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بسم الله الرحمن الرحيم

بسم الله الرحمن الرحيم. Glucose Metabolism: Gluconeogenesis. By. Reem M. Sallam , MD, PhD. Assistant Prof. , Clinical Chemistry Unit, Pathology Dept., College of Medicine, KSU sallam@ksu.edu.sa. Objectives.

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بسم الله الرحمن الرحيم

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  1. بسم الله الرحمن الرحيم

  2. Glucose Metabolism: Gluconeogenesis By Reem M. Sallam, MD, PhD Assistant Prof. , Clinical Chemistry Unit, Pathology Dept., College of Medicine, KSU sallam@ksu.edu.sa

  3. Objectives • The importance of gluconeogenesis as an important pathway for glucose production • The main reactions of gluconeogenesis • The rate-limiting enzymes of gluconeogenesis • Gluconeogensisis an energy-consuming, anabolic pathway

  4. Gluconeogenesis: An Overview • In the absence of dietary intake of carbohydrate, liver glycogen is an important source of glucose (through glycogenolysis) to meet the tissue needs for 10-18 hours. • During prolonged fasting, liver glycogen stores are depleted, and glucose is formed by gluconeogenesis. • During Overnight fast: • 90% of gluconeogenesis occurs in liver • 10% of gluconeogenesis occurs in Kidneys • During Prolonged fast: • 60% of gluconeogenesis occurs in liver • 40% of gluconeogenesis occurs in Kidneys • Gluconeogenesis requires both mitochondrial & cytosolic enzymes (exception: if gluconeogenesis starts by Glycerol, it will need only the cytosol)

  5. Gluconeogenic Pathway • Seven glycolytic reactions are reversible & are used in gluconeogenesis from lactate or pyruvate. • Three glycolyticreactions are irreversible & must be reversed (by 4 alternate reactions) in gluconeogenesis. These reactions are:

  6. GluconeogenicSubstrates • They are molecules that can be used to produce glucose through gluconeogenesis pathway. • They include: • Intermediates of glycolysis and of TCA cycle • Glycerol • Lactate & Pyruvate • Glucogenic amino acids The most important gluconeogenic precursors

  7. Gluconeogenic Substrates: Glycerol • Glycerol is released during the hydrolysis of Triacylglycerol (TAG) in adipose tissue. • In liver and kidney, glycerol will be phosphorylated by glycerol kinase to glycerol-P. • Glycerol-P will be oxidized by glycerol-P dehydrogenase to dihydroxyacetone phosphate(DHAP: an intermediate of glycolysis).

  8. Gluconeogenic Substrates: GlucogenicAmino Acids (AAs) • AAs can be derived from hydrolysis of tissue proteins. • Example of Glucogenic AA are: Alanine & Glycine amino acids are gluconeogenic substrates through conversion to Pyruvate

  9. Gluconeogenic Substrates: Lactate(Cori Cycle) • Lactate is released into the blood by exercising skeletal muscle & by cells lacking mitochondria (Anaerobic glycolysis of glucose). • Lactate is taken up by the liver and reconverted to glucose (gluconeogenesis) • Glucose will then be released to the circulation to be used by skeletal muscles.

  10. Gluconeogensis:Energy Consumed • With the formation of each molecule of glucose from pyruvate: • six high-energy phosphate bonds are cleaved • & two NADH are oxidized

  11. Regulation of Gluconeogenesis:by AMP • Elevated AMP  stimulates glycolysis (at the PFK-1 step) & inhibits gluconeogenesis (at the Fructose 1,6-bisphosphatase step)

  12. Regulation of Gluconeogenesis:PruvateCarboxylase regulation by Acetyl CoA • Fasting  ↑lipolysis in adipose tissue  ↑ Free Fatty Acid (FFA) to liver  The capacity of the liver for FA oxidation is exceeded  accumulation of Acetyl CoA  allosteric activation of pyruvate carboxylase to increase the Gluconeogensis rate

  13. Gluconeogenesis: Regulation by Glucagon ↑Glucagon (or ↓ Insulin/Glucagon ratio): stimulates gluconeogenesis by the following mechanisms: • Allosteric (glucagon lowers the level of Fructose 2,6-Bisphosphate activation of Fructose 1,6-Bisphosphatase & inhibition of PFK-1 (Reciprocal regulation of gluconeogenesis & glycolysis) • Induction (glucagon  induction of PEP-CK gene)

  14. Gluconeogenesis: Summary for Regulation • Reciprocal control • Gluconeogenesis & Glycolysis • Allosteric: • ↑Acetyl CoA stimulates Pyruvatecarboxylase • ↓ AMP or ↑ ATP • (i.e. energy-rich state in cells) • ↓ F 2,6-Bisphosphate • ↑Glucagon (or ↓ I/G ratio): stimulates gluconeogenesis by: • Allosteric regulation (glucagon  ↓ F 2,6-Bisphosphate) • Induction (glucagon  induction of PEP-CK gene)  Stimulate F 1,6-bisphosphatase

  15. Take Home Message • Gluconeogenesis: • Synthesis of glucose from noncarbohydrates • Anabolic • Energy-consuming • 4 Unique enzymes are required for • reversal of the 3 irreversible reactions • of glycolysis • Both gluconeogenesis & glycolysis are • reciprocally-regulated

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