MBBS Stage One Nutrition and Metabolism PDF

MBBS Stage one Nutrition and Metabolism The liver and Gluconeogenesis Dr Despo Papachristodoulou THE LIVER AND GLUCONEOGENESIS Outcomes: Explain why glucose is an important metabolic fuel Describe the sources of glucose that are available to the body (diet, liver glycogen, other me...

MBBS Stage one Nutrition and Metabolism The liver and Gluconeogenesis Dr Despo Papachristodoulou THE LIVER AND GLUCONEOGENESIS Outcomes: Explain why glucose is an important metabolic fuel Describe the sources of glucose that are available to the body (diet, liver glycogen, other metabolites by gluconeogenesis) Outline the process of gluconeogenesis in the liver from lactate or oxaloacetate Discuss the time course of blood glucose homeostasis after a meal Summarise the roles of insulin and glucagon in maintaining glucose homeostasis Describe the role of the liver in glucose uptake and in glucose production Location of pancreatic islets reflects their functional role  The requirement for glucose is continuous Glc is the preferred fuel source for all tissues some tissues have a continuous dependence on glucose  blood glucose concentration physiological circulating glc concentration 3.9-6.2 mM average fasting 4.4-5 mM for most adults  if it drops to 2.5 or less coma and death can result if it rises for an extended time, dehydration, wasting of body tissue and eventually death will result  The roles of glucose It is a source of energy glucose → pyruvate gives 2 ATP glucose → CO2 + H2O gives 31 ATP it is a source of NADPH needed for synthetic reactions (fatty acids, steroids) and drug metabolism  roles of glucose it is a source of pentose sugars for for synthetic reactions (nucleotides, DNA ) it is a source of carbon for other sugars and glycoconjugates (mannose,galactose, glucuronic acid  Advantages of glucose as a metabolic fuel Water soluble , so does NOT require a carrier in the circulation can cross the blood-brain barrier can be oxidised anaerobically  Disadvantages relatively low yield of ATP/mole compared to fatty acids osmotically active in high concentrations can directly damage cells or lead to accumulation of toxic by-products (fructose, sorbitol)  Pathways involving glucose Predominant pathways involving glucose are different in different tissues on the whole, all tissues use glucose the liver can provide glc for other tissues Role of glucose in skeletal muscle Main pathway function glycolysis Anaerobic muscle contraction Glycolysis/TCA cycle energy Glycogen synthesis Energy store for and degradation muscle contraction  Role of glucose Tissue Main pathway Function Heart/brain Glycolysis/TCA ENERGY Tissue Main pathway Function Adipose tissue glycolysis Production of glycerol P’ for TAGS Erythrocyte glycolysis Energy Pentose NADPH phosphate (G6PDH) pathway (shunt)  Glucose-6-phosphate dehydrogenase deficiency G6PD deficiency is the commonest human enzyme deficiency. X-linked hereditary disorder so, although most individuals with G6PD deficiency are asymptomatic, the symptomatic patients are predominantly male. More than 400 million people in the world are G6PD deficient particularly high incidence in African, Middle Eastern, and South Asian people. About 400 different mutations in the G6PD gene are known but not all of them cause clinical symptoms.  Triggers for Haemolytic anaemia in people with G6PD deficiency Favism resulting from the ingestion of fava beans (Vicia faba) has been known since antiquity. Some forms of G6PDH deficiency, particularly the Mediterranean variant are particularly susceptible to favism. Fava beans, which are a common food in the Mediterranean and the Middle East, contain alkaloids such as vicine which are potent oxidants.  Role of glucose in the liver Main pathway function Glycolysis/TCA cycle Production of acetyl CoA Pentose phosphate NADPH, pentoses Glycogen synthesis/ Glucose storage for glycogenolysis other tissues Gluconeogenesis Glucose for other tissues Blood glucose, insulin and glucagon in a normal person over 24 hours of normal eating behaviour (mixed meals)  Sources of blood glc Diet liver glycogen liver gluconeogenesis Sources of blood glucose after ingestion of 100 g glucose  Gluconeogenesis In conditions of carbohydrate deprivation glc is synthesised from non-carbohydrate sources in the liver Lactate glycerol other monosaccharides glucogenic amino acids (all except leu, lys) NOT FROM FATTY ACIDS  gluconeogenesis is not simply the reversal of glycolysis There are 3 irreversible reactions in glycolysis that must be bypassed. They are catalysed by hexokinase/ glucokinase phosphofructokinase pyruvate kinase all in the cytosol The irreversible reactions in glycolysis and the by-passing reactions in gluconeogenesis pyruvate kinase catalyses the conversion of PEP to pyruvate pyruvate carboxylase and PEP carboxykinase are needed for the conversion of pyruvate to PEP in gluconeogenesis  Regulation of gluconeogenesis Mobilisation of substrate – glycerol from fat breakdown – amino acids from muscle protein breakdown activation of enzymes – G6Pase F1,6bisPase,PEPCK (insulin/glucagon is low) – activation pyruvate carboxylase by acetyl CoA The Cori cycle and Glucose-alanine cycle  Blood glucose maintenance Insulin, glucagon and adrenaline (and to a lesser extent cortisol) and glucose itself, signal and co- ordinate the activities of – liver – adipose tissue – muscle tissue Maintain physiological blood glc concentrations needed to preserve brain function (and other tissues dependent on glc) Islets of Langerhans in the pancreas beta cells secrete insulin alpha cells secrete glucagon  insulin v glucagon insulin is an anabolic hormone. It promotes synthesis and storage glucagon is a catabolic hormone. It promotes degradation of stored fuel Sites of insulin action on metabolism + glycogen  Metabolic effects of insulin: Liver Inhibition of gluconeogenesis activation of glycogen synthesis (glycogen synthase activated) Increased Fatty Acid synthesis and lipid assembly Increased aa uptake and protein synthesis Metabolic effects of insulin: Muscle Increased glucose uptake by increasing glucose transporters (GLUT4) Increased aa uptake and protein synthesis activation of glycogen synthesis (glycogen synthase activated) Sites of glucagon action on metabolism  Metabolic effects of glucagon increase in blood glucose – ↑ glycogenolysis and gluconeogenesis (liver). Increase in circulating fatty acids and ketone bodies – ↑ adipose tissue lipolysis, ↑fatty acid oxidation in the liver and ketone body formation.. Decrease in plasma amino acids – ↑uptake by the liver for gluconeogenesis. LIVER: FED STATE glucose glc-6-P glc-1P GLYCOGEN pyruvate ace Co A FA FAT lactate  MUSCLE: FED STATE glucose glc-6-P glc-1P GLYCOGEN pyruvate ace Co A FA FAT lactate  MUSCLE: AEROBIC glucose glc-6-P glc-1P GLYCOGEN pyruvate ace Co A FA FAT lactate TCA, OX PHOS ATP  LIVER: FASTING STATE glucose glc-6-P glc-1P GLYCOGEN pyruvate ace Co A FA FAT lactate BRAIN: FED OR FASTING glucose glc-6-P glc-1P GLYCOGEN pyruvate ace Co A FA FAT lactate TCA, OX PHOS ATP ERYTHROCYTE : FED OR FASTING glucose glc-6-P glc-1P GLYCOGEN pyruvate ace Co A FA FAT lactate Glucose tolerance curves of normal and diabetic subjects Diabetes type 1 Diabetes type 2 normal