Chapter 5Endocrine Regulation of Glucose MetabolismOverview of Glucose HomeostasisGlucose metabolism is critical to normal physiological functioning. Glucose acts bothas a source of energy and as a source of starting material for nearly all types ofbiosynthetic reactions. The diagram shows the major players in the regulation andutilization of plasma glucose.Figure 1. The organs that control plasma glucose levels. The normal plasma glucoseconcentration varies between about 70 and 120 mg/dL (3.9-6.7 mM). Note that wholeblood glucose values are about 10-15% lower than plasma values due to the removalof cellular components during preparation of plasma.The brain uses about 120 grams of glucose daily: 60-70% of the total body glucosemetabolism. The brain has little stored glucose, and no other energy stores. Brainfunction begins to become seriously affected when glucose levels fall below ~40mg/dL; levels of glucose significantly below this can lead to permanent damage anddeath. The brain cannot use fatty acids for energy (fatty acids do not cross the blood-brain barrier); ketone bodies can enter the brain and can be used for energy inemergencies. The brain can only use glucose, or, under conditions of starvation,ketone bodies (acetoacetate and hydroxybutyrate) for energy.The diet is one source of circulating glucose, and provides carbon and energy sourcesfor liver gluconeogenesis.The liver is the major metabolic regulatory organ. About 90% of all circulatingglucose not derived directly from the diet comes from the liver. The liver containssignificant amounts of stored glycogen available for rapid release into circulation,and is capable of synthesizing large quantities of glucose from substrates such aslactate, amino acids, and glycerol released by other tissues. In addition tocontrolling plasma glucose, the liver is responsible for synthesis and release of thelipoproteins that adipose and other tissues use as the source of cholesterol and free55Chapter 5. Glucose Homeostasis Endocrine -- Dr. Brandtfatty acids. During prolonged starvation, the liver is the source of both glucose andthe ketone bodies required by the brain to replace glucose. The liver uses glycolysisprimarily as a source of biosynthetic intermediates, with amino acid and fatty acidbreakdown providing the majority of its fuel.Like the liver, the kidney has the ability to release glucose into the blood. Undernormal conditions gluconeogenesis in the kidney provides only a small contributionto the total circulating glucose; however, during prolonged starvation, the kidneycontribution may approach that of the liver. Kidney function is critical for glucosehomeostasis for another reason; plasma glucose continuously passes through thekidney and must be efficiently reabsorbed to prevent losses.The muscle cannot release glucose into circulation; however, its ability torapidly increase its glucose uptake is critical for dealing with sudden increases inplasma glucose. Skeletal muscle has an additional role in maintaining plasmaglucose levels: it releases free amino acids into circulation to serve as substrates forliver gluconeogenesis. The muscle can use glucose, fatty acids, and ketone bodies forenergy. The muscle normally maintains significant amounts of stored glycogen,small amounts of fatty acids, and contains a large pool of protein that can be brokendown in emergencies. The resting muscle uses fatty acids as its primary energysource; however, glucose (from its own glycogen stores and from circulation), ispreferred for rapid energy generation (e.g. in sudden exercise).The adipose tissue is the major site of fatty acid storage. Fatty acids are stored inthe form of triacylglycerol, which is synthesized in the adipose tissue from glycerol-phosphate and free fatty acids. The glycerol-phosphate used must be derived fromglycolysis in the adipose tissue; free glycerol cannot be phosphorylated becauseadipocytes lack the relevant kinase. In conditions when liver gluconeogenesis isnecessary the adipose tissue supplies free fatty acids and glycerol to the circulationto be taken up by the liver as substrate.Finally, the pancreas is the source of insulin and glucagon, two of the mostimportant metabolic regulatory hormones. The synthesis, release, and actions ofthese hormones is the major subject of this chapter.Glycolysis and GluconeogenesisGlycolysis (Figure 2) is a major energy production pathway used at least to somedegree in all cells. In addition, glycolytic intermediates and products act as carbonsources for nearly all biosynthetic reactions, and the reducing equivalents requiredfor most biosynthetic reactions are derived from the flow of glucose through thepentose phosphate pathway. Glucose homeostasis is thus of central importance inmetabolism and is heavily regulated.56Chapter 5. Glucose Homeostasis Endocrine -- Dr. BrandtGlucoseGlucose-6-PGlucose-1-PGlycogenFructose-6-PFructose-1,6-P2Glyceraldehyde-3-P + Dihydroxyacetone-PPhosphoenolpyruvate OxaloacetateHexokinaseGlucose-6-PhosphatasePhosphoglucoisomeraseFructoseBis PhosphataseAldolasePhosphoenolpyruvatecarboxykinasePhosphoglucomutaseGlycogenSynthasePhosphorylaseTCA intermediatesGlucoseGlucokinasePhosphofructokinaseTriose phosphateisomerase1,3-BisphosphoglycerateGlyceraldehyde-3-phosphatedehydrogenasePhosphoglyceratekinase3-Phosphoglycerate2-PhosphoglyceratePhosphoglyceratemutaseEnolasePyruvatePyruvatekinaseGlycerolPyruvatecarboxylaseLactateTCA CycleFatty acid biosynthesisAmino acid biosynthesisNucleotide biosynthesis}{Amino acidsPentose phosphate pathwayUDP-GlucoseUDP-GlucosePyrophosphorylaseSerineFigure 2. The glycolytic, gluconeogenic, pentose phosphate, and glycogen syntheticpathways. The primary regulated steps are catalyzed by the underlined enzymes.Note the convergence of the pathways at glucose-6-phosphate. Note also thatalthough glucose can be phosphorylated in all tissues, the reversal enzyme glucose-6-phosphatase is only found in liver and kidney.Metabolism of free glucose begins with a phosphorylation reaction that yieldsglucose-6-phosphate. This reaction is catalyzed by hexokinase in most tissues.57Chapter 5. Glucose Homeostasis Endocrine -- Dr. BrandtHexokinase has a relatively high affinity for glucose; in most tissues the rate of thehexokinase reaction is limited by the rate of glucose import into the cell, or byglucose-6-phosphate inhibition of the enzyme. In the liver and pancreas, anotherenzyme, glucokinase, also catalyzes this reaction. Unlike hexokinase,