, is proteolytically removed to form proinsulin. Once the post-translational formation of three vital disulfide bonds occurs, specific peptidases cleave proinsulin. The final product of the biosynthesis is mature and active insulin. Finally, insulin is packaged and stored in secretory granules, which accumulate in the cytoplasm, until release is triggered. prof. aza

Panel 2. Insulin secretion Panel 2.  Insulin secretion.  Insulin secretion in beta cells is triggered by rising blood glucose levels ... prof. aza

Panel 2. Insulin secretion - Insulin secretion in beta cells is triggered by rising blood glucose levels. Starting with the uptake of glucose by the GLUT2 transporter, the glycolytic phosphorylation of glucose causes a rise in the ATP:ADP ratio. This rise inactivates the potassium channel that depolarizes the membrane, causing the calcium channel to open up allowing calcium ions to flow inward. The ensuing rise in levels of calcium leads to the exocytotic release of insulin from their storage granule. prof. aza

The process by which insulin is released from beta cells, in response to changes in blood glucose concentration, is a complex and interesting mechanism that illustrates the intricate nature of insulin regulation. Type 2 glucose transporters (GLUT2) mediate the entry of glucose into beta cells (see panel 2). As the raw fuel for glycolysis, the universal energy-producing pathway, glucose is phosphorylated by the rate-limiting enzyme glucokinase. This modified glucose becomes effectively trapped within the beta cells and is further metabolized to create ATP, the central energy molecule. The increased ATP:ADP ratio causes the ATP-gated potassium channels in the cellular membrane to close up, preventing potassium ions from being shunted across the cell membrane. prof. aza

The ensuing rise in positive charge inside the cell, due to the increased concentration of potassium ions, leads to depolarization of the cell. The net effect is the activation of voltage-gated calcium channels, which transport calcium ions into the cell. The brisk increase in intracellular calcium concentrations triggers export of the insulin-storing granules by a process known as exocytosis. The ultimate result is the export of insulin from beta cells and its diffusion into nearby blood vessels. Extensive vascular capacity of surrounding pancreatic islets ensures the prompt diffusion of insulin (and glucose) between beta cells and blood vessels. prof. aza

The net effect is the activation of voltage-gated calcium channels, which transport calcium ions into the cell. The brisk increase in intracellular calcium concentrations triggers export of the insulin-storing granules by a process known as exocytosis. The ultimate result is the export of insulin from beta cells and its diffusion into nearby blood vessels. Extensive vascular capacity of surrounding pancreatic islets ensures the prompt diffusion of insulin (and glucose) between beta cells and blood vessels. prof. aza

Insulin release is a biphasic process Insulin release is a biphasic process. The initial amount of insulin released upon glucose absorption is dependent on the amounts available in storage. Once depleted, a second phase of insulin release is initiated. This latter release is prolonged since insulin has to be synthesized, processed, and secreted for the duration of the increase of blood glucose. Furthermore, beta cells also have to regenerate the stores of insulin initially depleted in the fast response phase. prof. aza

Panel 3. Insulin binding to the insulin receptor induces a signal transduction cascade which allows the glucose transporter (GLUT4) to transport glucose into the cell. prof. aza

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