Quote[/b] ]The glucose/fatty acid/ketone body cycle and its hormonal control explains the reciprocal relationship between the oxidation of glucose versus fatty acids or ketone bodies.
Under conditions of carbohydrate stress (i.e., depletion of liver glycogen stores), fatty acids are mobilized from adipose tissue and their rate of oxidation by muscle is increased which, in turn, decreases glucose utilization.
The low insulin-to-glucagon ratio in starvation activates lipolysis to elevate blood fatty acids as an alternative fuel to glucose; thus glucagon signals fat mobilization.
Conversely, when carbohydrate stress is removed by refeeding, fatty acid release by adipose tissue is decreased by insulin, thus decreasing fatty acid oxidation by the liver.
Glucose use by the muscle increases when insulin is present. These responses stabilize blood glucose.
The regulatory effect of fatty acid oxidation on glucose utilization is a logical necessity considering:
1) the small reserves of carbohydrate in the body
2) the obligatory requirement by some tissues (e.g., RBC, brain) for glucose.
In muscle, fatty acid oxidation decreases glucose utilization through negative effects on glucose transport as well as on the activities of hexokinase, phosphofructokinase-1, and pyruvate dehydrogenase.
The flux determining step for eventual fatty acid oxidation by muscle is the hormone-sensitive lipase of adipose tissue. This point is important since it is the elevated levels of plasma fatty acids that increase muscle oxidation of this fuel, leading to the changes indicated above.
Heart and skeletal muscle prefer fatty acids over glucose.
The brain does not use fatty acids as a substrate since they penetrate the blood-brain barrier poorly and require more oxygen for their consumption.
Fatty acids in the liver are oxidized to produce ATP to support the energy needs of gluconeogenesis.
Exceeding the limits of the citric acid cycle to oxidize acetyl CoA during gluconeogenesis promotes formation of ketone bodies from the excess acetyl CoA derived from -oxidation of fatty acids. Ketones are released into the blood as a source of energy for other tissues. Like fatty acids, ketone bodies are preferred by many tissues over glucose. The presence of ketone bodies and fatty acids has a "sparing effect" upon blood glucose to make glucose more available for use by the brain. Eventually ketones are also used as a fuel in the brain. The use of ketone bodies by the brain reduces glucose use in an analogous manner to the effect of fatty acids on muscle. Ketones never completely replace the need for glucose by the brain but they do decrease the rate of glucose use by 80% to 90% in the brain, and suppress the loss of protein in skeletal muscle to decrease muscle wasting. As noted earlier, an excessive build-up of ketones can lead to acidosis, which is prevented by ketone bodies promoting insulin release from the pancreas.
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THE TRANSITION FROM THE WELL-FED STATE TO PROLONGED STARVATION
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Phase I: In the well-fed state, glucose is provided by dietary carbohydrate.
Phase II: Once this supply is exhausted, hepatic glycogenolysis maintains blood glucose levels during the postabsorptive phase, which lasts up to 16 hours.
Phase III: As the glucose supply dwindles, liver gluconeogenesis becomes increasingly important until, in early starvation, it is the major source of blood glucose. All of these changes occur within just 20 or so hours after the last meal, depending on how well fed the individual was prior to the fast, how much hepatic glycogen was present, and the sort of physical activity during the fast. Dependence upon hepatic gluconeogenesis decreases, and renal gluconeogenesis becomes significant . This occurs because enough ketones have accumulated to permit uptake by the brain to meet some of the energy needs of this tissue.
Phase IV: Finally, the individual enters the prolonged starvation phase. Prolonged starvation is characterized by even less dependence upon gluconeogenesis, the energy needs of every tissue containing mitochondria being met to an even greater extent by either fatty acid or ketone body oxidation. As long as ketone body concentrations are high, proteolysis is restricted, and conservation of muscle proteins occurs. This continues until all the fat is gone, after which the body resorts solely to using muscle protein until death.
The well-fed state operates while food is being absorbed from the intestine, and is more correctly termed the absorptive state. Carbohydrates and fats are oxidized to CO2 and H2O in peripheral tissues to provide energy for synthetic reactions and to sustain cell function. After a meal, surplus fuel is converted to glycogen and/or fat by the action of insulin released from the pancreas. In the liver, glucose is converted primarily into glycogen or pyruvate, or pentoses for the generation of NADPH for synthetic processes. Excess pyruvate from glucose is used for lipogenesis and the synthesis and release of triglycerides (triacylglycerols) contained in VLDL. Fatty acids from the triglycerides are primarily stored in adipose tissue. Much of the absorbed glucose circulates to other tissues. The brain is dependent upon glucose catabolism for its production of ATP. In the well-fed state, the liver utilizes glucose and does not engage in gluconeogenesis. Thus, the Cori cycle is interrupted in the well-fed state. In muscle, insulin promotes storage of glucose as glycogen.
In the postabsorptive state, glucagon release from the pancreas begins. In response to glucagon, liver glycogenolysis provides the most glucose (75%) in this transitional period with gluconeogenesis from several substrates providing the remainder. The role of the glucose-alanine cycle is just developing. Alanine contributes as much carbons to gluconeogenesis as the other amino acids combined. Note: 50-60% of the glucose is consumed by the brain. Fat mobilization is minimal at this time. During the early (gluconeogenic) phase of starvation, the body is geared to synthesizing glucose to make up for the lack of dietary intake and the depletion of liver glycogen. Glucose oxidation, primarily by the brain, causes blood glucose levels to fall. In turn there is a further decline in the insulin-to-glucagon ratio which promotes the mobilization of fatty acids and of amino acids which are required for the acceleration of gluconeogenesis in the liver.
As starvation progresses, the amount of blood ketones rises. The brain turns to ketones as the preferred fuel which spares the use of glucose by the brain. Concurrently, ketone bodies reduce alanine release from muscle and decrease the demands for producing glucose which in turn helps to conserve protein. Thus glucose homeostasis is maintained by decreasing glucose use in the face of diminished glucose production. Decreased glucose production is essential for conserving the limited amounts of muscle protein. It is noteworthy that muscle dysfunction can occur with the loss of just 40% of muscle protein mass.
Organ relationships occurring in starvation: Red blood cells must continue to use glucose as they contain no mitochondria for oxidizing fatty acids or ketones. In the early period of starvation, lactate and amino acids are brought to the liver as precursors for the synthesis of the glucose needed not only for RBC, but also for the brain. At this time, fats are being mobilized and provide an alternate fuel for the liver and muscle so that these tissues decrease their oxidation of glucose; "glucose sparing". In theory, RBC spare glucose carbons as well because they can be recycled to the liver as lactate throughout starvation. As fatty acids continue to be released their excess uptake by the liver leads to ketone body production. Once ketone levels rise sufficiently in the blood, the brain can utilize them in lieu of glucose; the ultimate in glucose sparing.
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Table VI- Metabolic States and Signals
STATE
RESPONSE
SIGNAL
Feeding
Store fat, glucose, protein
High insulin, low glucagon
Fasting
Retrieve glucose and fat
Low insulin, high glucagon
Starvation
Retrieve fat and protein
Low insulin, high glucagon
Excitement
Retrieve glucose and fat quickly
High epinephrine
Diabetes
Retrieve fat and protein
Low insulin, high glucagon
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Table VII - Metabolic Movements of Storage Fuels as a Function of Metabolic State
Metabolic State Glycogen Fat Protein
Feeding Glycogen Synthesis
(Glucagon decreases)
(Insulin Increases) Fat Synthesis
(Glucagon decreases)
(Insulin Increases) Protein Synthesis
(Glucagon decreases)
(Insulin Increases)
Fasting Glycogen Degradation
(Glucagon increases)
(Insulin Decreases) Fat Degradation
(Glucagon Increases)
(Insulin Decreases) Protein Degradation
(Glucagon Increases)
(Insulin Decreases)
Starvation Glycogen EXHAUSTION
(Glucagon increases)
(Insulin Decreases) Fat Degradation
(Glucagon Increases)
(Insulin Decreases) EXTENSIVE Protein Degradation
(Glucagon Increases)
(Insulin Decreases)
Excitement Glycogen Degradation
(Epinephrine increases) Fat Degradation
(Epinephrine increases) Protein Degradation
(Epinephrine increases)
Diabetes Glycogen Degradation
(Glucagon increases)
(Insulin Decreases) Fat Degradation
(Glucagon Increases)
(Insulin Decreases) Protein Degradation
(Glucagon Increases)
(Insulin Decreases)
Glycogen: short-term reserve form of glucose
Fat: long-term storage form for energy (ATP)(fat produces no glucose equivalents)
Protein: long-term storage reserve of glucose and energy. Prolonged use for energy and glucose depletes muscle mass
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INSULIN-DEPENDENT DIABETES
The key metabolic issue in insulin-dependent diabetes is the lack of insulin. The metabolic picture parallels starvation in that glucagon is released. Even though both blood glucose and fatty acids are elevated, glucagon is secreted in response to increased blood amino acids. This excess glucagon exacerbates the problem by promoting glycogenolysis and lipolysis which further elevate the blood levels of glucose and fatty acids. Thus despite elevated blood glucose, protein and fats are mobilized, and ketone bodies are produced. Glucagon is released in response to elevated blood dietary amino acids, which are not being stored in protein in the absence of insulin (insulin stimulates protein synthesis). Since dietary glucose is still entering the body, there is a marked accumulation of blood glucose, as opposed to what occurs in starvation. Also the feedback mechanism is lost whereby excessive ketone bodies elicit a release of insulin to prevent ketoacidosis.
In diabetes, the control of blood glucose is defective. In juvenile diabetes, there is an inability to produce insulin. Administration of insulin can help to control blood glucose, though a tight control is difficult. With the advent of insulin pumps or the transplantation of isolated pancreatic cells from a donor will come the opportunity for diabetics to better control their insulin levels. In adult-onset diabetes, the problem is often associated with overeating. There is constant bombardment of cells with high levels of insulin and the cells respond by ridding themselves of insulin receptors. Thus in this form of diabetes, insulin administration is of little value.
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EXERCISE
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The fuel requirements for muscle in short, high-intensity exercise (e.g., a sprint) versus endurance activity (e.g., a marathon) differ considerably. In a sprint, the muscle requires a large amount of energy in a short period of time. In the first seconds of the high-intensity exercise, creatine phosphate is used to replenish the rapidly diminishing store of ATP
Creatine phosphokinase: creatine phosphate + ADP ---> creatine + ATP
Use of the creatine phosphate provides sufficient time for glycogenolysis to be activated by both hormonal and allosteric controls. The glucose-6-phosphate derived from glycogenolysis is largely consumed anaerobically via anaerobic glycolysis. Muscles used in sprinting are typically very bulky and therefore can contain tremendous stores of glycogen for the short-term, anaerobic activity.
In contrast, endurance activities require oxidative metabolism to sustain the muscle since glycogen can be depleted rather quickly. Although blood glucose may be used to some extent in such exercise, the principal fuel is fatty acids. Well-trained endurance athletes demonstrate an increased efficiency in mobilizing fats. Clearly it is desirable to not have elevated blood insulin levels before such an event since insulin slows lipolysis. When the ability to mobilize fats is inefficient, for whatever reason, the muscle will deplete its supply of glycogen and then have insufficient fatty acids available to sustain the muscle's energy demands. This is a situation termed "hitting the wall" because like a wall, a limited supply of fatty acids will stop you dead in your tracks.
