sources, glycogenolysis and gluconeogenesis, and glucose use by muscle, heart, adipose tissue, brain, and blood elements The liver plays a unique role in glucose homeostasis because it stores glucose as glycogen With fasting, this glycogen is degraded to glucose, which is released into the bloodstream In addition, the liver synthesizes new glucose from glycerol, lactate, and certain amino acids During fasting, lipolysis occurs, and the resultant fatty acids are used for the production of both energy and ketones (acetoacetate and β-hydroxybutyrate) by the liver The energy generated from the metabolism of fatty acids is essential to sustain maximal rates of gluconeogenesis and ureagenesis in the liver The ketones are an important auxiliary fuel for most tissues, including the brain Muscle contains significant quantities of glycogen and protein Under fasting conditions, the glycogen is degraded and used endogenously but is not released as free glucose into the bloodstream Certain amino acids, particularly alanine and glycine, are released from the muscle and subsequently used by the liver for gluconeogenesis Muscle derives an increasing proportion of its energy requirement from fatty acids as fasting proceeds Brain tissue is highly dependent on glucose for its energy requirements Under certain circumstances, it can extract a limited proportion of its energy requirement from other substrates (e.g., glycerol, ketones, lactate), although this process requires a period of adaptation and does not obviate the need for a constant supply of glucose Insulin is the primary hormone that regulates the blood glucose level Insulin stimulates the uptake of glucose and amino acids into skeletal, cardiac, and adipose tissue and promotes glycogen and protein synthesis It inhibits lipolysis and glycogenolysis The net effect of insulin action is to accelerate the removal of glucose and gluconeogenic substrates from the bloodstream Opposing or modulating the effects of insulin are cortisol, glucagon, epinephrine, and growth hormone The effects of these hormones include inhibition of glucose uptake by muscle, mobilization of amino acids for gluconeogenesis, activation of lipolysis, inhibition of insulin secretion, and induction of gluconeogenic enzymes The net effect is to increase the availability of gluconeogenic substrates to the liver, and to increase the accessibility and use of nonglucose fuels by other tissues