Diabetes in Pregnancy - 2 - Glucose Metabolism and Insulin Action
Glucose is one of the primary substrates for the production of energy in cells throughout our body, especially, in the brain, muscles, and kidneys. The two main sources of glucose are dietary carbohydrates, primarily, starches (large “sugar” polymers, or complex carbohydrates) from fruits, vegetables, and grains, and disaccharides (made up of only two “sugar” molecules), such as lactose from milk and sucrose from refined sugars. Through the digestion of these carbohydrates in the gut, they are first broken down to monosaccharides (single “sugar” molecules) before they can be absorbed. Once they cross the gut wall, these monosaccharides are transported via the blood to the liver where they are all converted into glucose molecules (also a monosaccharide). The other monosaccharides cannot be used for ‘fuel’ until they are converted into glucose, therefore, the liver’s role is pivotal in the distribution of this primary source of energy to other body tissues.
Once glucose has gotten into cells, several things can happen to it. First, if the cell needs ‘energy’, glucose can be broken down by a series of enzymes that ultimately results in the production of two molecules of pyruvate. (Pyruvate is the substrate for many important reactions that are not necessary for our discussion herein). As a consequence of the production of pyruvate from glucose, there is also the concomitant net production of two molecules of ATP (adenosine triphosphate) which is the common source of ‘fuel’ for most of the metabolic processes in the cell. Secondly, if there is more glucose than the cell needs, glucose can be converted to glycogen (a polymer of glucose) and stored in that form. Only the liver and muscles have the capability to make and store glycogen (interestingly, the brain does not!) but they are limited in how much they can store. Glycogen can rapidly be converted back to glucose when the need arises. Thirdly, if there is an excess beyond the capacity of the liver and muscles to store glycogen, glucose can be converted into ‘fatty acids.’ Fatty acids are stored in fat (adipose) tissues as triglycerides.
So, where does insulin fit into this picture? Well, none of the events above can occur unless glucose can actually get into the cell in the first place. Among insulin’s many functions, its primary role for sake of our discussion is to enhance the ability of cells to get glucose from the blood into the cell. Under normal circumstances, insulin secretion by the pancreatic ?-cells in the islets of Langerhans is proportional to the amount of glucose in the blood within a very tight ‘normal’ range for blood glucose levels. (Actual production of insulin within the ?-cells is under the influence of many different hormones, including several pregnancy-related hormones). Once insulin is secreted, it is transported in the blood and binds to specific receptors on the cell membrane. Binding of insulin to the cell membrane results in signals that activate several different metabolic processes (specific to the cell type to which the insulin has bound).
One of the messages that insulin sends to the cell by binding to it is to increase the number of plasma membrane glucose transporters, or GLUTs. GLUTs are stored in the cell and are ‘recruited’ to move to the cell membrane by the action of insulin. Once there, they facilitate the transport of glucose from the blood into the cell. GLUTs are continuously being ‘turned over’ and they only hang around in the cell membrane as long as enough insulin is bound to the cell to keep them there. Different GLUTs with different affinities for glucose, characteristically, reside in different tissues: GLUT1 is present in most tissues, GLUT2 is present in liver and pancreatic ?-cells, GLUT3 is found in the brain, and GLUT4 is found in the heart, adipose tissue and skeletal muscle. In addition to enhancing glucose transport, insulin stimulates glycogen and fat production, increases amino acid transport into cells, promotes the transcription of specific gene products, and stimulates growth, DNA synthesis, and cell replication.
In our next post, we will discuss how pregnancy alters the ‘normal’ state of affairs with regard to insulin production and action…