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Understanding Glucose Metabolism and Storage During the Fed State

This lecture explores the metabolic characteristics of the fed state, highlighting the increased plasma concentration of fuel molecules, the uptake, storage of glucose, and the role of insulin in regulating glucose metabolism. Key concepts include glucose transporters such as GLUT1, GLUT2, and GLUT4, their tissue-specific roles, and the process of glycogen synthesis. The lecture also addresses glycogen storage diseases stemming from deficiencies in glycogen synthesis and their associated symptoms. Understanding these mechanisms is essential for grasping how the body manages fuel during the fed state.

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Understanding Glucose Metabolism and Storage During the Fed State

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  1. BIOC/DENT/PHCY 230 LECTURE 7

  2. Fed state characterised by: • increased plasma concentration of fuel molecules • increased rate of uptake of fuel molecules from plasma • increased storage of fuel molecules in appropriate tissues • release of specific hormones to regulate fed state metabolism

  3. Glucose metabolism in the fed state • regulated by insulin glucose uptake in muscle and adipose tissue glycogen synthesis gluconeogenesis glycogenolysis

  4. Movement of glucose is regulated by specific transporters Glucose transporters may: • be insulin dependent or independent • have a high or low affinity for glucose • be ubiquitous or restricted in tissue distribution • move glucose up or down its concentration gradient

  5. high affinity low affinity

  6. Model mechanism for glucose transport

  7. SGLT1 Na+ glc glc glc glc Glucose uptake from small intestine • glucose is moved across the enterocyte cell membrane by co-transport with Na+ enterocyte intestinal lumen

  8. GLUT2 transports glucose out of the enterocyte GLUT2 glc glc glc glc enterocyte Insulin independent Low affinity, high capacity (KM 7-20mM) hepatic portal vein

  9. Fructose has its own transporter GLUT2 GLUT5 fru fru fru fru fru enterocyte hepatic portal vein • insulin independent

  10. Stimulation of insulin secretion • there are many stimuli that can promote insulin secretion • pancreatic b-cells use GLUT1 and GLUT2 to sense blood glucose levels • GLUT1 has a KM around physiological plasma [glucose] • GLUT2 has a higher KM • insulin secretion is stimulated by glucose concentrations around 8mM

  11. GLUT4 is an insulin sensitive transporter • GLUT4 cycles between the plasma membrane and intracellular vesicles • insulin stimulates the translocation of GLUT4 to the plasma membrane • insulin increases the rate of transport by GLUT4

  12. GLUT1 GLUT3 glc glc Glucose uptake by the brain KM ~ plasma [glucose] • low KM • regulates entry into neurons glc blood brain barrier neuronal cell membrane

  13. Properties of glucose transporters

  14. Glycogen • glycogen is the storage body for glucose • main stores are in skeletal muscle and liver • provides a reserve of glucose that can be mobilised between feeding or during exercise • structure: a branched chain polymer • synthesis occurs when glucose is plentiful in the fed state and is stimulated by insulin

  15. Glycogen biosynthesis • straight chain glucose polymers are synthesised by glycogen synthase • glycogen synthase can’t join together free glucose units • requires a primer to initiate synthesis • glycogenin is a protein, on which this primer is synthesised • glucose is added to glycogenin in the form of UDP-glucose

  16. UDPG synthesis

  17. glycogenin tyr Synthesis of glycogen primer on glycogenin Glycogen synthase extends this primer

  18. Activation of glucose

  19. branching enzyme(amylo-(1,4 1,6)-transglycosylase) Glycogen has a branched structure

  20. Glycogen Storage Diseases • Glycogen Synthase Deficiency (Liver) • glycogen synthesis slower; poor glycogen reserve • symptoms:fasted state - hypoglycemia • fed state - hyperglycemia • glucose intolerance • treatment: avoid long periods of fasting; diet • Branching enzyme deficiency: • abnormal glycogen structure...cell damage • consequences: liver cirrhosis, neuromuscular defects, death within 3 years

  21. The take home message • glucose metabolism in the fed state is characterised by glucose uptake and storage • insulin is a key mediator of glucose metabolism in the fed state • a variety of glucose transporters mediate glucose uptake depending on tissue requirements • glycogen is the storage body for glucose • the highly branched structure of glycogen improves the efficiency of glucose mobilisation • defects in glycogen synthesis can cause disease

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