PANCREAS AND GLUCOSE

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

•Control the sugar levels in the body

•Produce enzymes that CHOP (digest) food1) Exocrine

2) Endocrine

A closer look: Endocrine Pancreatic cells Islets of Langerhans

has FOUR major cell types:

1) Alpha cell

2) Beta cell

3) Gamma cell (PP cell)

4) Delta cell

Islets of Langerhans!!!

A closer look: Endocrine Pancreatic cells1) Alpha cells glucagon2) Beta cells insulin3) Gamma cells pancreatic polypeptide4) 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 bloodClinical 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

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 nervosaClinical 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

Glucagon

Both

Insulin

• 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 is stored as a hexamer (left).

Its active form is a monomer (below).

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 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.

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

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

(Sneak preview for your 11/11 lecture)

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.

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 glucagonwork in tandem to maintain blood glucose levels in response to foodintake, 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 onback on November 11th for a fascinating presentation on diabetes.”

-Wilford Brimley