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. 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.
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. 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.
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.
How insulin works
Insulin molecules circulate throughout the blood stream until they bind to their associated (insulin) receptors. The insulin receptors promote the uptake of glucose into various tissues that contain type 4 glucose transporters (GLUT4). Such tissues include skeletal muscles (which burn glucose for energy) and fat tissues (which convert glucose to triglycerides for storage). The initial binding of insulin to its receptor initiates a signal transduction cascade that communicates the message delivered by insulin: remove glucose from blood plasma (see panel 3). Among the wide array of cellular responses resulting from insulin activation, the key step in glucose metabolism is the immediate activation and increased levels of GLUT4 glucose transporters. By the facilitative transport of glucose into the cells, the glucose transporters effectively remove glucose from the blood stream. Insulin binding results in changes in the activities and concentrations of intracellular enzymes such as GLUT4. These changes can last from minutes to hours.
As important as insulin is to preventing too high of a blood glucose level, it is just as important that there not be too much insulin and hypoglycemia. As one step in monitoring insulin levels, the enzyme insulinase (found in the liver and kidneys) breaks down blood-circulating insulin resulting in a half-life of about six minutes for the hormone. This degradative process ensures that levels of circulating insulin are modulated and that blood glucose levels do not get dangerously low.