By Juliana Xie
By Juliana Xie Pan-creas! • Greek: “pan” = all; “creas” = flesh • Pancreas is like a fish! Head, body, and tail. • Important anatomical relationships 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 What makes the pancreas such an important organ? •Outline pancreatic gross and cellular anatomy •Discuss the normal function of the pancreas in glucose metabolism Pancreas: two major roles 2) Endocrine • Produce enzymes that CHOP (digest) food 1) Exocrine • Control the sugar levels in the body 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 A closer look: Endocrine Pancreatic cells 1) 2) 3) 4) • Alpha cells glucagon Beta cells insulin Gamma cells pancreatic polypeptide Delta cells somatostatin Observe how these cells lie in close proximity of capillaries. 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 1000fold overproduction of glucagon -blood glucose raises via gluconeogenesis and lipolysis -causes diabetes mellitus 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 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 • 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. Pancreas and Glucose Homeostasis • Glucose regulation works in a system of organs Pancreas and Glucose Homeostasis 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 Hormonal Regulation of Glucose Metabolism LUKE D. PIPER 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 Goals of Glucose Regulation • 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 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 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 Insulin Action: Visual Aid Recall: insulin is anabolic 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 Glucagon • 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 …yep, this is it. 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 Glucagon Action: Visual Aid Glucagon operates via G-protein signaling to activate protein kinase A. Here, PKA activates enzymes involved in glycogen breakdown and deactivates enzymes involved in glycogen synthesis. In adipose, the same type of pathway is used. There, the pathway targets enzymes involved in lipolysis. Glucagon Regulation • Glucagon secretion is stimulated by: Low blood glucose Amino acid ingestion Epinephrine • Glucagon secretion is inhibited by: High blood glucose Insulin 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) 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 Fact • Blood glucose must be tightly regulated • Normally, insulin and glucagon work together to ensure it is • Problems arise when this regulation fails (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 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 The Brain. Most researchers agree: it is important. CNS requires continuous supply of glucose Even brief denial of glucose to brain can cause long-term damage 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 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 Feed/Fast Cycle Summarized The key is that insulin and glucagon work in tandem to maintain blood glucose levels in response to food intake, or lack thereof. 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 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 on back on November 11th for a fascinating presentation on diabetes.” -Wilford Brimley
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