1. BIOC/DENT/PHCY 230 LECTURE 7

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

3. Glucose metabolism in the fed state o 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: o be insulin dependent or independent o have a high or low affinity for glucose o be ubiquitous or restricted in tissue distribution o move glucose up or down its concentration gradient

5. high affinity low affinity

6. Model mechanism for glucose transport

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

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

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

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

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

12. GLUT1GLUT3 blood brain barrier neuronal cell membrane K M ~ plasma [glucose] o low K M o regulates entry into neurons glc Glucose uptake by the brain

13. Properties of glucose transporters

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

15. Glycogen biosynthesis o straight chain glucose polymers are synthesised by glycogen synthase o glycogen synthase can’t join together free glucose units o requires a primer to initiate synthesis o glycogenin is a protein, on which this primer is synthesised o 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. Glycogen has a branched structure branching enzyme (amylo-(1,4 1,6)-transglycosylase)

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

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