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Carbohydrate Metabolism I & II Central Aspects of Macronutrient

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Carbohydrate Metabolism I & II Central Aspects of Macronutrient Carbohydrate Metabolism I & II - General concepts of glucose metabolism - - Glycolysis - -TCA - FScN4621W Xiaoli Chen, PhD Food Science and Nutrition University of Minnesota 1 Central Aspects of Macronutrient Metabolism Macronutrients (carbohydrate, lipid, protein) Catabolic metabolism Oxidation Metabolites (smaller molecules) Anabolic metabolism Energy (ATP) Synthesis of cellular components or energy stores Chemical Reactions Cellular Activities 2 Central Aspects of Macronutrient Metabolism High-energy compounds ◦ ATP (adenosine triphosphate) ◦ NADPH (reduced nicotinamide adenine dinucleotide phosphate) ◦ NADH (reduced nicotinamide adenine dinucleotide) ◦ FADH2 (reduced flavin adenine dinucleotide) Oxidation of macronutrients NADH NADPH FADH2 ATP and NADPH are required ATP for anabolic metabolism 3 1 Unit I General Concepts of Glucose Metabolism Metabolic pathways of glucose Glucose homeostasis Glucose transport in tissues Glucose metabolism in specific tissues 4 Overview Digestion, Absorption and Transport of Carbs ◦ Final products of digestion: ________,glucose ________, fructose and ________galactose Cellular fuels ◦ Glucose, fatty acids, ketone bodies, amino acids, other gluoconeogenic precursors (glycerol, lactate, propionate) Glucose: primary metabolic fuel in humans ◦ Provide 32% to 70% of the energy in diet of American population All tissues are able to use glucose as energy fuels ◦ Glucose has different metabolic fate in different tissues Physiological states determine glucose metabolic fate ◦ Fed/fasted – glucose is metabolized through distinct pathways Main goal – the maintenance of circulating glucose 5 Overview How your body metabolizes carbohydrates At the tissue and organ level ◦ Different tissues/organs have different roles in the regulation of energy metabolism (metabolic pathways and substrates and metabolite flows) At the subcellular level ◦ Each organelle or compartment has specific roles in the regulation of metabolic pathways 6 2 General Concepts Anabolic pathways ◦ Synthesis of larger compounds/molecules from smaller precursors Catabolic pathways ◦ Breakdown of larger molecules Amphibolic pathways ◦ Links between anabolic and catabolic pathways ◦ Example: citric acid cycle (TCA cycle) 7 General Concepts Aerobic pathway ◦ Aerobic is an adjective that means "requiring air", where "air" usually means oxygen ◦ Where does aerobic metabolism occur in the cell? ◦ What are the end products of aerobic metabolism? ◦ Example: Anaerobic pathway ◦ Anaerobic – without air, as opposed to aerobic ◦ Where does anaerobic metabolism occur in the cell? ◦ What are the end products of anaerobic metabolism? ◦ Example: 8 What you need to know about Carbohydrate Metabolic Pathways Pathway Catabolic/ Physiological Tissue Function Anabolic State Glycolysis Glycogenesis Gluconeogenesis Glycogenolysis Pentose phosphate pathway 9 3 What you need to know about Carbohydrate Metabolic Pathways Pathway Rate-limiting Key How is it regulated reaction(s) enzymes by hormones? Glycolysis Glycogenesis Gluconeogenesis Glycogenolysis Pentose phosphate pathway 10 Circulating Glucose Glucose levels in the blood are kept within a strictly regulated concentration range ◦ Postabsorptive state: 4.5-5.5 m mol/L ◦ In starvation: 3.3-3.9 m mol/L ◦ After ingestion of carbohydrate meal: 6.5-7.2 m mol/L 11 Pathways of glucose metabolism Glycolysis ◦ the metabolic pathway that converts glucose C6H12O6, into pyruvate Glycogenesis = glycogen synthesis ◦ the process of glycogen synthesis Gluconeogenesis ◦ Gluconeogenesis, (GNG) is a metabolic pathway that ◦ results in the generation of glucose from non-carbohydrate carbon substrates Glycogenolysis = glycogen breakdown ◦ the breakdown of glycogen (n) to glucose-6-phosphate and glycogen (n-1). 12 4 Glucose Homeostasis How dietary glucose is metabolized after a meal In the fed state After a meal Glycolysis Other glycolytic Liver Glycogenesis tissues Pancreas Gluconeogenesis FAT Glycogenolysis 2-3% brain insulin 20% of Glucose GLUT3 Glycolysis absorpted 22% GLUT1 glucose Glucose In the circulation insulin Glycolysis GLUT4 Glycogenesis Glycogenolysis muscle insulin Lactate Diet Glycolysis Glucose CHO conversion carbohydrate GLUT4 to Fat Small intestine Adipose tissue 13 Glucose Homeostasis How the circulating glucose is maintained during fasting FOOD GLYCOGEN X Fed NON HEXOSE STORES PRECURSORS FastCirculating Fast Glucose Gluconeogenesis Glycogenolysis Prolonged Fast Kidney Gluconeogenesis 14 How does each tissue or organ play a role in glucose homeostasis? Fed state 1. What happens to blood glucose levels after a meal? 2. What does the body do to maintain normal blood glucose levels? Pancreas – Islet ◦ Secrets insulin in response to high blood glucose levels Liver ◦ Makes glycogen from dietary glucose ◦ Converts glucose to fatty acids if the amount of absorbed glucose is more than what the body can use and store. Muscle ◦ Takes up glucose from the circulation ◦ Oxidizes it for energy ◦ Makes glycogen from it Adipose tissue ◦ Takes up glucose from the circulation 15 5 How does each tissue or organ play a role in glucose homeostasis? Fasting 1. What happens to blood glucose levels during fasting? 2. What does the body do to maintain normal blood glucose levels? Liver ◦ Breaks down glycogen and releases glucose to the circulation ◦ Makes glucose and releases it to the circulation Kidneys ◦ Makes glucose and releases it to the circulation Pancreas - Islet ◦ Stops making and secreting insulin Muscle and Adipose tissue ◦ GLUT4 activity decreases ◦ Slows down taking up glucose form the circulation 16 Glucose Uptake by Tissues A key regulatory step controlling glucose homeostasis Glucose uptake is facilitated by glucose transporters Glucose transporters: GLUT1, GLUT2, GLUT3, GLUT4, GLUT5 Different tissue expression and functional regulation of glucose transport ◦ Insulin-independent glucose uptake: GLUT1, GLUT2, GLUT3 and GLUT5 ◦ Insulin-dependent glucose uptake: GLUT4 17 Glucose Uptake by Tissues Transporter Major site Proposed function GLUT2 Liver, pancreatic β-cells, kidney, Glucose small intestine, regulation GLUT4 Skeletal muscle, cardiac Insulin-mediated muscle, adipose tissue glucose uptake GLUT5 Small intestine, adipose tissue, Fructose muscle transporter SGLT-1 Small intestine, kidney Glucose uptake GLUT1 Placenta, brain,erythrocytes, Basal glucose adipose tissue uptake GLUT3 Brain, nerve, placenta, kidney High-affinity glucose uptake 18 6 How GLUTs regulate glucose metabolism? In fed state, two main GLUTs are involved in glucose metabolism ◦ GLUT2 ◦ GLUT4 Insulin-dependent glucose uptake via GLUT4 ◦ ~80% of blood glucose is transported into skeletal muscle via GLUT4 ◦ ~20% of blood glucose to adipose tissue via GLUT4 Insulin-independent glucose uptake via GLUT2 ◦ Liver ◦ Pancreatic β-cells 19 How GLUT2 regulate glucose metabolism in fed state? Diet Glucose Liver Pancreas Energy storage Glucose sensor Glycogen Insulin Fatty acids 20 Glucose-stimulated insulin release (First-tier response to elevated blood glucose) Pancreas -β cells: insulin -α cells: glucagon GLUT2 1. What is the organ/cell that produces insulin? 2. What is the trigger of insulin release? 3. What is the glucose transporter that transports glucose into the β cell? 4. What does insulin do to the body? 21 7 How GLUT2 regulate glucose homeostasis in fed state? First-tier response: high glucose levels stimulate insulin secretion from β cells in panaceas GLUT2 plays an important role in the control of first-tier response to elevated blood glucose levels GLUT2 facilitates the influx (uptake) of glucose into the β cell, which then triggers insulin release GLUT2 facilitates the uptake of glucose into liver cells for glycogen synthesis and fatty acid synthesis (upon the consumption of high carbohydrate diet) How GLUT4 plays a role in the regulation of glucose homeostasis in fed state? Insulin-Stimulated Glucose Uptake by Tissues (Second-tier response to elevated blood glucose) 1st tier response Dietary glucose Insulin secretion 2nd tier response After a meal, elevated blood glucose levels trigger 1st tier response How does insulin Insulin starts 2nd tier response regulate the uptake of glucose into tissues? Glucose transporter and tissues are involved in 2nd tier response in glucose metabolism • Glucose transporter : __________GLUT4 • Tissues: _________,Muscle ____________ Adipose tissue 24 8 Insulin regulates GLUT4 translocation from the intracellular compartment to the cell surface Adipose tissue and skeletal muscle basal + insulin Insulin-stimulated Fed Fasting Insulin resistance Type2 diabetes 25 Exercise stimulates GLUT4 translocation from the intracellular compartment to the cell surface Skeletal muscle Rest Exercise Exercise-stimulated Exercise Insulin resistance Type2 diabetes 26 How GLUT4 regulate glucose homeostasis in fed state? Second-tier response: high insulin levels stimulate GLUT4 translocation and activity GLUT4 plays an important role in the control of second-tier response GLUT4 facilitates glucose uptake into muscle and adipose tissue, causing the reduction in circulating glucose levels 9 Different role of GLUT2 and GLUT4 in glucose homeostasis Tissue distribution Role in body response to dietary glucose What happens to glucose homeostasis if GLUT2 or GLUT4 is defective, respectively? 28 Carbohydrate Metabolism in Liver LIVER: Central organ for glucose Glucose homeostasis • In liver glucose can be: - completely oxidized for energy - stored as glycogen - partially oxidized to provide carbon
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