Homeostatic Control of Blood Glucose

Homeostasis

The body keeps several physiological parameters within a defined range, including body temperature, blood pressure, and the concentration of blood glucose. The defined ranges of these parameters are maintained to optimize the health of the organism within the environment it is living.

Homeostasis is the ability of a system to keep a certain parameter within a defined range or near set point. Often environmental factors or changes around the system cause the parameter to move outside its normal range. A homeostatic system senses the change in the parameter and then triggers effectors to return the parameter to its normal range.

Occasionally, the homeostatic systems in an organism breakdown or environmental conditions become so extreme that the homeostatic system cannot keep the parameters within their normal ranges. This can often lead to damage to tissues and organs and eventually disease. Many of the drugs we have developed were designed to return parameters to their normal ranges and restore health.

Homeostatic systems have at least three essential components: sensors, controllers and effectors. Sensors measure the current value of the parameter (e.g. blood pressure, blood glucose, body temperature). Controllers compare the measured value of the parameter with its set point. If the controller measure a significant different between the measured value and set point, it will activate effectors that return the parameter to the set point. The set point of the parameter is usually determined by the current physiological needs of the organism.

If you have driven a relatively new car, you have likely used a homeostatic system: cruise control. Cruise control is designed to keep the car’s speed at set point. The driver enters the set point, say 65 MPH. A sensor in the car detects the car’s current speed. The sensors sends that information to the controller which compares the current speed with the speed set by the driver. If the car’s current speed falls below the set point (e.g. car is going up a hill), the controller activates an effector, the accelerator, to increase the speed of the car. Biological homeostatic systems use similar components, but because those components have arise through evolution rather than design, the components can be more difficult to identify.

Homeostasis of Blood Glucose

The human body tries to keep blood glucose concentration within a narrow range of 3.9 mmol/L (72 mg/dL) to about 5.6 mM (100 mg/dL). We define this range as normal because when concentrations remain outside this range for prolonged periods, illness and disease can result.

Another illustration of how important blood glucose concentration is to the body comes from research done a patients who were under severe caloric restriction. The patients’ blood was drawn over time and the amount of different metabolites was measured. What is remarkable is that even after days of caloric restriction, blood glucose is held at a constant concentration, despite the near complete exhaustion of glycogen stores in less than a day.

Why does the body try to maintain blood glucose concentrations even under extreme circumstances? One reason is to maintain a ready supply of energy for the brain. The brain accounts for about 2% of the body’s weight but consumes about 20% of its energy. As alternative, the brain can use ketone bodies derived from fatty acids, but glucose is the preferred energy source. One consequence to an organism of a low concentration of blood glucose (hypoglycemia) is loss of brain function which can be catastrophic to the health of the organism.

Given the importance of glucose as an energy source for the brain, why not keep blood glucose concentrations high to ensure a consistent and adequate supply of glucose for the brain? Glucose reacts with proteins in a process called glycation. The reaction does not depend on any specific enzyme but the rate increass as the concentration of glucose increases. Glycation results in the covalent attachment of glucose to proteins which can alter the structure and function of proteins causing damage to tissues or changes in cell behavior. Many of the pathologic conditions associated with diabetes are likely due to tissue damage resulting from glycation of proteins.

Hormonal Control of Blood Glucose

Two hormones are primarily responsible for controlling the concentration of glucose in the blood: insulin and glucagon. Insulin levels increase when blood glucose levels are high and causes a decrease in blood glucose concentration. Glucagon levels increase at low blood glucose concentrations and cause the blood glucose levels to rise. Remarkably, the production of both hormones are very sensitive to changes in concentration near the set point of blood glucose concentration. So, to a large extent we can understand how the body controls blood glucose concentration by understanding how glucose concentrations regulate the production of insulin and glucagon.

Insulin

Beta-cells in the pancreas sense blood glucose concentrations and release insulin when glucose concentrations rise above a certain point. Beta-cells store insulin in secretory granules which fuse with the cell membrane to release insulin in bursts. In H&E-stained samples of the pancreas (left image), beta-cells localize to a region called the islet of Langerhans. The name describes a collection of hormone secreting cells that exist in a sea of pancreatic acinar cells, which secrete digestive enzymes.

This graph shows a time course of insulin release after an increase in blood glucose. The first phase comprises a burst of insulin that is released from secretory granules that have fused with the cell membrane. The second phase represents the synthesis of new insulin and its release via secretory granule. If blood glucose levels remain high after the initial release of insulin, beta-cells will continue to synthesize and release insulin .

The response of beta-cells to blood glucose levels is usually sufficient to rapidly return blood glucose concentrations to the normal range. After eating a meal, the intestines absorbs much of the glucose in the food and release it into the circulatory system. This can raise blood glucose levels above the maximum threshold of the normal range, but within a few hours, insulin has returned blood glucose concentrations to the normal range.

How insulin reduces blood glucose concentrations

Insulin affects cells in many different tissues and organs to reduce blood glucose concentrations. Insulin stimulates skeletal muscle and adipose tissue to take up glucose of interstitial fluid. IInsulin also inhibits lipolysis in adipocyte to lower lipid levels in the blood. In the liver, inuslin inhibits glycogenolysis and gluconeogenesis while stimulating glycogen synthesis, which further reduces blood glucose levels. Thus, insulin regulates the distribution of energy throughout the body.

How do beta-cells sense glucose concentration?

To be able to respond to increases in blood glucose and secrete insulin, beta-cells need a mechanism to meausure blood glucose concentrations and secrete insulin when the concentration reaches a specific level.

Beta-cells link glucose concentration to depolarization of their cell membranes which stimulates secretion of insulin. Beta-cells express glucose transporters (primarily GLUT1 and GLUT3) in their cell membranes. Glucose diffuses into beta-cells and is metabolized via glycolysis and the TCA cycle to gerenate ATP. When glucose concentrations in interstitial fluid are high, the concentration of ATP in beta-cells increases. The high concentration of ATP causes ATP-sensitive potassium channels to close. The closing of the potassium channels increases membrane potential (becomes less negative). The depolarization of the cell membrane induces voltage-sensitive calcium channels to open. The influx of calcium raises cytoslic calcium concentrations, which stimulates fusion of secretory vesicles filled with insulin with the cell membrane.

Although the mechanism above links glucose concentration to release of insulin, a critical need of the body is to set insulin release to a specific concentration of glucose. Releasing insulin at low blood glucose concentrations would reduce blood glucose concentration to dangerous levels.

A key to setting release to minimal concentration of blood glucose is that beta-cells express the enyme glucokinase. Recall that glucokinase is a member of the hexokinase familty that converts glucose to glucose-6-phosphate. Glucose-6-phosphate cannot diffuse through GLUT channels and is either metabolized or stored as glycogen. Glukokinase differs from other members of the hexokinase family in having a much higher Km. A higher Km means that glucokinase requires a higher concentration of glucose to become active, and consequently, beta-cells require higher concetrations of glucose to generate enough ATP to close potassium channels in their cell membranes.

Glucagon

How does the body respond when the concentration of blood glucose falls below its normal level to avoid hypoglycemia? Alpha-cells in the pancreas, which reside next to beta-cells, sense low glucose levels and release glucagon. Glucagon is a short polypeptide that affects different organs and tissues.

Glucagon changes several metabolic pathways in the liver. Glucose stimulates both glycogenolysis and gluconeogensis while also inhibiting glycogen synthesis. The increased glucose in liver cells is released to the circulatory system, which raises blood glucose conecentrations.

Glugacon also appears to increase lipolysis in white adipose tissue. LIpolysis breaksdown triglycerides into glycerol and free fatty acids. Glycerol is released into the circultory system and can be converted to glucose in the liver via glyconeogenesis. Free fatty acids are insoluble in water and associate with albumin in blood. Cells in the liver use receptor-mediated endocytosis to take up albumin. The associated fatty acids are metabolized by beta-oxidation to produce acetyl-CoA. Excess acetyl-CoA is converted into ketone bodies. Many tissues can use ketone bodies instead of glucose, which helps keep blood glucose concentrations high.

Another important set of hormones that increase blood glucose concentrations are glucocorticoids. Glucorcorticoids are primarily produced in the adrenal glands and increase blood glucose by stimulating breakdown of protein in skeletal muscle cells to amino acids. Skeletal muscle cells release the amino acids into the circulatory systems, which are taken up by cells in the liver. Liver cells convert amino acids to glucose via gluconeogenesis.

Llike beta-cells, alpha-cells also link glucose concentration with release of glucagon (lower concentration stimulates glucagon secretion). The exact mechanism that connects low glucose concentration in alpha-cells with secretion of glucagon is not well understood but may employ a similar mechanism to the one used in alpha-cells to link glucose concentration to release of insuling.

A critical regulator of glucagon secretion is insulin. Insulin inhibits release of glucagon. Thus, in addition to stimulating uptake of glucose in tissues, insulin also prevents activation of pathways that increase glucose concentrations.

Thus, the body has two mechanisms that keep blood glucose concentrations within a narrow range. Insulin is produced when blood glucose concentration becomes too high and causes skeletal muscle to take up more glucose. Glucagon is produced when blood glucose concentration is too low and causes the liver to produce and release more glucose.