Pancreas and glucose

1. Pancreas and glucose By Juliana Xie

2. Pan-creas! • Greek: “pan” = all; “creas” = flesh • Pancreas is like a fish! Head, body, and tail. • Important anatomical relationships

3. Why care about the pancreas? • The diseased pancreas can cause a LOT of trouble • Diabetes: • In the United States, 25.8 million adults and children (8.3% of population) have diabetes • Systemic disease • Pancreatic cancer – 4th most common cause of cancer-related death, extremely poor prognosis • Pancreatitis is an emergency situation

4. What makes the pancreas such an important organ? • Outline pancreatic gross and cellular anatomy • Discuss the normal function of the pancreas in glucose metabolism

5. Pancreas: two major roles • Control the sugar levels in the body 2) Endocrine • Produce enzymes that CHOP (digest) food 1) Exocrine

6. A closer look: Endocrine Pancreatic cells Islets of Langerhans!!! Islets of Langerhans has FOUR major cell types: 1) Alpha cell 2) Beta cell 3) Gamma cell (PP cell) 4) Delta cell

7. A closer look: Endocrine Pancreatic cells • Alpha cells  glucagon • Beta cells  insulin • Gamma cells  pancreatic polypeptide • Delta cells  somatostatin • Observe how these cells lie in close proximity of capillaries.

8. Alpha cells • Alpha cells make up 33-46% of the human islet cells • Make and secrete glucagon to elevate glucose levels in blood Clinical correlation: Too much glucagon – glucagonoma -rare tumor of the alpha cells that cause up to 1000-fold overproduction of glucagon -blood glucose raises via gluconeogenesis and lipolysis -causes diabetes mellitus

9. Beta cells • Make up 65-80% of the cells in the islets • Pathology: • Type 1 diabetes mellitus • Insulin-dependent diabetes • Autoimmune disease • Body cannot make insulin • Type 2 diabetes mellitus • Non insulin-dependent diabetes • Body can still make insulin, but tissues are insensitive to its actions

10. Gamma cells • Predominantly reside in the head of the pancreas • Makes and releases pancreatic polypeptide (PP) in response to ingestion of food • Inhibitory functions • Found to be elevated in anorexia nervosa Clinical correlation: -too much PP – Pancreatic polypeptidoma -can cause weight loss, diabetes mellitus

11. Delta Cells • Produce somatostatin INHIBITORY • Produced in multiple tissues, antigrowth effects • Suppress the release of insulin and glucagon Clinical correlation: Too much somatostatin – somatostatinoma -extreme reduction in secretion of insulin and cause diabetes.

12. Pancreas and Glucose Homeostasis • Glucose regulation works in a system of organs

13. Pancreas and Glucose Homeostasis

14. Clinical correlation: glucose test • Normal fasting blood sugar: 72 to 126 mg/dL • After a meal: less than 180 mg/dL 90 minutes after eating is normal

15. Hormonal Regulation of Glucose Metabolism Luke D. Piper

16. Overview: Learning Objectives Assuming I know what I’m doing up here, students should ultimately be able to: • Discuss the actions of insulin and glucagon • Discuss the mechanisms that regulate secretion of insulin and glucagon • Discuss potential problems arising from poor glucose regulation • Discuss how eating and fasting affect blood sugar, and how the body responds

17. Goals of Glucose Regulation Insulin • Get glucose into cells for utilization/storage • Glucose is primary fuel for cellular energy • Can be stored in liver and muscles as glycogen • Breakdown stored energy into glucose • Glycogen breakdown can quickly supply glucose • Lipids and proteins can be converted to glucose • Keep blood glucose from becoming too low or too high  Hypo- and hyperglycemia can both be dangerous Glucagon Both

18. Insulin Insulin is stored as a hexamer(left).Its active form is a monomer (below). • Polypeptide hormone • Produced in the Pancreas  Specifically, the β cells of the islets of Langerhans • Principle action: facilitates glucose uptake and glycogen synthesis • Other actions: facilitates lipid and protein synthesis • Insulin is primarily anabolic

19. Insulin: Principle Actions • Glucose uptake  Signaling pathway increases membrane expression of GLUT4 transporter  Allows glucose to enter cell • Especially important in muscle and adipose • Muscles: energy and storage • Adipose: long-term storage  Note: not all cells need insulin to get glucose • Glycogen synthesis • Signaling pathway promotes storage of glucose as glycogen • Especially important in liver

20. Insulin Action: Visual Aid Recall: insulin is anabolic

21. Insulin Regulation • Insulin secretion is stimulated by: • High blood glucose levels • Amino acid ingestion • Gastrointestinal hormones (e.g., cholecystokinin) • Insulin secretion is inhibited by: • Scarcity of dietary fuel • Epinephrine

22. Glucagon …yep, this is it. • Also a polypeptide hormone • Also produced in the pancreas • Specifically, the α cells of the islets of Langerhans • Principle action: mobilization of stored energy • Directly opposes most of insulin’s effects • Pancreas coordinates release of glucagon and insulin • Glucagon is primarily catabolic

23. Glucagon: Principle Actions • Increases blood glucose • Triggers glycogen breakdown in liver (glycogenolysis) • Activates glucose production pathways (gluconeogenesis) • Elicits breakdown of stored lipids (lipolysis) • Glycerol used in gluconeogenesis • Free fatty acids can be made into ketone bodies • Amino acid metabolism • Taken up by liver; used in gluconeogenesis • Theme: glucagon engages energy reserves

24. Glucagon Action: Visual Aid Glucagon operates via G-protein signalingto activate protein kinase A. Here, PKA activates enzymes involved in glycogenbreakdown and deactivates enzymes involved in glycogen synthesis. In adipose, the same type of pathway is used. There, the pathway targets enzymes involved in lipolysis.

25. Glucagon Regulation • Glucagon secretion is stimulated by: • Low blood glucose • Amino acid ingestion • Epinephrine • Glucagon secretion is inhibited by: • High blood glucose • Insulin

26. Super Fun and Totally Cool Mnemonic • Insulin gets glucose into cells  (so that they can use it or store it) • Glucagon is for when the glucose is gone  (and you need to mobilize storage)

27. Overview: Learning Objectives Assuming I know what I’m doing up here, students should ultimately be able to: • Discuss the actions of insulin and glucagon • Discuss the mechanisms that regulate secretion of insulin and glucagon • Discuss potential problems arising from poor glucose regulation • Discuss how eating and fasting affect blood sugar, and how the body responds

28. Fact • Blood glucose must be tightly regulated • Normally, insulin and glucagon work together to ensure it is • Problems arise when this regulation fails

29. (Sneak preview for your 11/11 lecture) Hyperglycemia • Too much glucose in blood • Often suggests malfunction in insulin pathway • Often seen in diabetes mellitus • Chronic hyperglycemia carries several long term effects: • Increased risk of cardiovascular disease and stroke • Frequent hunger, thirst, and need for urination • Tissue damage (e.g., retinopathy, nephropathy, neuropathy) • Ketoacidosis

30. Hypoglycemia • Too little glucose in blood • A number of potential causes: • Improper insulin dosage in diabetes patients • Oversecretion of bodily insulin • Long-term fasting • Liver dysfunction due to alcohol • Body responds via glucagon and epinephrine • This is a medical emergency • CNS requires continuous supply of glucose • Even brief denial of glucose to brain can cause long-term damage The Brain. Most researchers agree: it is important.

31. Overview: Learning Objectives Assuming I know what I’m doing up here, students should ultimately be able to: • Discuss the actions of insulin and glucagon • Discuss the mechanisms that regulate secretion of insulin and glucagon • Discuss potential problems arising from poor glucose regulation • Discuss how eating and fasting affect blood sugar, and how the body responds

32. Feeding, Fasting, and Blood Sugar • Feeding: Consuming a meal • Breakdown of carbs = sharp increase in blood glucose • Body responds with insulin • Glucagon inhibited (unless meal is predominantly protein) • Fasting: Skipping a meal, or otherwise refraining from eating • Glucose steadily falling • Insulin falls, glucagon/epinephrine rise • Body calls upon storage to meet energy demands • Fun fact: typical 70kg man has about 135,000 calories stored as fat

33. Feed/Fast Cycle Summarized The key is that insulin and glucagonwork in tandem to maintain blood glucose levels in response to foodintake, or lack thereof.

34. Overview: Learning Objectives Assuming I know what I’m doing up here, students should ultimately be able to: • Discuss the actions of insulin and glucagon • Discuss the mechanisms that regulate secretion of insulin and glucagon • Discuss potential problems arising from poor glucose regulation • Discuss how eating and fasting affect blood sugar, and how the body responds

35. My Personal Takeaway • The human body is elegantly designed to control many physiological parameters essential for its survival. • At the very least, I hope you take away some appreciation for the incredible capabilities of our physiology. • Regardless, thank you for your attention and have a good week. “Well that sure was fun. But hey everyone, make sure you come onback on November 11th for a fascinating presentation on diabetes.” -Wilford Brimley