BIOC/DENT/PHCY 230 LECTURE 7

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

17. UDPG synthesis

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

19. Activation of glucose

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

22. 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

23. 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