Chapter 5 Endocrine Regulation of Glucose Metabolism Overview of Glucose Homeostasis Glucose metabolism is critical to normal physiological functioning Glucose acts both as a source of energy and as a source of starting material for nearly all types of biosynthetic reactions The diagram shows the major players in the regulation and utilization of plasma glucose Figure 1 The organs that control plasma glucose levels The normal plasma glucose concentration varies between about 70 and 120 mg dL 3 9 6 7 mM Note that whole blood glucose values are about 10 15 lower than plasma values due to the removal of cellular components during preparation of plasma The brain uses about 120 grams of glucose daily 60 70 of the total body glucose metabolism The brain has little stored glucose and no other energy stores Brain function begins to become seriously affected when glucose levels fall below 40 mg dL levels of glucose significantly below this can lead to permanent damage and death The brain cannot use fatty acids for energy fatty acids do not cross the bloodbrain barrier ketone bodies can enter the brain and can be used for energy in emergencies 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 sources for liver gluconeogenesis The liver is the major metabolic regulatory organ About 90 of all circulating glucose not derived directly from the diet comes from the liver The liver contains significant amounts of stored glycogen available for rapid release into circulation and is capable of synthesizing large quantities of glucose from substrates such as lactate amino acids and glycerol released by other tissues In addition to controlling plasma glucose the liver is responsible for synthesis and release of the lipoproteins that adipose and other tissues use as the source of cholesterol and free 55 Chapter 5 Glucose Homeostasis Endocrine Dr Brandt fatty acids During prolonged starvation the liver is the source of both glucose and the ketone bodies required by the brain to replace glucose The liver uses glycolysis primarily as a source of biosynthetic intermediates with amino acid and fatty acid breakdown providing the majority of its fuel Like the liver the kidney has the ability to release glucose into the blood Under normal conditions gluconeogenesis in the kidney provides only a small contribution to the total circulating glucose however during prolonged starvation the kidney contribution may approach that of the liver Kidney function is critical for glucose homeostasis for another reason plasma glucose continuously passes through the kidney and must be efficiently reabsorbed to prevent losses The muscle cannot release glucose into circulation however its ability to rapidly increase its glucose uptake is critical for dealing with sudden increases in plasma glucose Skeletal muscle has an additional role in maintaining plasma glucose levels it releases free amino acids into circulation to serve as substrates for liver gluconeogenesis The muscle can use glucose fatty acids and ketone bodies for energy The muscle normally maintains significant amounts of stored glycogen small amounts of fatty acids and contains a large pool of protein that can be broken down in emergencies The resting muscle uses fatty acids as its primary energy source however glucose from its own glycogen stores and from circulation is preferred for rapid energy generation e g in sudden exercise The adipose tissue is the major site of fatty acid storage Fatty acids are stored in the form of triacylglycerol which is synthesized in the adipose tissue from glycerolphosphate and free fatty acids The glycerol phosphate used must be derived from glycolysis in the adipose tissue free glycerol cannot be phosphorylated because adipocytes lack the relevant kinase In conditions when liver gluconeogenesis is necessary the adipose tissue supplies free fatty acids and glycerol to the circulation to be taken up by the liver as substrate Finally the pancreas is the source of insulin and glucagon two of the most important metabolic regulatory hormones The synthesis release and actions of these hormones is the major subject of this chapter Glycolysis and Gluconeogenesis Glycolysis Figure 2 is a major energy production pathway used at least to some degree in all cells In addition glycolytic intermediates and products act as carbon sources for nearly all biosynthetic reactions and the reducing equivalents required for most biosynthetic reactions are derived from the flow of glucose through the pentose phosphate pathway Glucose homeostasis is thus of central importance in metabolism and is heavily regulated 56 Chapter 5 Glucose Homeostasis Endocrine Dr Brandt Glucose Pentose phosphate pathway Hexokinase Glucokinase Glucose Phospho glucomutase Glucose 6 P UDP Glucose Pyrophosphorylase Glucose 1 P Phospho glucoisomerase Glucose 6Phosphatase Glycogen Synthase UDP Glucose Glycogen Phosphorylase Fructose 6 P Fructose Bis Phosphatase Phosphofructokinase Fructose 1 6 P 2 Aldolase Glyceraldehyde 3 P Dihydroxyacetone P Glycerol Triose phosphate isomerase Glyceraldehyde 3 phosphate dehydrogenase 1 3 Bisphosphoglycerate Phosphoglycerate kinase Serine 3 Phosphoglycerate Phosphoglycerate mutase 2 Phosphoglycerate Phosphoenolpyruvate carboxykinase Phosphoenolpyruvate Oxaloacetate Enolase Pyruvate kinase Pyruvate carboxylase Pyruvate Amino acids TCA intermediates Lactate TCA Cycle Fatty acid biosynthesis Amino acid biosynthesis Nucleotide biosynthesis Figure 2 The glycolytic gluconeogenic pentose phosphate and glycogen synthetic pathways The primary regulated steps are catalyzed by the underlined enzymes Note the convergence of the pathways at glucose 6 phosphate Note also that although glucose can be phosphorylated in all tissues the reversal enzyme glucose 6phosphatase is only found in liver and kidney Metabolism of free glucose begins with a phosphorylation reaction that yields glucose 6 phosphate This reaction is catalyzed by hexokinase in most tissues 57 Chapter 5 Glucose Homeostasis Endocrine Dr Brandt Hexokinase has a relatively high affinity for glucose in most tissues the rate of the hexokinase reaction is limited by the rate of glucose import into the cell or by glucose 6 phosphate inhibition of the enzyme In the liver and pancreas another enzyme glucokinase also catalyzes this reaction Unlike hexokinase