Glucose Homeostasis: Biochemistry and Molecular Biology

• Lecture 18 focuses on Glucose Homeostasis
• The lecture covers chapters 11 and 16 of "Biochemistry and Molecular Biology".

Learning Outcomes

• Able to explain why glucose is an important metabolic fuel
• Able to describe the sources of glucose available to the body
• Able to outline the time course of blood glucose homeostasis after a meal
• Able to explain the importance of liver glycogen in blood glucose maintenance
• Able to explain skeletal muscle glycogen as a metabolic fuel
• Able to outline the enzyme reactions in glycogen synthesis and degradation
• Able to give an example control mechanism in the regulation of glycogen metabolism
• Able to outline gluconeogenesis in the liver
• Able to summarise the roles of insulin and glucagon maintaining glucose homeostasis

The Requirement for Glucose

• Preferred fuel source for all tissues
• Some tissues depend on glucose continuously
• The physiological circulating concentration is 3.9-6.7 mM average
• In most adults, fasting levels are 4.4-5 mM
• Coma and death can result if glucose drops to 2.5 mM or less
• If elevated for an extended time dehydration, wasting of body tissue, and death will result

Roles of Glucose

• Acts as a source of energy
• Required for synthetic reactions like fatty acids and steroids synthesis
• The pentose phosphate pathway converts glucose to pentose sugars for nucleotide synthesis
• The pentose phosphate pathway reduces NADP to NADPH for 'reducing power'
• It is a source of carbon for other sugars

Advantages and Disadvantages of Glucose

• Advantages, it's water-soluble so it doesn't need a carrier in circulation
• Advantages, it can cross the blood-brain barrier
• Advantages, it can be oxidised anaerobically
• Disadvantages, it has a relatively low yield of ATP/mole compared to fatty acids
• Disadvantages, it's osmotically active
• Disadvantages, in high concentrations it can damage cells or accumulate toxic by-products

Sources of Blood Glucose

• Diet supplies glucose for 0-4 hours post ingestion
• Liver provides glycogen for roughly 2-24 hours max
• Liver provides gluconeogenesis from 4 hours onwards until death

Structure and Function of Glucose and Glycogen

• Glucose is a Monosaccharide
• Circulates at roughly 10g in plasma
• Is osmotically active
• Acts as an immediate energy source
• Glycogen is a Polysaccharide
• Tissues store roughly 400g
• Shows low osmolarity
• Used as a medium-term fuel

Glycogen Structure

• Has a branched structure
• Contains terminal residues
• Contains -1,6 bonds
• Contains -1,4 glycosidic bonds

Role of Glycogen in the Liver

• 100-120g of glycogen present in liver
• The liver is sensitive to blood glucose concentration
• Acts to maintain blood glucose under the control of insulin and glucagon

Role of Glycogen in Muscle

• 250 – 300g of glycogen present in muscles
• Fuel for exercise
• The muscle is sensitive to energy needs of the tissue
• Muscle is sensitive to adrenaline, calcium, AMP, ATP

Glycogen Synthesis and Breakdown

• Glycogen synthesis involves glycogen synthase
• Glycogen synthase requires energy (ATP hydrolysis)
• Glycogen synthase proceeds via an 'activated' intermediate: UDP glucose
• Glycogen breakdown involves glycogen phosphorylase, also known as glycogenolysis
• Glycogen phosphorylase involves phosphorolysis using Pi (not ATP)
• Final product in liver: glucose
• Final product in muscle: glucose-6-phosphate entering glycolysis pathway
• Synthesis and breakdown pathways are not a direct reversal of each other
• Independent regulation prevents 'futile cycle'

Glycogen Synthesis (1)

• Activation of glucose is performed by hexokinase (muscle) or glucokinase (liver)
• Glucose 6-phosphate is converted by Phosphoglucomutase
• Glucose 1-phosphate converted to UDP glucose pyrophosphorylase

Glycogen Synthesis (2)

• UDP-glucose + Glycogen primer with n glucose molecules are converted by Glycogen synthase
• Glycogen primer gets UDP molecule added and becomes a strand with n+1 glucose molecules
• A 'branching enzyme' is required to catalyse formation of -1,6 bonds

Glycogen Breakdown (1)

• Glycogen chains broken down by addition of Pi by Glycogen phosphorylase
• Glycogen phosphorylase produces Glucose-1-phosphate and a shorter Glycogen chain
• 'debranching enzyme' is required to catalyse breakage of -1,6 bonds

Glycogen Breakdown (2)

• The liver is the main organ responsible for regulating blood sugar concentration
• The muscle takes up free glucose; and once it's phosphorylated, it cannot leave from the muscle
• Only the liver (and kidney) glycogen can be used to create free glucose to aid in blood sugar regulation

Regulation of Glycogen Metabolism

• The pathway is under allosteric control
• The pathway is under hormonal control
• One example of hormonal control is glucagon/adrenaline

Hormonal Regulation

• Hormones bind cell surface receptors and activate internal signalling pathways
• Internal signalling activates a protein kinase
• Kinase deactivates Glycogen synthase
• Kinase activates Glycogen phosphorylase

Gluconeogenesis

• In conditions of carbohydrate deprivation glucose is synthesised from non-carbohydrate sources in the liver
• Non-carbohydrate sources used include lactate, glucogenic amino acids (except Leu, Lys), and glycerol from stored triglyceride fat.
• Gluconeogenesis does NOT use fatty acids

Gluconeogenesis and Glycolysis

• Gluconeogenesis is not simply the reversal of glycolysis
• Three irreversible reactions in glycolysis must be bypassed
• These three catalytic reactions include: hexokinase/ glucokinase, phosphofructokinase, and pyruvate kinase
• These irreversible reactions all occur in the cytosol

Reversal of Kinase Reactions

• The action of phosphatases reverses kinase reactions
• These are not reversals of reactions in glycolysis, as no ATP is produced
• Water is used to hydrolyse the phosphate ester, releasing Pi

Reversal of Pyruvate Kinase

1. Pyruvate carboxylated by pyruvate carboxylase within mitochondria, yielding oxaloacetate
2. Oxaloacetate is converted into PEP by the action of PEP carboxykinase, requiring GTP

Pyruvate Carboxylase Reaction

• Allows regeneration of glucose from pyruvate
• The Cori cycle sees lactate from muscle converted to glucose in the liver
• Glucose returns to the muscle and is used in glycolysis
• The enzyme lactate dehydrogenase converts lactate to pyruvate

Blood Glucose Maintenance

• Insulin, glucagon and adrenaline, cortisol, and glucose itself coordinate activities of liver, adipose, and muscle tissue
• Needed to maintain physiological blood glucose concentrations
• Needed to preserve function of brain and other tissues

Islets of Langerhans

• Islets of Langerhans in the pancreas contain ALPHA CELLS, which produce glucagon
• They contain BETA CELLS, which produce insulin

Insulin vs Glucagon

• Insulin is an anabolic hormone that promotes synthesis and storage
• Glucagon is a catabolic hormone that promotes degradation of stored fuel

Metabolic Effects of Insulin

• In the liver: activates glycogen synthesis (glycogen synthase activated), increases amino acid uptake and protein synthesis, increases Fatty Acid synthesis and lipid assembly, and inhibits gluconeogenesis
• In muscle: activates glycogen synthesis (glycogen synthase activated), increases amino acid uptake and protein synthesis, and increases glucose uptake by increasing translocation of glucose transporters (GLUT4) from cytosol to membrane

Metabolic Effects of Glucagon

• Increase in blood glucose through glycogenolysis and gluconeogenesis (liver)
• Increase in circulating fatty acids and ketone bodies through adipose tissue lipolysis, and fatty acid oxidation and ketone body formation in the liver
• Decrease in plasma amino acids through uptake by the liver for gluconeogenesis
• Glucagon has No effect on muscle cells due to the absence of glucagon receptors