Skip to main content
UploadLanguage (EN)Support
BusinessMobileSocial MediaMarketingTechnologyArt & PhotosCareerDesignEducationPresentations & Public SpeakingGovernment & NonprofitHealthcareInternetLawLeadership & ManagementAutomotiveEngineeringSoftwareRecruiting & HRRetailSalesServicesScienceSmall Business & EntrepreneurshipFoodEnvironmentEconomy & FinanceData & AnalyticsInvestor RelationsSportsSpiritualNews & PoliticsTravelSelf ImprovementReal EstateEntertainment & HumorHealth & MedicineDevices & HardwareLifestyle
Prof Viyatprajna Acharya, profile picture
Uploaded byProf Viyatprajna Acharya
PPTX, PDF31 views

4 Gluconeogenesis- maintaining glucose homeostasis

How and why glucose need to be synthesised from different non-carbohydrate sources and its level in blood is maintained. Its regulation and applied importance. Futile cycles, hyperlactatemia explained.

Health & Medicine◦
Download to read offline
Gluconeogenesis Prof Dr Viyatprajna Acharya MD, PhD Medical Biochemistry
Why constant glucose maintenance level is essential?? • Brain & nervous system, renal medulla, RBCs, testes, embryonic tissues- glucose is major/ sole source of energy • Brain- 120g/day; more than half the glucose stored as glycogen in mm. & liver • Supply of glucose from this store is not always adequate- in between meals, longer fasts, rigorous exercises
Neo= new; Gluco=Glucose; genesis= synthesis • New glucose synthesis from non-carbohydrate sources • Lactate, Pyruvate • Glucogenic AA • Glycerol • Propionyl CoA derived from odd chain FA
Where does it take place? • Liver • Renal cortex- lesser extent • Epithelial cells of lining of intestine • Organellar location- partly in cytoplasm and partly in mitochondria
An overview
Gluconeogenesis is not exact reversal of glycolysis Key gluconeogenetic enzymes Pyruvate carboxylase Phosphoenolpyruvate carboxykinase Fru-1,6-bisphosphatase Glucose--phosphatase
• Pyruvate enters the mitochondria by a symport • Pyruvate carboxylase is a mitochondrial enzyme • Needs ATP and biotin
Malate aspartate shuttle transports OA to cytoplasm • MDH is present in both cytoplasm and mitochondria • OA may be transported in the form of Asp • When Ala is the substrate for gluconeogenesis, Malate shuttle predominates- NADH generation is required • When Lactate is the substrate, Asp shuttle operates as already enough NADH available
PEPCK acts in the cytoplasm • GTP or ITP donate the P • PEPCK has two isoforms- C & M- coded by separate genes, PCK1 & PCK2 • C form more important for gluconeogenesis • PEP formed in mitochondria takes help of carrier to come to cytoplasm
Formation of Fru-1,6-BP is freely reversible • Hydrolytic step • Further change from Fru-6-P to Glu-6-P- Freely reversible
Glu-6-Phosphatase- active in liver; absent in mm. • Kidney and intestinal mucosa- enzyme is present in lesser extent
Bioenergetics • 6 ATPs required to generate one glucose molecule • Gluconeogenesis requires 4 ATP, 2 GTP, and 2 NADH for synthesis of one glucose molecule from pyruvate • energy-dependent pathway supported by fatty acid oxidation. 2Pyruvate → 2OA = 2ATP 2OA → 2PEP = 2 ATP 2 x 3-Phosphoglycerate → 2x 1,3 BP-glycerate = 2 ATP
Lactate Cori’s cycle • Lactate generated in the mm. is transported to liver and gets converted to pyruvate • Pyruvate enters into gluconeogenesis
Glucogenic AA- Ala, Glu & Asp • By transamination get converted to respective keto acids • Enter the TCA cycle and OA is formed • Ala- major AA • Clinical significance: Muscle wasting in uncontrolled type I DM
Glucose-Alanine Cycle (Cahill cycle) • Ala transported from mm to liver • Transaminated to pyruvate • Gluconeogenesis • Important in starvation • Net transfer of N from mm to liver and energy from liver to mm is affected • Intertwined with Cori’s cycle
Glycerol • Glycerol is phosphorylated to Glycerol-3-P by ATP • Glycerol-3-P → DHAP • Liver cytosol
Propionyl CoA • Only odd chain FA • Minor source
Regulation of gluconeogenesis • Gluconeogenesis and glycolysis reciprocally regulated • Pyruvate carboxylase- Acetyl CoA activates; • Fru-1,6-Bisphosphatase- Citrate activates; Fru-2,6-BP & AMP depress • ATP- ↑ • Hormones- Insulin inhibits; Glucagon & cortisol activate
Hormonal regulation • Insulin- decrease gluconeogenesis • Glucagon, cortisol- Enhance gluconeogenesis by inducing synthesis of hepatic transaminases ↓ Provide the substrates for gluconeogenesis • High Glucagon/Insulin ratio- induction of synthesis of gluconeogenic enzymes- PEPCK, Fru-1,6-bisphosphatase, Glu-6-phosphatase • Glucagon elevates the expression of PEPCK by increasing cAMP in liver • Cortisol activates PEPCK at gene level- ↑transcription • Glycolytic enzymes- HK, PFK and PK are inhibited- insulin prevents this inhibition
GN/ DN ratio- High GN → Generate glucose; Low GN → Lock glucose • In gluconeogenesis, protein breaks down and urea is excreted in urine • Ratio between Glucose (Dextrose) and urea nitrogen- GN or DN ratio • Normally- 3.65 • 1gm of urea nitrogen forms- 3.65gm of glucose • High GN ratio- catabolic state; Insulin deficiency, starvation, pyrexia, hyperthyroidism, cancer • Low GN ratio- anabolic state • Alongside insulin and glucagon, GN ratio also regulates •Glycogenesis •Lipogenesis •Protein synthesis •Glycolysis
Futile cycles- need to be prevented • If opposing cycles take place, then there’ll be waste of energy without any metabolic gain • Gluconeogenesis Glycolysis • By preventing futile cycles- Allow directional control of metabolism Enable fine regulation of blood glucose Generate heat in some tissues (minor physiological role) Prevent wasteful ATP hydrolysis
Clinical significance • Pyruvate carboxylase deficiency- inherited disease; mental retardation, Lactic acidosis, hypoglycemia & hyperammonemia • PEPCK deficiency- hypoglycemia, lactic acidosis, hypotonia & hepatomegaly • Fru-1,6-BPase deficiency- Hypoglycemia, ketosis and lactic acidosis • PDH deficiency (inherited)- Hyperlactatemia • As poisoning- PDH deficiency by quenching SH groups of lipoamide component • Ethanol- inhibits gluconeogenesis; raised NADH released from ethanol metabolism, leads to hyperlactatemia
Hyperlactatemia • Normal lactate level in blood- 0.5- 1mM/L; upper level 2mM/L • Lactate/pyruvate- 25:1 • If less than 25, deficiency of gluconeogenetic enzymes might be there • >5mM/L- lactic acidosis, blood pH falls • In between 2-5mM/L, the blood pH may remain normal • Causes- shock, cardiopulmonary failure, ethanol metabolism- excess NADH production favors lactate formation
For more ppt on medical biochemistry www.drvpacharya.com