31 MUBMED2GIHEP Post-absorption Carbs 2024-25.pptx

Royal College of Surgeons in Ireland – Medical University of Bahrain Post-absorption processing of carbohydrates Module : GIHEP Class: MedYear2 Semester 1 Lecturer : Paul O’Farrell Date : 23 September 2024 Learning objectives Describe glycogen synthesis and metabolism in th...

Royal College of Surgeons in Ireland – Medical University of Bahrain Post-absorption processing of carbohydrates Module : GIHEP Class: MedYear2 Semester 1 Lecturer : Paul O’Farrell Date : 23 September 2024 Learning objectives Describe glycogen synthesis and metabolism in the fed & fasting states Describe the hormonal regulation of glycogen by insulin, glucagon and the catecholamines Explain the Cori Cycle and its role in the fasting state Explain the role of gluconeogenesis in maintaining plasma glucose Describe a pathophysiological example: e.g. Glycogen Storage Disorders: Von Gierkes Disease Carbohydrate metabolism glycogen synthesis synthesis of glycogen from glucose (from Glycogen food sources) glycogen glycogenolysis glycogenolysis synthesis degradation of glycogen into glucose glucose gluconeogenesis glycolysis synthesis of glucose from non- gluconeogenesis carbohydrate sources such as carbon skeletons of amino acids pyruvate glycolysis degradation of glucose to pyruvate acetyl coA Kreb’s cycle (TCA, CAC) conversion of acetyl coA into carbon dioxide, water and NADH Kreb’s cycle oxidative phosphorylation extraction of energy in NADH to generate Oxidative phosphorylation ATP Fed and fasting states Nutrients Plentiful: build up stores A major physiological switch in the body, mediated by insulin and glucagon (and adrenaline) Nutrients limited: use stores to maintain functions Fed state High levels of – Plasma glucose – Plasma amino acids – Plasma triglycerides Control – Insulin increased – Glucagon decreased Response – Liver: makes glycogen, triglycerides, and protein – Adipose: makes triglyceride – Muscle: Makes glycogen, protein Tissues use glucose as fuel Fasting state Reduced levels of – Plasma glucose – Plasma amino acids – Plasma triglycerides Control – Insulin decreased – Glucagon increased, adrenaline increased Response – Liver: glycogenolysis, gluconeogenesis, β-oxidation, ketogenesis – Adipose: lipolysis – Muscle: proteolysis supplies AAs for gluconeogenesis; muscle uses fatty acids and ketone bodies as fuel. Glycogenolysis: muscle uses its own glycogen for energy, but does NOT export glucose to the bloodstream – Brain uses glucose and ketone bodies (later) as fuel Glycogen Constant source of blood glucose needed for life Glucose greatly preferred by the brain; needed by cells without mitochondria, like the erythrocyte Dietary intake unreliable  Glucose is stored in a readily mobilizable form – glycogen – In Liver (~100g) [and muscle (~400g)] Glycogen A homopolymer of glucose joined by Lippencott’s 11.3 α-1,4 and α-1,6 glycosidic bonds Glycogen flux: glycogen is a dynamic resource Synthesis of glycogen “glycogenesis” Occurs in cytosol Requires ATP and uridine triphosphate (UTP) Glucose  glucose-6-P Glucose-1-P generated from glucose-6-P by phosphoglucomutase UDP-glucose synthesised by UDP-glucose pyrophosphorylase UDP-glucose and glycogen are the substrates for glycogen synthase Synthesis of glycogen Glycogen synthase makes α-1,4 linkages between UDP-Glucose and the non-reducing end of a glycogen chain (UDP is released) It cannot initiate chains, only elongate them Initiation is by a protein – glycogenin 1st glucose is added to a specific tyrosine residue in glycogenin The glucose is attached via its reducing end (position 1) Transfer of the 1st few glucose molecules is catalysed by glycogenin itself, after which glycogen synthase can operate Non-Reducing end Reducing end Glycogen branching Branches made by “branching enzyme” Breaks a chain of 5-8 glucose residues off the non- reducing end of glycogen (breaks α-1,4 bond), attaches it to a residue in a chain via α-1,6 bond. [amylo- α-1,4 - α-1,6-transglucosidase] Now we have 2 non-reducing ends available to glycogen synthase Synthesis and branching continues ……. Glycogen synthesis Lippencott’s 11.5 Glycogenolysis – degradation of glycogen Glycogen phosphorylase cleaves the α-1,4 bond at the non-reducing end of a glycogen branch, generating glucose-1-phosphate. Continues until 4 glucose residues before a branch point “debranching enzyme” i) oligo-α-(1,4)-α-(1,4) glucan transferase removes the last 3 residues and transfers them to a non-reducing end ii) Amylo- α-(1,6) glucosidase releases free glucose from the α- (1,6) bond Each of these activities is carried out by a separate domain of debranching enzyme Glycogenolysis – degradation of glycogen The main direct product of glycogen breakdown is glucose-1- phosphate (a small amount of free glucose is released from branch points) Phosphoglucomutase converts G-1-P to G-6-P Glucose-6-phosphate translocase moves G-6-P into the ER Within the ER Glucose-6-phosphatase releases free glucose, which can then be released to the bloodstream (Liver) Muscle cells do not have glucose-6-phosphatase and do not release glucose to the bloodstream Glycogenolysis – degradation of glycogen Phosphoglucomutase Glucose-6-phosphate G6P Translocase Glucose-6-phosphatase Glucose Glucose  Regulation of Glycogen Metabolism - determined by the energy requirements of the cell Fed state  ▲synthesis ▼degradation Fasting state  ▼ synthesis ▲ degradation - Primary points of regulation are: Glycogen Synthase Glycogen Phosphorylase - Regulation occurs by: - Allosteric regulation - Hormonal regulation Allosteric regulation of Glycogen Synthesis In the liver Glucose-6-P allosterically - activates Glycogen Synthase - inhibits Glycogen Phosphorylase In muscle, Ca2+ (released during contraction) and AMP (generated by ATP depletion) activate Glycogen Phosphorylase  Hormonal Regulation of Glycogen Synthesis - Activities of glycogen synthase and glycogen phosphorylase are controlled by phosphorylation/dephosphorylation Protein Kinases  phosphorylation Phosphatases  dephosphorylation Glycogen Breakdown Protein Protein Kinase A Phosphatase 1 Glycogen Glycogen Glycogen synthase phosphorylase Synthesis Active ”a” form Inactive ”b” form  Hormonal Regulation of Glycogen Synthesis Glucagon - secreted from the pancreas when blood sugar is low (fasting state) - binds glucagon receptor (GsPCR) in liver → increases cAMP and activates protein kinase A → inactivates PP1 → inactivates glucagon synthase and activates phosphorylase → glycogen is broken down and glucose is released Adrenaline - released from adrenal glands during exercise - binds a-adrenoreceptor (GsPCR) in liver or muscle → increases cAMP and activates protein kinase A → inactivates PP1 → inactivates glucagon synthase and activates phosphorylase → glycogen is broken down and glucose is released Insulin - secreted from the pancreas when blood sugar is high (fed state) - binds Insulin Receptors (RTK) in Liver and Muscle → activates PP1 → activates glucagon synthase and inactivates phosphorylase → glycogen is synthesised (ie, glucose is stored) *Cortisol has mixed effects- increasing glycogen synthesis in liver and promoting breakdown in muscle Hormonal Regulation of Glycogen Synthesis Glucose utilization/ glycogen depletion Glycogen stores don’t last forever... Gluconeogenesis (see also Year1 FFP1 anabolic pathways) Some tissues specifically need glucose – RBC, brain, testes, lens of eye Glycogen stores will only last 10-18 hrs When glycogen is depleted, glucose must be formed from other precursors This occurs through the process of gluconeogenesis – Can be conceptualized as a reversal of glycolysis – Shared enzymes – Irreversible steps of glycolysis? Gluconeogenesis and glycolysis 1 – pyruvate carboxylase 2 – PEP-carboxy kinase } Pyruvate kinase 3 – fructose-1,6-bisphosphatase }phosphofructokinase 4 – glucose-6-phosphatase (G-6-P translocase) } Hexokinase, glucokinase 2 ADP 2 ATP Note energy requirements Substrates for gluconeogenesis: Lactate – released into blood by exercising muscle; - see the ‘Cori Cycle’ Glycerol – from fat stores (triglycerides) Amino-acids – from tissue protein breakdown  The Cori Cycle Metabolic pathway named after its discoverers, Carl and Gerty Cori (1929) - sometimes referred to as the lactic acid cycle Lactate produced by muscle cells during metabolism is converted into glucose Steps of the Cori cycle 1. Lactate is transported to the liver through the blood. 2. Lactate is processed by lactate dehydrogenase (LDH) into pyruvate. 3. Pyruvate goes though gluconeogenesis to produce glucose. 4. Finally, glucose is exported into the blood and taken up by the muscles.  Glycogen Storage Disorders - a group of inherited metabolic disorders caused by a deficiency of enzymes required for glycogen synthesis or breakdown in muscle or liver cells - Results in chronic hypoglycaemia - also enlarged liver, muscle fatigue, cramps - There are at known to be 12 types of GSD (named I-XII) with disease severity depending on the particular enzyme affected and its tissue distribution - GSDs can affect the liver, the muscles, or both. Glycogen storage disorders 12 different GSDs have been described GSD I Von Gierkes’s Disease – 1a Glucose-6-phosphatase deficiency 1b G6P-translocase deficiency – Hypoglycemia, lactic acidosis, ketosis – 25% of all GSD’s – Incidence: 1/100,000 live births Von Gierkes Disease Other GSDs info only Kumar and Clarke 6th ed Reading Lippencott’s 7th ed, Chapters 10 11 24 Meisenberg & Simmons 4th ed Chapter 24 Glycogen metabolism in humans (review article link)