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3. Islet Cell Hormones And Hormonal Regulation of Fuel Metabolism M2-Endocrine Sequence Arno K. Kumagai, M.D Dept. of Internal Medicine Winter 2009

4. Normal Physiology ISLET CELL HORMONES Beta Cells: INSULIN (AND AMYLIN) Alpha Cells: GLUCAGON A. Kumagai

5. Normal Physiology ISLET CELL HORMONES Beta Cells: INSULIN (AND AMYLIN) Alpha Cells: GLUCAGON Image found at Dr. Thomas CaceciDr. Thomas Caceci

6. Response to a meal Islet hormone secretion varies with circulating glucose levels Meal increases: Glucose increased insulin decreased glucagon Amino acids, FA increased insulin Source Undetermined

7. Normal Insulin Physiology STIMULI FOR INSULIN SECRETION: GLUCOSE Amino Acids Fatty Acids INSULIN A. Kumagai

8. Insulin Action www.hannal.co.kr

9. Insulin Actions Insulin stores stuff… MharrschMharrsch, Flickr

10. Insulin Action SKELETAL MUSCLE Increases glucose transport Increases glycogen synthesis Inhibits gluconeogenesis FAT Increases glucose transport Increases lipogenesis Inhibits lipolysis Increases glycogen synthesis Increases glycolysis Inhibits gluconeogenesis A. Kumagai

11. Normal Glucose Metabolism GLUCOSE SUPPLY GLUCOSE DEMAND BRAIN Insulin-independent tissues DIET (-)(-) INSULIN Hepatic glucose production (+)(+) INSULIN Insulin-dependent tissues MUSCLE A. Kumagai

12. Normal Glucose Metabolism: The Fasting State or “Feeding the Head” GLUCOSE SUPPLY GLUCOSE DEMAND (+)(+) (-)(-) INSULIN BRAIN Insulin-independent tissues Hepatic glucose production DIET Insulin-dependent tissues MUSCLE A. Kumagai

13. Metabolic Changes During Fasting Long term - Lipid mobilization Short term - Glycogen mobilization Intermediate - Gluconeo- genesis BRAIN The adult brain is completely dependent on glucose for normal metabolism until >5 days into a fast The Brain = Obligate Glucose Consumer Source Undetermined (Brain) A. Kumagai

14. Normal Glucose Metabolism: The Fed State GLUCOSE SUPPLY GLUCOSE DEMAND (+)(+) (-)(-) INSULIN BRAIN Insulin-independent tissues DIET Hepatic glucose production MUSCLE A. Kumagai

15. INSULIN-GLUCAGON RELATIONSHIPS INSULIN GLUCAGON Glycogenesis and decreased blood glucose Glucoenogenesis and increased blood glucose STORAGEMOBILIZATION A. Kumagai

16. Insulin Action Increases glycogen synthesis Increases glycolysis Inhibits gluconeogenesis SKELETAL MUSCLE Increases glucose transport Increases glycogen synthesis Inhibits gluconeogenesis FAT Increases glucose transport Increases lipogenesis Inhibits lipolysis A. Kumagai

17. Insulin-regulated steps in muscle carbohydrate metabolism Facilitated glucose transport GLUT4 Hexokinase Glycogen synthase Glycogen synthase P inactive active PFK Glucose-FA cycle Amino acids AA Protein (Citrate inhib PKF accum hexose P reduce conc gradient for glucose entry) = insulin-sensitive (+) I I (-) I I Source Undetermined

18. Insulin Action Increases glycogen synthesis Increases glycolysis Inhibits gluconeogenesis SKELETAL MUSCLE Increases glucose transport Increases glycogen synthesis Inhibits gluconeogenesis FAT Increases glucose transport Increases lipogenesis Inhibits lipolysis A. Kumagai

19. Carbohydrate Metabolism in Hepatocytes Insulin inhibits glucose production Insulin Stimulates glycogen storage Insulin inhibits Glycogen breakdown Source Undetermined

20. Insulin Action Increases glycogen synthesis Increases glycolysis Inhibits gluconeogenesis SKELETAL MUSCLE Increases glucose transport Increases glycogen synthesis Inhibits gluconeogenesis FAT Increases glucose transport Increases lipogenesis Inhibits lipolysis A. Kumagai

21. Insulin-regulated carbohydrate metabolism: adipocyte Facilitated glucose transport PDH ACC Lipogenesis Glycogen synthase Lipolysis HSL LPL Insulin inhibits lipolysis by stimulating lipoprotein lipase (LPL) and inhibiting hormone-sensitive lipase (HSL) GLUT4 I (+) (-) Source Undetermined

22. Fuel Metabolism: Take-Home Points Understand: 1. That insulin binding to its receptor initiates a cascade of signaling pathways that results in translocation of the insulin-sensitive GLUT4 to the plasma membrane and increased glucose uptake. 2.The changes in insulin secretion in fasting and fed states and the physiologic “rationale” for preserving brain glucose uptake.

23. Fuel Metabolism: Take-Home Points Understand: 3. The actions of insulin on skeletal muscle, liver, and fat. 4.The biochemistry: understand that insulin stores (e.g., stimulates glycogen synthase and lipoprotein lipase) and inhibits catabolism (e.g., inhibits HSL).

24. Additional Source Information for more information see: http://open.umich.edu/wiki/CitationPolicy Slide 4: Arno Kumagai Slide 5: Dr. Thomas Caceci, Image found at http://education.vetmed.vt.edu/curriculum/vm8054/labs/labtoc.htmhttp://education.vetmed.vt.edu/curriculum/vm8054/labs/labtoc.htm Slide 6: Source Undetermined Slide 7: Arno Kumagai Slide 8: www.hannal.co.krwww.hannal.co.kr Slide 9: Mharrsch, Flickr, http://www.flickr.com/photos/mharrsch/http://www.flickr.com/photos/mharrsch/ Slide 10: Arno Kumagai Slide 11: Arno Kumagai Slide 12: Arno Kumagai Slide 13: Arno Kumagai; Source Undetermined Slide 14: Arno Kumagai Slide 15: Arno Kumagai Slide 16: Arno Kumagai Slide 17: Source Undetermined Slide 18: Arno Kumagai Slide 19: Source Undetermined Slide 20: Arno Kumagai Slide 21: Source Undetermined