Carbohydrate Metabolism.pdf

Carbohydrate Metabolism JOHN SULLIVAN M.D PH.D. Carbohydrates: Monosaccharides Simple – ‘sugars’ mono and disaccharides ◦ ◦ ◦ ◦ energy monosaccharide Glucose primary I synthesize Fructose – fruit sugar (processed foods - high-fructose corn syrup) Galactose – does not occur alone in foods, joins with...

Carbohydrate Metabolism JOHN SULLIVAN M.D PH.D. Carbohydrates: Monosaccharides Simple – ‘sugars’ mono and disaccharides ◦ ◦ ◦ ◦ energy monosaccharide Glucose primary I synthesize Fructose – fruit sugar (processed foods - high-fructose corn syrup) Galactose – does not occur alone in foods, joins with glucose -> lactose Ribose – 5 carbon, very little in diet, produced from the food we eat, component of nucleotides Carbohydrates: Disaccharides clog's upliverprocesses tattyliver Complex Carbohydrates : Oligo and Polysaccharides microflora Absorption of Carbs: Fed State Dietary carbs are absorbed in the digestive tract using specific enzymes (called glycosidases) and transporters on enterocytes (intestinal cells). NO carbohydrate digestiontakesplace instomach Gut Absorbs Monosaccharides firstdigest miledWI food Starts in the mouth (salivary amylase) carbs w food mixed Continues in small intestines ◦ Pancreatic amylase – starch -> maltosepoly di ◦ Enzymes – Maltase, sucrase, lactase di mono locatedontopofenterocytes Absorb monosaccharides only Large intestines ◦ Some bacteria ferment undigested carbs and remaining fiber is excreted GLUTNat tk pumpusesATPto establishcongradienthighNatoutsidecell Natreallywants in itdragsGlucoseGalactose across w it GLUT 5 Absorption of enzymesMonosaccharides It Lactose, sucrose and products of transporters starch digestion (i.e. maltose) are converted to monosaccharides by glycosidases on the membrane of absorptive cells. Facilitative transport on serosal side and luminal side (GLUT 1-5) GLUT 2 Egham glucosergalactose movefructose enterocytes move glucose Na+-Glucose cotransporter (SGLT1) Malabsorption syndromes (e.g. Fructose malabsorption, Celiac disease, inflammatory bowel) GLUT 1 BmBuEn slower process Glucose Diffusion In Capillaries: BBB Glucose diffuses through pores in continuous capillaries Hypoglycemia – 18-54 mg/dL ◦ Slow rate of glucose through the BBB at low levels glucose Metabolism of Sugars by Colonic Microorganisms gig'Irmin Ying mew Dietary fiber Rapidly digested and form: ◦ Gases (hydrogen, CO2 and methane) y ◦ Short-chain fatty acids (SCFA; acetic acid, propionic acid and butyric acid) ◦ Lactate Undigested sugars (e.g. fructose and lactose) Can increase retention of water in the colon – resulting in diarrhea Lactose intolerance ◦ Pain, bloating, nausea and flatulence – dairy products ◦ Low levels of lactase (levels decline after birth) – hypolactasia (most of the population) ◦ Congenital lactase deficiency ◦ Injury IBDcandestroy Dietary Fiber Resistant to digestion by human enzymes (plant material – polysaccharide derivatives and lignin) Soluble – pectins, gums, mucilages ◦ Disease reduction – may lower blood cholesterol (binds bile acids) ◦ Slows rate of glucose absorption reducing high blood glucose levels after a meal Insoluble – cellulose, lignins ◦ Add bulk to stool and promote movement through digestive track ◦ Helps prevent constipation – regular bowel movements ◦ Prevent hemorrhoids – swollen blood vessels in the anal/rectal area (caused by straining) ◦ Diverticular disease ◦ Improved motility ◦ Stool consistency – retain water and more gel-like consistancy Carbohydrate Absorption and the Glycemic Index Indication of how rapidly blood glucose levels rise after consumption Glycemic response to ingested foods depends on: ◦ Fiber ◦ Fat content ◦ Method of preparation (whole food vs processed) High glycemic foods can be used before and after exercise to increase blood sugar rapidly and immediately available for use by muscles. (e.g. dates, watermelon, ripe banana) Low glycemic foods can be used before exercise to slowly increase glucose levels so that as exercise progresses, glucose is slowly being absorbed to help maintain levels during exercise. (e.g. ‘trail mix’ and dried fruits) High-glycemic index foods – sugary cereals, sweetened beverages, snack (e.g. cookies, cakes), instant or quick cooking grains. ◦ Sugar spikes ◦ Fatigue and irritability ◦ Insulin resistance (diabetes and cardiovascular health) ◦ Increased hunger (difficulty managing weight - obesity) Fate of Glucose After a meal the glucose leaves the intestines and travels in blood to liver via the hepatic portal vein (blood vessel that carries blood from intestines to liver), the liver is the first tissue it passes through. What doHepatocytes do Hepatocytes (liver cells) take up a portion of glucose 1. 2. 3. 4. ATP generation Glycogen storage Triacylglycerol synthesis Biosynthetic reactions Insulin promotes uptake of glucose by promoting use as a fuel, storage, and triacylglycerol synthesis Liver does not require insulin for direct uptake of glucose. Most Fructose and Galactose is converted to glucose by the liver, stored as glycogen or stored as TG. Non-Alcoholic Fatty Liver Disease NAFLD - Accumulation of fat in the liver cells ◦ Simple fatty liver (steatosis) ◦ Non-alcoholic steatohepatitis (NASH) – more severe Multiple etiologies – Insulin resistance, diabetes type 2, obesity, poor diet ◦ Diets high in refined sugars (high fructose corn syrup) ◦ Fructose primarily processed in the liver and excess leads to increase production of triglycerides Enlarged liver Jaundice Abdominal pain Elevated liver enzymes ◦ Leads to accumulation of fats in liver ◦ Promote inflammation (reactive oxygen species from metabolism) Hormonal Regulation and Metabolic Homeostasis Maintain blood glucose despite daily variations in intake (70-100mg/dL) Hypoglycemia – Light-headedness, dizziness, confusion, seizures, coma, death Hyperglycemia – Insulin resistance, metabolic syndromes, diabetes X Postprandial Glucose (Fed State) From 70-100mg/dL -> 120-140mg/dL within 30 min – 1 hour Blood glucose begins to decrease and by 2 hours in fasting range IF blood glucose continues to rise after a meal (postprandial hyperglycemia) ◦ High concentration causes osmotic shift – tissues become dehydrated and impair function, blood pressure can rise ◦ Hyperosmolar coma from brain dehydration IF blood glucose continues to drop after a meal ◦ Tissues suffer from lack of energy ◦ Light-headedness, dizziness, drowsiness, coma from lack of energy to brain ◦ RBC unable to maintain integrity of membrane – hemolysis Excess and deficiency avoided via hormonal regulation and homeostasis *After 5 to 6 weeks of starvation, blood glucose levels decrease to only approximately 65 mg/dL Hormones of Metabolic Homeostasis: Glucagon Targets Liver and Adipocyte Increase release of glucose from liver ◦ Gluconeogenesis difference ◦ Glycogenolysis Increase release of fatty acids and glycerol form adipocytes ◦ Lipolysis MOA: second messenger ◦ Binds to cell surface receptors ◦ Activates cAMP -> protein kinase A -> phosphorylates key regulatory enzymes ◦ Insulin promotes dephosphorylation of these key enzymes Insulin oBinds to cell surface tyrosine kinase receptors o Liver o Muscle o Adipose oPromotes: o Lipogenesis o Glycogenesis o Protein synthesis oInhibits: o Gluconeogenesis o Glycogenolysis o Lipolysis Major Insulin Counterregulatory Hormones oGlucagon oEpinephrine/Norepinephrine – ‘fight or flight’ oCortisol – glucocorticoid steroid ‘stress hormone’ Glucose Oxidation: Energy Production Oxidation of Glucose: Overview Oxidized to CO2 First oxidized to pyruvate (glycolysis; 3 carbon) Pyruvate oxidized to acetyl-CoA (2 carbon) Acetyl group enters the TCA cycle (Krebs) – completely oxidized to CO2 and H2O Energy from the oxidation reaction used to produce ATP which is used for anabolic reactions and energy consuming processes inefficient net 2 ATP but alot ofcellshaveto utilize Glycolysis Glucose is broken down into 2 pyruvate molecules in cytoplasm of cell In the presence of O2 (aerobic): TCA ◦ Mitochondria – TCA and ETC ◦ 30-32 mol of ATP per mole of glucose Absence of O2 (anaerobic) ETC aerobic respiration anaerobic respiration Substrate-level phosphorylation – produce ATP without ETC ◦ Net 2 ATP highintensityexercisesanaerobic glycolysis m lots lactic acid Anaerobic Glycolysis: Absence of Oxygen continue to produce NAD topowerglycolysis in cytoplasm Glucose becomes lactate Tissue dependent on it ◦ ◦ ◦ ◦ RBC, WBC Kidney Medulla Eye Skeletal muscle Fate of lactate ◦ Converted to glucose (gluconeogenesis) ◦ Used as energy by heart and skeletal muscle Cori cycle (lactic acid cycle) ◦ Interconversion of lactate and glucose between muscle and liver Lactic Acidosis – overproduction of lactic acid reduces buffering capacity and lowers blood pH Other Functions of Glycolysis Generates precursors for biosynthetic pathways ◦ Ribose sugars for nucleotide synthesis (pentose phosphate pathway) ◦ Glycerol ‘backbone’ for triacylglycerols ◦ 2,3-Bisphosphoglycerate – modulator of O2 binding to heme in RBC Ozdelievery ◦ Amino acids alanine serine glutamate anaerobic glycolysis Hypoxia Decreased ATP production Accumulation of lactic acid (anaerobic) Mitochondrial disfunction – generate ROS Na+/K+ pump disfunctions Endoplasmic reticulum releases Ca2+ ◦ ◦ ◦ ◦ Cell swelling Membrane potential changes Calcium signaling dysregulation Cell death pathways degree of celltype hypoxia depends on neurons dieinseconds Aerobic Glycolysis Pyruvate Converted to Acetyl CoA X ◦ 2 carbon molecule ◦ Does not convert back into glucose Mitochondria ◦ RBC rely on anaerobic glycolysis Links glycolysis to TCA cycle Some pyruvate becomes Oxaloacetate to help maintain levels in order for TCA cycle to continue Ggg need to becomes lactate NOOz TCA cycle Continuous loop of 8 metabolic reactions within the mitochondria whathappens on Major pathway for fuel oxidation generate acetyl CoA The other intermediates are precursors for biosynthetic pathways (particularly in the liver) Anaplerotic reactions (replace intermediates): needed for TCA cycle saga◦◦ Oxaloacetate Produced from pyruvate dietary ◦ Key intermediate for gluconeogenesis The intermediates of the TCA cycle A D Electron Transport Chain (ETC) lots of H Both FAD and NAD+ are electronaccepting coenzymes. Electrons is passed from Protein Complex 1 ->4 ◦ Results in protons being pumped into the inner mitochondrial membrane space ◦ Creates large H+ gradient ◦ ATP synthase less H Cyanide poisoning – targets complex 4 and binds to iron in the heme contains don'tmemorizenames cytochrome know just heme Cytochromes contain heme Iron Deficiency Anemia fatigue be reduced energy production pump pump Energy Allocation from Glucose Oxidation brown fat of heat generate alot Glucose Storage: Energy Storage Liver Glycogen Liver stores reach maximum at 200-300grams after a carb rich meal Fat stores are relatively limitless As glycogen stores fill the liver converts excess to glucose triacylglycerol ◦ Both the glycerol and fatty acid moieties when glycogenstores till then I turns glucose to fat Glycogen Helps Regulate Blood Glucose Levels Liver glycogen is a source of blood glucose ◦ Regulated by hormonal changes ◦ Insulin activates glycogen synthase (glycogenesis) ◦ Maintain fasting blood glucose 80-90mg/dL ◦ Brain and RBC have continuous supply ◦ Low dietary glucose signaled by decrease in insulin/glucagon ratio – activates glycogenolysis and inhibits glycogen synthesis (i.e. glycogen synthase) ◦ Epinephrine – increases blood glucose and other fuels for exercise and emergency situations activates glycogenolysis Anabolic reaction: ◦ Activated sugars attached to nucleotides ◦ Glucose 6-phosphate -> UDP – glucose -> glycogen Glucagon Glycogenolysis Counterregulatory Hormones Insulin ◦ Break down glycogen (glycogen phosphorylase induced by glucagon) ◦ Maintain blood glucose levels (liver) ◦ Emergent energy source for many cells Key regulatory enzymes: ◦ Glucose 6 phosphatase (liver) ◦ Glycogen synthase insulin pro mots ◦ Glycogen phosphorylase glucagon promotes Blood Glucose Homeostasis Maintain blood levels 70-100mg/dL Must be maintained for Brain and RBCs Needed for quick energy ◦ Stress ◦ Fight or flight ◦ Exercise Glucose 6-phosphate serves as the gateway to glycogenesis and gluconeogenesis Glycogen Storage Diseases (GSDs) Inborn error of metabolism Rare genetic disorders often diagnosed in childhood – inability to breakdown glycogen Several types (each has specific enzyme deficiency) ◦ Type I (GSD I) or Von Gierke disease – glucose 6 phosphatase – key enzyme for glycogenolysis us lysosomes help breakdown ◦ Type II (GSD II) or Pompe disease – lysosomal acid alpha glucosidase (GAA) glycogen ◦ Type V (GSD 5) or McArdle disease – glycogen phosphorylase (muscle) Symptoms: ◦ Hypoglycemia b ◦ Enlarged liver ◦ Muscle weakness ◦ Growth retardation Management ◦ Dietary modifications – special diet with frequent meals to maintain blood glucose levels ◦ Enzyme replacement therapy ◦ Medications Making ‘New’ Glucose Gluconeogenesis whatare the substrates Making glucose from non-carbohydrate substrates Amino acids (e.g. alanine) – amino acid pools Glycerol – from lipolysis in adipocytes 11.84 guvnor Lactate – anaerobic glycolysis in RBC and Muscle Glucagon levels higher than insulin* Maintains blood glucose during sleep, fasting, and during elevated oxidation – trauma, exercise Energy dependent process Gluconeogenesis Intermediates Primarily a reversal of glycolysis Pyruvate Oxaloacetate – TCA cycle intermediate, gluconeogenesis and amino acid metabolism Dihydroxyacetone-P Glucose 6-phosphatase Red arrows indicate steps that differ from glycolysis Gluconeogenesis: Metabolic Crossroads Primarily a reversal of glycolysis Acetyl CoA cannot be used for gluconeogenesis Gluconeogenesis Normally amount of body protein used for gluconeogenesis is low – protein sparing for short fasts Increased during prolonged or severe illness, longterm fasting or starvation ◦ Lead to destruction of vital tissue proteins (e.g. skeletal and heart muscle) Glycogen stores deplete -> triacylglycerols are degraded to fatty acids and glycerol Overnight fast – primarily glycogenolysis and gluconeogenesis Prolonged fast >24 hours – gluconeogenesis only source of blood glucose Timing of Glucose Utilization Dietary glucose decreases within hours after a meal Short-term fasting up to 24 hours ◦ Deplete glycogen stores Long-term fasting greater than 24 hours ◦ Rely on gluconeogenesis Prolonged fasting ◦ Gluconeogenesis ◦ Ketogenesis Anorexia Nervosa Intense fear of gaining weight and a distorted body image – leads to restrictive eating habits and other behaviors aimed at achieving extreme thinness. Prolonged fasting or severe caloric restriction leads to detrimental effects on the body ◦ Chronic energy deficiency – breaks down tissues for fuel, including muscle mass (protein catabolism) ◦ Loss of lean body mass – weakness, fatigue and compromised physical function ◦ Hormonal changes – decrease in IGF-1 and increased cortisol ◦ Lack of nutrient intake ◦ Engagement in excessive physical activity Leads to severe complications – electrolyte imbalances, cardiovascular issues, bone density loss, and disruption in organ function Treatment: multidisciplinary, medical, nutritional, and psychological interventions Glucose Biosynthetic Pathways Pentose Phosphate Pathway (PPP) Also known as hexose monophosphate shunt (HMP shunt) Present in all cells (cytosol) Runs parallel to glycolysis and generates nucleotides and NADPH needed forsynthesisreactions Glucose -> Ribose 5 phosphate, CO2 and NADPH ◦ Ribose 5-phosphate for nucleotide synthesis ◦ NADPH -> fatty acid synthesis, glutathione/other detox reactions ◦ Biosynthetic pathways ◦ Regenerates antioxidants (Important in RBCs) Activating Glucose for Biosynthesis Bound to nucleotide for transfer (i.e. UDP) Anabolic reactions – glycogen and glycolipid synthesis etc. antioxidant Nucleotide sugars (UDP-glucose) breastmilkmother ◦ Donate sugar residues to glycogen, glycoproteins and glycolipids UDP-glucoronate ◦ Increase solubility in blood to promote excretion ◦ Excretion of bilirubin, drugs, xenobiotics Glycoproteins Carbohydrate chains attached to proteins in endoplasmic reticulum and Golgi complex Found in mucus, blood, compartments within cells (lysosomes), ECM, cell membrane with carbs facing outward (receptors, transporters, cell attachment, cell-cell recognition (ABO blood type) ◦ Most protein in blood are glycoproteins: ◦ Hormones ◦ Antibodies ◦ enzymes (clotting cascade) ◦ structural components of ECM Glycolipids Carbohydrate chains attached to lipids Many belong to class -> sphingolipids (cerebrosides and gangliosides) Cell membrane with carbs facing outward ◦ cell recognition factors (ABO blood types) ◦ Intercellular communication Questions What is the role of insulin in glucose metabolism and what are the key tissues affected? store glucose diveradiposemuscle glycogen How does impaired insulin signaling contribute to hyperglycemia in Type 2diabetics? reducedinsulin sensitivity What is the significance of gluconeogenesis during a fast? In Type 2 diabetic patients? makes glucose from glycerol amino increased gluconeogenesis no even tho there is glucose lactate acid What substrates contribute to the production of glucose during gluconeogenesis?