Elevated concentrations of glucose in blood stimulate release of insulin, and insulin acts on cells thoughout the body to stimulate uptake, utilization and storage of glucose.
The effects of insulin on glucose metabolism vary depending on the target tissue. Two important effects are:. Insulin facilitates entry of glucose into muscle, adipose and several other tissues. The only mechanism by which cells can take up glucose is by facilitated diffusion through a family of hexose transporters. In many tissues - muscle being a prime example - the major transporter used for uptake of glucose called GLUT4 is made available in the plasma membrane through the action of insulin.
When insulin concentrations are low, GLUT4 glucose transporters are present in cytoplasmic vesicles, where they are useless for transporting glucose. Binding of insulin to receptors on such cells leads rapidly to fusion of those vesicles with the plasma membrane and insertion of the glucose transporters, thereby giving the cell an ability to efficiently take up glucose.
When blood levels of insulin decrease and insulin receptors are no longer occupied, the glucose transporters are recycled back into the cytoplasm. It should be noted here that there are some tissues that do not require insulin for efficient uptake of glucose: important examples are brain and the liver. This is because these cells don't use GLUT4 for importing glucose, but rather, another transporter that is not insulin-dependent. Insulin stimulates the liver to store glucose in the form of glycogen.
A large fraction of glucose absorbed from the small intestine is immediately taken up by hepatocytes, which convert it into the storage polymer glycogen.
Insulin has several effects in liver which stimulate glycogen synthesis. First, it activates the enzyme hexokinase, which phosphorylates glucose, trapping it within the cell. Coincidently, insulin acts to inhibit the activity of glucosephosphatase. Insulin also activates several of the enzymes that are directly involved in glycogen synthesis, including phosphofructokinase and glycogen synthase. The net effect is clear: when the supply of glucose is abundant, insulin "tells" the liver to bank as much of it as possible for use later.
A well-known effect of insulin is to decrease the concentration of glucose in blood , which should make sense considering the mechanisms described above. Another important consideration is that, as blood glucose concentrations fall, insulin secretion ceases. In the absense of insulin, a bulk of the cells in the body become unable to take up glucose, and begin a switch to using alternative fuels like fatty acids for energy.
Neurons, however, require a constant supply of glucose, which in the short term, is provided from glycogen reserves. When insulin levels in blood fall, glycogen synthesis in the liver diminishes and enzymes responsible for breakdown of glycogen become active.
Glycogen breakdown is stimulated not only by the absense of insulin but by the presence of glucagon , which is secreted when blood glucose levels fall below the normal range. The metabolic pathways for utilization of fats and carbohydrates are deeply and intricately intertwined.
Considering insulin's profound effects on carbohydrate metabolism, it stands to reason that insulin also has important effects on lipid metabolism, including the following:. In the Protein Recycling Animation we see a group of storage vesicles enriched with GLUT4 proteins continuously recycling from the Cell Membrane to an inactive location in the cytosol.
GLUT4 is a protein that facilitates the movement of glucose into the cell. When high levels of glucose are detected by beta cells in the pancreas, insulin is released by the cells. The insulin circulates through the blood stream until it binds to an insulin receptor embedded in the cell membrane of a muscle, fat, or brain cell.
Once the insulin binds to the receptor, phosphate groups are added to the intracellular domain of the receptor. Since the receptor itself adds the phosphate groups, the process is called autophosphorylation. This phosphorylation event sets off a cascade of molecular events. The activated receptor protein then adds a phosphate group to another closely associated protein.
This effectively passes the signal from the receptor to the next step in the signal pathway. Proteins that add phosphate groups to another protein are called kinases. Kinases are often components of signal pathways, and phosphorylation is an important component in the transmission of a signal from one compartment to another.
In this system, the signal corresponds to the level of blood glucose and is transmitted from outside to inside the cell. As their name implies, glucose transporter proteins act as vehicles to ferry glucose inside the cell. To get detailed images of how GLUT4 is transported and moves through the cell membrane, the researchers used high-resolution imaging to observe GLUT4 that had been tagged with a fluorescent dye. The researchers then observed fat cells suspended in a neutral liquid and later soaked the cells in an insulin solution, to determine the activity of GLUT4 in the absence of insulin and in its presence.
In the neutral liquid, the researchers found that individual molecules of GLUT4 as well as GLUT4 clusters were distributed across the cell membrane in equal numbers. Inside the cell, GLUT4 was contained in balloon-like structures known as vesicles. The vesicles transported GLUT4 to the cell membrane and merged with the membrane, a process known as fusion.
After fusion, the individual molecules of GLUT4 are the first to enter the cell membrane, moving at a continuous but relatively infrequent rate. The researchers termed this process fusion with release. When exposed to insulin, however, the rate of total GLUT4 entry into the cell membrane peaked, quadrupling within three minutes. The researchers saw a dramatic rise in fusion with release — 60 times more often on cells exposed to insulin than on cells not exposed to insulin.
Based on the total amount of glucose the cells took in, the researchers deduced that glucose was taken into the cell by individual GLUT4 molecules as well as by clustered GLUT4. The researchers also noted that after four minutes, entry of GLUT4 into the cell membrane started to decrease, dropping to levels observed in the neutral liquid in 10 to 15 minutes.
The research team next plans to examine the activity of glucose transporters in human fat cells, Zimmerberg said.
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