Lecture 19.5: Endocrine Pancreaas

2 types of pancreatic tissue

Acini

Islets of Langerhans

Acini tissues

Exocrine glands

Secrete digestive enzymes and juices into duodenum

Islets of Langerhans tissue

Endocrine glands

Secrete insulin and glucagon

Pancreatic islets

1-2% of pancreatic volume

Endocrine pancreas high reserve capacity

More than 70% of insulin secreting cells must be lost for dysfunction

Endocrine pancreas vascularization

High

More than exocrine pancreas

Adrenergic and cholinergic innervation of endocrine pancreas

Beta-2 adrenergic agonists enhance insulin secretion

Alpha-2 adrenergic agonists inhibit insulin release

Activation of the SNS inhibits insulin secretion

Feeding induced PNS activation stimulates insulin secretion

How many endocrine cell types are there?

5

Where and how are islet cell hormones transported?

To the liver via hepatic portal vein

What is the most predominant islet cell type?

Beta

65-80%

Insulin, C-peptide, pro insulin, amylin

What is the second most prominent islet cell type?

Alpha

15-20%

Glucagon and proglucagon

What is the third most prominent islet cell type?

Delta

Less than 10%

Somatostatin

What is the fourth most prominent islet cell type?

Gamma/F cells

Less than 5%

Pancreatic polypeptide

What is the least prominent islet cell type?

Epsilon

Less than 1%

Ghrelin

What does somatostatin inhibit?

Insulin and glucagon

What does insulin inhibit?

Glucagon

What does glucagon stimulate?

Insulin and somatostatin

Insulin

Anabolic hormone secreted by beta cells of pancreatic islets

Derived from Latin word insula

Major regulator of glucose and lipid metabolism

Stimulates cell growth and differentiation

What processes does insulin inhibit?

Gluconeogenesis

Glycogenolysis

Lipolysis

What processes does insulin stimulate?

Lipogenesis

Glycogen and protein synthesis

Glucose uptake by muscle and fat

Where is preproinsulin synthesized?

In ribosomes

Where does preproinsulin cleavage, folding, and bond formation occur?

In the ER

What is insulin secretion accompanied by?

An equimolar secretion of C-peptide

Where is proinsulin transported to?

Golgi

Packed in secretory vesicles

Where does proinsulin cleavage occur?

In secretory vesicles

Stimulatory signals for insulin release

Fatty acids

Ketone bodies

Glucagon

Cholecystokinin

High glucose

High amino acids

High GLP-1

Inhibitory signals of insulin release

Leptin

Chronically elevated glucose

Somatostatin

Epinephrine

Infection

Low glucose

Glucose-stimulated insulin release from pancreatic Beta-cells

Increased glycolysis

Increased intracellular ATP

Cytosolic ATP blocks kATP channels which blocks K+ efflux

Membrane depolarization

Voltage gated Ca2+ channels open

influx of Ca, which promotes exocytotic release of insulin from secretory vesicles

Insulin receptor mechanism

Belongs to a family of RTK‘s that includes IGF-1 receptor

Tetrameric proteins comprise of two alpha and two beta subunits

Extracellular alpha subunits contain insulin binding sites

Insulin regulated TPK autophosphorylation sites located on Beta subunit

Insulin receptor signaling

Insulin binding to Alpha subunit of IR

Auto fusion of tyrosine kinase in the beta subunit

Receptor kinase activation leads to phosphorylation of IRS

Binding of IRS to PI3K leads to three pathways

Metabolic pathway

GLUT4-mediated glucose uptake by SKM and Adipose Tissue

Increased glycogen storage

Increased protein synthesis via mTOR activation

3 pathways resulting from binding of IRS to PI3K

Metabolic

Mitogenic

Transcriptional

GLUT4

Key role in SKM and adipose

GLUT1

Major player in the liver

Physiological functions of insulin

Major role in fuel homeostasis

Acts on peripheral tissues to increase uptake of glucose and amino acids by increasing GLUT4

Without it most tissues do not take in glucose and amino acids well, except for the brain

Net result of insulin production

Increases glycogen production in the liver and muscle

Stimulates lipid synthesis from free fatty acids and triglycerides in adipose tissue

What does insulin promote?

Fuel storage (anabolism)

What does insulin prevent?

The breakdown and release of fuel that has already been stored (catabolism)

What does total lack of insulin mean?

Not compatible with life

Same goes for too much insulin

GLUT1

Blood

Blood-brain barrier

Heart

Insulin-independent

GLUT2

Liver

Pancreas

Small intestine

Insulin-independent

High Km

Low affinity

GLUT3

Brain

Neurons

Sperm

Insulin-independent

Low Km

High affinity

GLUT4

Skeletal muscle

Adipose tissue

Heart

Insulin action on cells

Dominates in fed state metabolism

Increases glucose uptake in cells except active muscle cells

Increases glucose use and storage

Increases protein synthesis

Increases fat synthesis

Metabolic effects of insulin on the liver

Promotes anabolism and inhibits catabolism

How does insulin promote anabolism in the liver?

Stimulates glycogen synthesis and storage

Stimulates glycolysis

Stimulates lipogenesis

Increases protein, triglyceride, and VLDL formation

How does insulin inhibit catabolism in the liver?

Decreasing hepatic, glycogenolysis, ketogenesis and gluconeogenesis

Metabolic effects of insulin on muscle

Promotes protein synthesis, glycogen synthesis, and increases glucose uptake

How does insulin promote protein synthesis in muscle?

Increased amino acid transport

Stimulation of ribosomal protein synthesis

How does insulin promote glycogen synthesis in muscle?

Enhanced by increased glucose transport

Enhanced activity of glycogen synthase

Inhibiting activity of glycogen phosphorylase

Metabolic effects of insulin on adipose tissue

Promotes triglyceride storage

Inhibits lipolysis

Overall increases fat storage in adipose tissue

How does insulin promote triglyceride storage in adipose tissue?

Increases production of lipoprotein lipase

Hydrolysis of triglycerides from circulating lipoproteins

Increasing glucose uptake by fat cells

Increasing cellular levels of alpha-glycerol phosphate, esterification of fatty acids to triglycerides

How do amino acids stimulate insulin release?

Increasing uptake into cells and increasing protein synthesis

How do keto acids stimulate insulin release?

In increasing glucose uptake to prevent lipid and protein utilization

How does adrenal epinephrine inhibit insulin release?

Epinephrine binds to alpha adrenergic receptors on beta cells

Maintenance of blood glucose levels

Structure of glucagon

Peptide hormone with 29 amino acids

Produced by Alpha cells of the endocrine pancreas

Actions of glucagon

Acts on the liver to cause breakdown of glycogen, releasing glucose into the bloodstream

Inhibits glycolysis

Increases production of glucose from amino acids

Increases lipolysis to free fatty acids for metabolism

Function of glucagon

Maintenance of blood glucose levels during fasting

How do increased blood glucose levels affect glucagon release?

Inhibits it

Fasting stimulates glucagon release

How do amino acids affect glucagon release?

Stimulating it

Eating a high protein and low carb meal

How do fatty acids and ketones affect glucagon release?

Inhibit it

How does stress affect glucagon release?

Stimulates it

Increases availability of glucose for energy

How does exercise affect glucagon release?

Stimulates it

How does insulin affect glucagon release?

Inhibits it

What are the main target tissues of glucagon receptor signals?

Liver

Muscle

Adipose tissue

What is the major biological role of glucagon receptor signaling?

To oppose hypoglycemic effects of insulin by inducing hepatic glucose production

Glucagon receptor signaling

Binds to Gas-coupled receptor, increasing cyclic AMP and PKA activity

Activated PLC-mediated IP3 pathway, increasing Ca+

What does glucagon action activate?

Glycogen phosphorylase, the rate limiting enzyme of glycogenolysis

Cleaves a glucose 1-phosphate molecule off glycogen in the liver

Lipases, breaking down triglycerides in adipose tissue

What does glucagon action inactivate?

Glycogen synthesis by phosphorylation in the liver

What does glucagon action increase?

Phosphoenolpyruvate carboxykinase

Stimulates gluconeogenesis in the liver

What does glucagon action inhibit?

Acetyl CoA carboxylase, decreasing free fatty acid formation from acetyl CoA

Net result of glucagon action

Increased production of glucose and substrates for metabolism

Metabolic effects of glucagon

Dominate in fasted conditions

Counter regulatory hormone that opposes insulin action

Hepatic effects

Hepatic effects of glucagon

Increased hepatic glucose production, via glycogenolysis and gluconeogenesis

Increased hepatic uptake of amino acid which fuels gluconeogenesis

Stimulation of fatty acid oxidation and ketogenesis

Stimulates TG breakdown in adipose tissue under conditions of starvation

No direct affect on SKM

Indirect effects on SKM: high glucagon promotes muscle protein breakdown and amino acid release

Somatostatin

Produced by Delta cells of the pancreatic islets

Synthesized from preprosomatostatin in pancreas

Secretion stimulated by glucose amino acids, enteric hormones, and glucagon

Inhibitory G protein, coupled receptors

Exerts paracrine effects on other islet cells

Regulates its own secretion in autocrine manner

Key functions of somatostatin

Inhibits gut motility

Inhibits enteric peptides

Inhibits pancreatic exocrine function

Pancreatic polypeptide

36-Amino acid peptide

Produced by gamma or F cells of islet of Langerhans

Secretion regulation of pancreatic polypeptide

Food intake signals

Energy status

Vagal stimulation increases PP

Hormones

Key functions of pancreatic polypeptide

Inhibit G.I. motility

Inhibits pancreatic exocrine secretions

Regulate satiety and body weight

Glucocorticoids

Cortisol

Stimulate gluconeogenesis and lipolysis

Increase breakdown of proteins

Epinephrine/Norepinephrine

Stimulates glucagon release while inhibiting insulin level levels

Stimulate glycogenolysis and lipolysis

Growth hormone

Stimulates glycogenolysis and lipolysis