Discuss briefly the regulation of blood glucose concentration (a) after a meal, (b) following a prolonged fast and (c) during an exercise

Outline:

·        Highlight the key hormones involved

·        Stimulus for their secretion

·        Effects of these hormones

·        Direction of flow of nutrients

Essay:

(a)        The body maintain blood glucose concentration at a relatively constant level. After a meal, there is a sudden increase in the amount of nutrients (glucose, fatty acids and amino acids) in the body which must be utilized or stored somehow to prevent a drastic increase in blood glucose levels. The hormone insulin induces efficient storage of the excess nutrients while suppressing mobilization of endogenous substrates. Insulin stimulates glucose oxidation and storage while simultaneously inhibiting glucose production. Therefore, insulin either lowers the basal circulating glucose concentration or limits the rise in plasma glucose that results from a dietary carbohydrate load. The stored nutrients can then be made available during subsequent fasting periods to maintain glucose delivery to the central nervous system and free fatty acid delivery to the muscle mass and viscera.

            Insulin is secreted by the b cells of the pancreatic islets. Glucose is the main stimulant for the release of insulin. Arginine, leucine, and other amino acids also stimulate insulin secretion as do a variety of gastrointestinal hormones secreted in response to ingestion of a meal, such as CCK, GIP and secretin. The major targets for insulin action are the liver, the adipose tissue, and the muscles.

            In the liver, insulin enhances inward movement of glucose by inducing hepatic glucokinase which catalyzes phosphorylation of the incoming glucose to glucose-6-phosphate. Insulin then promotes storage of glucose as glycogen by activating the glycogen synthase-enzyme complex. At the same time, insulin stimulate glycolysis, which converts glucose to pyruvate and lactate, by increasing the activities of phosphofructokinase and pyruvate kinase. Insulin also rapidly inhibits hepatic glycogenolysis and therefore hepatic glucose output by decreasing glycogen phosphorylase activity. In addition, insulin inhibits gluconeogenesis by decreasing the hepatic uptake of precursor amino acids and their availability from muscle.

            In the muscle, insulin stimulates the transport of glucose into muscle cells. Depending on the insulin concentration, 20% to 50% of the glucose that enters undergoes oxidation. The remainder is specifically directed to storage as glycogen by insulin activation of glycogen synthase. In adipose tissue, insulin stimulates the transport of glucose into the cells. Much of this glucose is then converted to glycerophosphate, which is used in the esterification of fatty acids and permits their storage as triglycerides. Adipose tissue can also metabolize glucose by means of the pentose phosphate pathway, producing NADPH, essential for fat synthesis.

            By increasing the influx of glucose into tissues and promoting its utilization and storage, insulin helps to buffer any major increase in blood glucose concentration after a meal.

(b)        In the fasting state, the individual totally depends on endogenous substrates for energy. A prolonged fast is a form of stress on the body, activating the sympathetic nervous system. Stimulation of the sympathetic nerves to the pancreas causes the release of glucagon from the a-cells. A low insulin:glucagon ratio, due to glucose insufficiency, also stimulates the release of glucagon.

            Glucagon is secreted in response to glucose deficiency and acts to increase circulating glucose levels. Hypoglycemia due to fasting causes a twofold to fourfold increase in plasma glucagon levels. Glucagon mediates its action via cAMP as a secondary messenger.

            The dominant effect of glucagon is on the liver. In the liver, glucagon stimulates glycogenolysis through activation of glycogen phosphorylase, The glucose-1-phosphate released as a result of glycogen phosphorylase activation is prevented from undergoing resynthesis to glycogen by a simultaneous inhibition of glycogen synthase. Glucagon also stimulates gluconeogenesis by increasing the hepatic extraction of amino acids, decreasing the activity of PFK-1 while increasing the activity of fructose-1,6-bisphosphatase. The result is an increase in gluconeogenesis and a decrease in glycolysis.

            The low levels of insulin reverse many its anabolic effects and helps to raise blood glucose concentration. Insulin has a tonic inhibitory action on glucagon. Low levels of insulin enable the catabolic effects of glucagon to be expressed fully. Low insulin levels also depress the transport of glucose into the muscles and adipose tissue.

            Glucagon has little or no influence on glucose use by peripheral tissues. Another hormone, cortisol, secreted by the adrenal cortex, decreases glucose utilization peripherally and in the liver. Cortisol increases hepatic glucose 6-phosphatase activity, releasing more glucose into the circulation and decreases hepatic lipogenesis. Cortisol is necessary for glucagon to exert its gluconeogenetic action during fasting.

            As fasting continues, the central nervous system no longer depends entirely on glucose as an energy source, and two-thirds of its needs are eventually met by the ketoacids. As less glucose is needed for oxidation, gluconeogenesis diminishes and protein breakdown declines.

(c)        During an exercise, increased amount of glucose is needed to meet the energy demands of the contracting muscles. The metabolic response to exercise resembles the response to fasting, in that the mobilization and generation of fuels for oxidation are dominant factors. The type and amounts of expended substrate vary with the intensity and duration of the exercise. During very intense, short-term exercise, stored creatine phosphate and ATP provide the energy at a rate of 50 kcal/min. When these stores are depleted, additional intense exercise for up to 2 minutes can be sustained by breakdown of muscle glycogen to glucose-6-phosphate, with glycolysis yielding the necessary energy. This is mediated by glucagon.

            Exercise of sufficient intensity and duration increase plasma glucagon levels. Neural mechanisms may mediate some of these responses. In particular, vagal stimulation and acetylcholine acutely increase glucagon secretion. To offset the drain of glucose and maintain a normal plasma glucose level, hepatic glucose production must increase up to fivefold. Glucagon stimulates glycogenolysis and gluconeogenesis in the liver to increase hepatic output of glucose. With exercise of longer duration, however, gluconeogenesis becomes increasingly important as liver glycogen stores become depleted. To support gluconeogenesis, amino acids are increasingly released by muscle proteolysis, and their fractional uptake by the liver is enhanced. The activities of key gluconeogenic enzymes such as PEPCK and transcription of their genes are increased. These events are coordinated by increased sympathetic neural activity and the relative effects of the hormones gucagon and insulin. Eventually, fatty acids liberated from adipose tissue triglycerides become the predominant substrate and supply two-thirds of the energy needs during sustained exercise.

            During recovery from exercise, muscle and liver glycogen stores must be rebuilt; these processes being mediated by the anabolic effects of insulin.