Glucose Homeostasis Flashcards
How are energy sources stored?
- Energy sources are stored as glycogen (carbohydrates), protein (amino acids) or triacylglycerol (fatty acids + glycerol).
- Circulating free fatty acids, glucose, and amino acids can be used for energy; amino acids are a minor energy source.
- Under most circumstances, the most important circulating fuel is glucose.
Lactate, Free Fatty Acids and Ketone Bodies
- Lactate, free fatty acids and ketone bodies provide fuel in response to specific physiological conditions.
- Lactate usually recycles back to glucose, but may provide energy for heart function.
- Fatty acids are an important fuel in muscle during sustained, aerobic exercise and for a variety of tissues as one progresses through starvation.
Why can’t the brain use fatty acids as a fuel source?
- However, the brain can NEVER use fatty acids as a fuel because it lacks the necessary pathway for their oxidation.
- Besides, it would be detrimental for the brain to use fatty acids. The higher oxygen requirement for using fatty acids as a fuel could not be met by the brain that normally consumes oxygen at a maximal rate to sustain the oxidation of glucose.
The Fate of Dietary Glucose
- After a typical meal, a significant portion of dietary glucose bypasses the liver, and upon reaching the pancreas promotes the release of insulin from beta-cells.
- Insulin then becomes available to accelerate the storage and metabolism of glucose in a variety of tissues; most notably liver, muscle and adipose.
- Surplus fuel is converted to glycogen and fat under the positive influence of insulin.
Liver and Glucose
- The liver has the capacity to metabolize large amounts of glucose as well as fructose and galactose using specific kinases for each.
- In the liver, glucose is first stored as glycogen and then excess may be metabolized to fatty acids, which are stored as triacylglycerols. T
- hus in the well-fed state, the liver utilizes glucose and does not engage in the de novo synthesis of glucose, unless one is consuming a high protein, very low carbohydrate diet.
- Much of the absorbed glucose circulates to other tissues.
- The brain depends upon the complete oxidation of glucose to CO2 for its production of ATP.
- Red blood cells only metabolize glucose anaerobically for energy production.
- Muscle stores some glucose as glycogen or may metabolize glucose aerobically or anaerobically, depending on the capillary and mitochondrial content associated with a particular muscle.
Blood GlucoseHomeostasis
- Maintenance of blood glucose levels is defined as blood glucose homeostasis.
- The brain’s dependence on glucose under normal conditions requires a complex series of events to ensure that the glucose supply does not diminish appreciably.
- Control of glucose homeostasis is so well-regulated that a very obese individual can fast for months with less than a 25% reduction in blood glucose levels.
- However, glucose homeostasis is lost if insulin levels are not well-regulated such as in type 1 diabetes or in a patient with an insulinoma (insulin-secreting tumor).
High Protein Diet and Blood Glucose Homeostasis
- In individuals consuming a high protein diet, normal blood glucose levels must be maintained without the benefit of sufficient amounts of dietary glucose.
- Amino acids from the hydrolysis of proteins provide precursors for synthesis of glucose in the liver by promoting the release of glucagon from alpha-cells of the pancreas.
- These mechanisms are important for preventing hypoglycemia for individuals on a high protein diet.
The Polyol Pathway
- In typical glucose metabolism, serum glucose is taken up by the cells and initially phosphorylated through the action of hexokinase.
- Yet another pathway exists: the Polyol pathway. Here, glucose is reduced to sorbitol through the action of aldose reductase (consuming NADPH as the reducing substrate).
- Sorbitol can later be reduced by the action of sorbitol dehydrogenase to form fructose that may enter the glycolytic pathway via fructose-6- phosphate.
- At typical glucose levels, this is a lesser pathway due to the lower affinity that aldose reductase has for glucose when compared to hexokinase. In the hyperglycemic state (diabetes mellitus), hexokinase becomes saturated, shunting to the polyol pathway and the accumulation of sorbitol. The accumulation of sorbitol has been implicated in the pathogenesis of vascular and neurologic disease seen in diabetes mellitus.
Sources of Blood Glucose
•Well fed state, absorptive phase
-exogenous (dietary)
•postabsorptive state (4-20 hours after last intake)
-liver glycogen
•early starvation
-de novo glucose synthesis in the liver largely from amino acids - although muscle contains glycogen, this tissue lacks glucose-6-phosphatase and hence cannot produce glucose
Key Substrates for Gluconeogenesis
•Amino acids (primarily alanine) and lactic acid are the key substrates for gluconeogenesis.
Well Fed State
- In the well-fed state, dietary carbohydrate provides the vast majority of the energy needs of the body when at rest, with a small contribution of fatty acids primarily to meet energy needs of the heart.
- The large influx of dietary glucose does not create a severe hyperglycemia because the balance of insulin and glucagon maintains blood glucose homeostasis.
- The pancreas responds to elevated blood glucose by releasing insulin from the beta-cells. Insulin lowers blood glucose through its anabolic effects on glucose uptake by muscle and adipose tissue, and on glycolysis and glycogenesis in liver and muscle.
- Thus, insulin is essential for the proper metabolism of all carbohydrates.
•Just about everything that happens to glucose, amino acids, and fat in the well-fed (absorptive) state depends upon a high ratio of insulin to glucagon, as well as a high ratio of insulin to cortisol that favors protein storage.
Post Absorptive State
- Once dietary glucose is exhausted, the postabsorptive phase of food deprivation (fasting) begins.
- Maintenance of blood glucose now depends on the ability of the body to synthesize glucose either from glycogen or de novo.
- Liver glycogenolysis, activated by glucagon, provides the most glucose (75%) during this transition period.
- This is essential because the complete activation of gluconeogenesis requires about 10 hours.
- This long period of activation is accounted for by the time required to induce several gluconeogenic enzymes especially phosphoenolpyruvate carboxykinase.
- Consequently, while gluconeogenesis is slowly activated, hepatic glycogen breakdown meets the demands for blood glucose.
- As hepatic glycogen dwindles, gluconeogenesis becomes increasingly important.
- Finally, in early starvation, gluconeogenesis becomes the major source of blood glucose.
- The slow rate of gluconeogenesis in the postabsorptive state meets only about 25% of the glucose needs primarily from lactate (10% to 15%) and alanine (5% to 10%).
- The major sites of glucose use during this phase are red blood cells and the brain, which consume about 25% and 55% of the glucose, respectively.
- Red blood cells recycle the carbons from glucose, as lactate, back to the liver to resynthesize glucose.
- In the postabsorptive state, mobilization of fatty acids from triacylglycerol stores commences.
- The contribution of fatty acids as a fuel, though small, gradually increases in peripheral tissues (except brain and red blood cells).
- To spare glucose, oxidation of fatty acids increases during the postabsorptive phase.
•At this time there is still no contribution of ketones to body fuel needs.
Early Starvation
- True starvation commences about 24 hours after the last food intake and comprises the “early” or gluconeogenic phase that is characterized by events that occur in the period of 1 to 5 days after the last meal.
- As food deprivation progresses into early starvation, the body’s glucose needs depend completely on hepatic gluconeogenesis, primarily from lactate and alanine, as well as most other amino acids.
- Amino acids are mobilized from muscle protein stores because of the decreased ratio of insulin to cortisol. This allows expression of cortisol’s catabolic effect on protein metabolism, and thus muscle protein undergoes net degradation.
- This mobilization of amino acids for gluconeogenesis is critical because, in the gluconeogenic phase, the brain still depends solely on glucose even though other peripheral tissues begin to switch to fatty acids.
- Hormone-sensitive lipase of adipose tissue is rate-determining for eventual fatty acid oxidation by muscle and other tissues, and the fall in insulin and rise in glucagon promote release of free fatty acids.
-This point is important since it is the elevated levels of plasma fatty acids that increase tissue oxidation of this fuel.
- However, the brain cannot use fatty acids as a substrate since they penetrate the blood-brain barrier poorly and require too much oxygen for their consumption.
- At this time, only small amounts of ketones have accumulated in the blood, and therefore can only meet limited amounts of the energy needs of the brain. Hence, in early starvation, conservation of glucose for use by the brain (and RBCs) is essential.
- Although not used directly, fatty acids still benefit the brain in two major ways through their obligatory role in promoting hepatic gluconeogenesis and in their ability to conserve glucose in peripheral tissues. Their effects on gluconeogenesis include
1) stimulating pyruvate carboxylase through production of acetyl CoA
2) providing energy
3) generating NADH when amino acids, especially alanine, serve as the precursor for about half of the glucose produced.
•Recall that fatty acids cannot be used for the net synthesis of glucose. Therefore, proteins must be hydrolyzed within muscle to produce the amino acids required for glucose synthesis in liver.
-This is important to remember in the context of weight loss. Dieting alone causes a decrease in both fat and muscle mass. In order to improve body composition, exercise and protein intake is essential to replace muscle loss.
Prolonged Starvation
•The regulatory effect of fatty acid oxidation on glucose utilization in peripheral tissues (except RBC and brain) 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.
•The increased oxidation of fatty acids by muscle causes glucose utilization to diminish largely through the inhibitory effect of acetyl CoA on pyruvate dehydrogenase.
-Inhibiting pyruvate dehydrogenase diverts the glucose carbons to alanine, lactate or other amino acids for use in hepatic gluconeogenesis.
- After about 5 days food deprivation, the body begins transitioning to the prolonged starvation phase characterized by even less dependence upon hepatic gluconeogenesis. However, gluconeogenesis remains active to provide glucose for red blood cells, since red blood cells can use no fuel other than glucose.
- The energy needs of tissues containing mitochondria are now being met to a great extent by oxidation of either fatty acids or ketone bodies.
- Ketones, produced from excess fatty acids in liver, provide an alternate fuel and limit glucose oxidation in a similar way as do fats in muscle.
- In prolonged starvation ketones are used as a fuel in the brain along with most other tissues (except RBCs and liver).
- Use of ketone bodies by the brain inhibits oxidation of glucose as they do in muscle, by the same mechanism as during oxidation of fatty acids.
- Decreased oxidation of glucose by the brain reduces glucose use, thus contributing to maintaining blood glucose homeostasis.
-This is important because ketone bodies also suppress the loss of protein in skeletal muscle to decrease muscle wasting, and thereby decrease glucose production. Hence both glucose production and use decrease in parallel, and blood glucose levels are preserved.
- As long as the concentration of ketone bodies remains high, proteolysis is restricted, and conservation of muscle proteins occurs.
- This process continues until all the fat stores are depleted. Once this occurs, gluconeogenesis ceases because of the obligatory role of fatty acids, and blood glucose levels rapidly decline. Consequently all fuel supplies disappear from the blood.
