Index: - Overview: Catabolism and Anabolism. Few concepts:, NADPH. - Overview: Metabolism glucose, fatty acids and amino acids. - Table summary: Principal anabolic and catabolic pathways, and their main substrates and products. - Key Junctions: metabolites, such as glucose 6 P, pyruvate and acetyl-coa, link different pathways. - Composition/Use of Fuels Stores. The energy reserves of humans. Caloric Homeostasis. - Glucose Homeostasis: Five phases - Hormonal control of glucose homeostasis: Insulin and glucagon. - Metabolic effects of insulin - Metabolic effects of glucagon - Postprandial metabolism - Post absorptive metabolism (overnight fast) - Prolonged fasting - Obesity. Fatty Liver. Metabolic syndrome. -Diabetes I and I -- Oxidation of Ethanol. Fatty Liver. BOOKS: Metabolic Interrelationships (chapter 13, Devlin 4 th edition, chapter 20 Devlin 5 th edition) Glucose Homeostasis, Fuel Metabolism and Insulin (Medical Biochemistry, 2 nd edition, Dominiczak) The Integration of Metabolism (chapter 30, Stryer 5 th edition) Manintenance of Blood Glucose Levels (chapter 31, basic Medical Biochemistry, Marks Marks and Smith) METABOLISM CATABOLIC Carbohydrates Lipids Proteins O 2 Amino acids Simple sugars Fatty acids CO 2, H 2 O, NH 3 Reducing Power (NADPH) ENERGY ANABOLIC Carbohydrates Lipids Proteins Overview- Few concepts: is the universal currency of energy Overview Metabolism of glucose Glycogen is generated by the oxidation of fuel molecules such as glusose, fatty acids and amino acids. Acetil coa TCA CO 2 NADH FADH 2 H+ NADPH is the major electron donor in reductive biosyntheses Biomolecules are constructed from a small set of building blocks Biosynthetic and degradative pathways are almost always distinct. Electron Transport chain GLYCOGENOLYSIS GLYCOLISIS Glucose Pyruvate- Lactate GLYCOGENESIS Pentose Phosphate Pathway (NADPH) GLUCONEOGENESIS Acetil coa TCA CO 2 Glycolysis and other metabolic pathways Glucose glycogenolysis CATABOLIC Overview Metabolism of Lipids LIPOLYSIS TAG Glycerol LIPOGENESIS Fatty Acids 16C Lipogenesis pyruvate lactate Fat Acetil (Lipogenesis) coa TCA Fatty Acids β OXID Acetil CoA TCA CO 2 Palmitic (16C) Malonil CoA FATTY ACID SYNTHESIS 1
Overview Metabolism of Amino Acids COOH H--C--R NH 3 Carbon skeletons NH 4+ Urea Cycle α Keto acid UREA Glucogenic aa TCA CO 2 Pyruvate Intermediates TCA Ketogenic aa Acetyl CoA Ketonic bodies Catabolic: PROTEOLYSIS, AMINO ACID OXIDATION Anabolic: PROTEIN SYNTHESIS, KETOGENESIS Pathway Main Substrates End Products CATABOLIC Glycolysis glucose pyruvate, Tricarboxylic pyruvate, Acetil CoA NADH, H +, FADH 2, acid cycle CO 2, H2O, Glycogenolysis glycogen G1P, glucose Pentose phosphate glucose 6P NADPH, H +, pathway pentoses, CO 2 Lipolysis triglycerides glycerol, fatty acids Proteolysis proteins amino acids-glucose amino acids-ketones ANABOLIC Gluconeogenesis Lactate, Ala, Glycerol glucose Glycogen synthesis G1P glycogen Protein synthesis amino acids proteins Lipogenesis Acetyl-CoA, glycerol fatty acids, triglycerides Overview: GLYCOLYSIS GLYCOGENESIS Gluc6P Glucose PENTOSE PHOSPHATE KEY Junctions: Glucose 6 P Pyruvate Acetyl CoA Lipogenesis Gluconeogenesis Synthesis Amino acids Fat (Lipogenesis) Catabolic destinies of PYRUVATE (producted by glicolysis) Pyruvate Acetil coa 2
COMPOSITION/USE OF FUEL STORES TRIACYLGLYCEROL (triglycerides) -Adipose triacylglycerol is the major fuel storage form -Highly efficient with more stored calories per gr and less water (15%) than other fuel stores (muscle is about 80% water) GLYCOGEN STORES (small but critical) -Liver glycogen is used to maintain blood glucose during the early stages of fasting - Muscle glycogen is oxidized for muscle contraction PROTEIN (which is not solely a fuel source, can be degraded to only a limited extent) -~1/3 of total body protein can be degraded without pathology -Oxidation of to much protein for energy severely compromises key bodily functions -Fatty acid oxidation and ketogenesis serve to spare the body s use of protein as fuel source THE ENERGY RESERVES OF HUMANS Fuel reserves Stored Fuel Tissue (g) (Kcal) Glycogen Liver 70 280 Glycogen Muscle 120 480 Glucose Body fluids 20 80 Fat Adipose 15,000 135,000 Protein Muscle 6,000 24,000 Average sedentaryy person (70Kg) consumes (per day): 200-300g carbohydrates (4kcal/g)= 800-1200kcal 70-100g protein (4kcal/g)= 280-400 kcal 60-90 gr fat (9kcal/g)= 540-810 Kcal Meets daily energy requirements of = 1620-2410 THE ENERGY RESERVES OF HUMANS Fuel reserves Stored Fuel Tissue (g) (Kcal) Glycogen Liver 70 280 Glycogen Muscle 120 480 Glucose Body fluids 20 80 Fat Adipose 15,000 135,000 Protein Muscle 6,000 24,000 - Energy reserves in the well-fed state are considerable - Used between meals and overnight to maintain blood glucose - Glycogen reserves are really minimal compared to fat reserves I II III IV V GLUCOSE HOMEOSTASIS Phase Origin of blood Tissues Major I Exogenous All Glucose HORMONAL CONTROL OF GLUCOSE HOMEOSTASIS Interpretation of fasting plasma glucose concentration Blood glucose Diabetes mellitus glucose >126mg/dl Imparied fasting glucose110 gluc>126 mg/dl Normal <110 mg/dl Hypoglycemic action: INSULIN (Decreses plasma glucose) Hyperglycemic action: GLUCAGON, EPINEPHRINE CORTISOL, GROWTH HORMONE (increase plasma glucose) Danger- Hypoglycemia glucose 45mg/dl Causes of hypoglycemia Exercise Fasting Excess of insulinoma: excess inhhibition of exogenous insulin of endogenous endogenou glucose insulin production (alcohol) 3
SECRETION OF INSULIN Plasma insulin Oral glucose Metabolic effects of insulin No insulin dependent Insulin dependent /ADP ratio Acetil-CoA + GLUCOSE stimulates the secretion of Insulin + Amino acids (branched-chain aa) + Stimulation of the vagus nerve time Insulin dependent + glucose transport GLUT-4 + glycolysis + glycogen synthesis + lypogenesis + protein synthesis - lipolysis Metabolic effects of glucagon + Endogenous production of glucose + Movilization of the fuel reserves - Utilization of glucose - Storage of metabolic fuels Postprandial metabolism + Diet supplies all of the body s energy requirements + Insulin releases + glucose transport GLUT-4 + glycolysis + glycogen synthesis + lypogenesis + aa uptake +protein synthesis - lipolysis Postabsorptive metabolism (overnight fast) Steady State Glucose production = its tissue uptake (glycogenolysis) 80% brain erythrocytes 20% Insulin Glucagon Prolonged fasting 3 days Chronic low Insulin /High glucagon 20% -glycogensynthesis + hepatic glycogenolysis Liver: glucose producting organ 80% Gluc- Brain, erythrocytes 20% Gluc-insulin dependent tissues Look phase IV and V Homeost. Glucose + Gluconeogenesis from aa and glycerol from lipids + protein degradation + glutamine+alanine released in large amounts + lyposisis in adipose= Fatty acids for oxid in muscle and liver + Liver acetyl co A-Ketone bodies 4
x Prolonged fasting 3-5 days Chronic low Insulin /High glucagon OBESITY gluconeogenesis Brain - Skeletal muscle decreases its use of ketone bodies - Ketone body leves in blood -Brain: ketonebodies - Liver gluconeogenesis slows - Fat(FAs) from adipose tissue is the 1 st fuel - Muscle protein is less degraded - Fat from the diet or synthesized in the liver from glucose and aa is transported and stores in adipose tissue - The individual stay in the well-fed state such that stored fat not get re-cycled during the fasting pahse -Excess calories in the diet from fat, carbohydrate and protein accumulates as stored fat Increased Insulin OBESITY and Insulin Resistance CLASSIFICATION OF DIABETES Syndrome Comments - Obesity leads to insulin resistance: - number and affinity of insulin receptors may be reduced -Post-receptor signaling responses such as activation of glucose transport may be impaired - In general: the greater amount of body fat, the greater the insulin resistance in obese individuals -Plasma insulin levels are elevated to compensate -As long as enugh insulin is produced by the beta cells, blood glucose levels remain normal -May lead to type 2 Diabetes Mellitus (NIDDM) Type 1 autoimmune destruction of βcells (INSULIN-DEPENDENT) Type 2 (90%) insulin resistance and βcell failure (NONINSULIN-DEPENDENT) Other types Gestational diabetes genetic defects of βcells (e.g. mutations of glucokinase gene). Rare insulin resistance syndromes. Diseases of exocrine pancreas. Endocrine diseases (acromegaly, Cushing's syndrome). Drugs and chemical-induced diabetes, Infections (e.g. mumps). Rare syndromes with the presence of antireceptor antibodies. Diabetes accompanying other genetic diseases (e.g. Down syndrome) any degree of glucose intolerance diagnosed in pregnancy Comparison of type 1 and type 2 diabetes mellitus DIABETES TYPE 2 Onset usually under 20 years of age usually over 40 years of age Insulin absent: immune destruction preserved: combination of Synthesis of βcells impaired βcell function and insulin Plasma low or absent low, normal, or high Insulin concentration Genetic inheritance not associated with HLA Susceptibility associated with HLA polygenic antigens Islet cell antibodies yes no at diagnosis Obesity uncommon common Ketoacidosis yes possible as a result of major stress - Insulin resistance is couple to insufficient production of insulin by pancreatic Beta cells to overcome the insulin resistance - The majority of patients are obese - Insulin levels are elevated, but lower than non-diabetic obese individuals - Hyperglycemia Prevent lipolysis and fatty acid release - Ketoacidosis is rare 5
DIABETES TYPE 1 Increased gluconeogenesis decreased glucose uptake Hyperglycemia Diabetic ketoacidosis Insulin LacK Increased Lipolysis Increased ketogenesis - Defective production (absence) of insulin secretion. - Insulin/glucagon: cannot increase. Glucagon liver gluconeogenic and ketogenic [glucose]blood X glycolysis, glycogenesis, lipogenesis - Muscle and adipose tissues fail for glucose uptake- manintains hyperglycemia - Accelerated Gluconeogenesis (protein degradation)- maintains hyperglycemia - Uncontrolled lipolysis leads to: ketogenesis and hypertriacylglycerolemia - Gross elevation of all fuel in blood with sever wasting of body tissues---death Glycosuria ketonemia Osmotic diuresis Ketonuria Acidosis Deshydration Compensatory hyperventilation METABOLIC SYNDROME Insulin resistance syndrome OXIDATION OF ETHANOL IN THE LIVER Etanol+ NAD + acetaldehido + NADH + H (alcohol desydrogenase) Metabolic risk factors: Abdominal obesity Males 102 cm Females 88 cm -Atherogenic dyslipidemia High TAG 150mg/dL Low HDL < 40-50mg/dL High LDL -Elevated blood pressure >130/85 mmhg Insulin resitance Glucose 110mg/dL -Prothrombotic state (high plasminogen activator inhibitor 1 in blood) - Proinglammatory state (elevated C-reactive protein in blood) Acetaldehido + NAD + acetate + NADH + H (aldehyde dehydrogenase) NADH INH. Gluconeogenesis INH. Fatty acid oxidation Hypoglycemia Acumulation of hepatic TAG (fatty liver) Accumulation of lactate (Metabolic acidosis) NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) Steatosis Steatohepatitis Cirrhosis Liver scarring NASH: NON ALCOHOLIC Liver cancer STEATOHEPATITIS % of people with NASH that have also: Risk factors: -Overweight and obesity 70% -Metabolic syndrome -Insulin resistance 75% -Hyperlipidemia 80% 6