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: ________, ________, and ________ 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 Glucose Uptake by Tissues A key regulatory step controlling glucose homeostasis Facilitated glucose uptake: mediated 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 15 5 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 16 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 ◦ ~20% of blood glucose to adipose tissue Insulin-independent glucose uptake via GLUT2 ◦ Liver ◦ Pancreatic β-cells 17 How GLUT2 regulate glucose metabolism in fed state? Diet Glucose Liver Pancreas Energy storage Glucose sensor Glycogen Insulin Fatty acids 18 6 Glucose-stimulated insulin release (First-tier response to elevated blood glucose) Pancreas -β cells: insulin -α cells: glucagon GLUT2 1. Which tissue/organ produces insulin? 2. Why insulin is produced? 19 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 triggers 1st tier response How insulin regulates Insulin starts 2nd tier response glucose uptake? Glucose transporter and tissues are involved in 2nd tier response in glucose metabolism • Glucose transporter : __________ • Tissues: _________, ____________ 20 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 21 7 Exercise stimulates GLUT4 translocation from the intracellular compartment to the cell surface Skeletal muscle Rest Exercise Exercise-stimulated Exercise Insulin resistance Type2 diabetes 22 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? 23 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 for synthesis of fatty acids & ribose-5-phosphate M • Liver can also produce and release glucose to the circulation when glucose levels are down Liver Pathways: M: mitochondria Metabolite flows: 24 8 Carbohydrate Metabolism in Skeletal Muscle In skeletal muscle Glucose glucose can be: • oxidized for energy • stored as glycogen Pathways: M Metabolite flows: Q: Does skeletal muscle release glucose into blood? Muscle M: mitochondria 25 Carbohydrate Metabolism in Brain Glucose In brain: Complete oxidation of glucose for energy (glycolysis and TCA cycle) Largely relies on glucose M as a fuel Brain M: mitochondria 26 Carbohydrate Metabolism in Red Blood Cells Glucose In red blood cells Glucose can be metabolized into lactate (glycolysis) What is missing? Red blood cell Q: why glucose can not be completely oxidized in red blood cells? 27 9 Carbohydrate metabolism in Adipose Tissue In adipose tissue Glucose Glucose can be partially and/or Glucose completely oxidized for: Glucose 6-P Fructose 1,6-biP • De novo lipogenesis fed Pyruvate (provide acetyl CoA for FA synthesis and glycerol Acetyl-CoA TCA 3-phosphate for TAG Fatty acids Glycerol 3-phosphate synthesis) • Release metabolic fuel: Triacylglycerol TAG is hydrolyzed to release fatty acids and Fatty acids + Glycerol fasting glycerol Fatty acids Adipose cell Liver 28 Carbohydrate metabolism in Adipose Tissue Fed In adipose tissue Glucose Glucose can be partially and/or Glucose completely oxidized for: Glucose 6-P Fructose 1,6-biP • De novo lipogenesis fed Pyruvate (provide acetyl CoA for FA synthesis and glycerol Acetyl-CoA TCA 3-phosphate for TAG Fatty acids Glycerol 3-phosphate synthesis) • Release metabolic fuel: Triacylglycerol TAG is hydrolyzed to release fatty acids and glycerol Fatty acids Adipose cell Liver 29 Carbohydrate metabolism in Adipose Tissue Fasting In adipose tissue Glucose X Glucose can be partially and/or Glucose X completely oxidized for: Glucose 6-P X X Fructose 1,6-biP X • De novo lipogenesis Pyruvate (provide acetyl CoA for X FA synthesis and glycerol Acetyl-CoA X TCA X 3-phosphate for TAG Fatty acids Glycerol 3-phosphate synthesis) • Release metabolic fuel: Triacylglycerol TAG is hydrolyzed to release fatty acids and Fatty acids + Glycerol fasting glycerol Fatty