5- Endocrine Pancreas

Acini

What is the exocrine portion of the pancreas called?

Secrete digestive juices into the duodenum

What is the role of the acini?

Islets of Langerhans

What is the endocrine portion of the pancreas called?

Secrete hormones directly into the bloodstream

What is the role of the Islets of Langerhans?

Less than 3%, about 1 gram

Approximately what percentage and weight do the Islets of Langerhans constitute of the pancreas?

10%

What percentage of pancreatic blood flow do the Islets of Langerhans receive?

Adrenergic, Cholinergic, Peptidergic

What are the types of neurons that richly innervate the islet cells?

Beta, Alpha, Delta, γ, ε

What are the five cell types associated with the Islets of Langerhans?

Insulin and amylin

What hormones do beta cells produce?

60%

What percentage of all islet cells do beta cells constitute?

Glucagon

What hormone do alpha cells produce?

25%

What percentage of all islet cells do alpha cells constitute?

Somatostatin

What hormone do delta cells produce?

10%

What percentage of all islet cells do delta cells constitute?

Pancreatic polypeptide

What does the γ cell produce?

Ghrelin

What does the ε cell produce?

Small capillaries

Around what structures are islets arranged into which hormones are secreted directly?

Pancreatic acini

What surrounds the Islet of Langerhans?

Paracrine regulation

What is the significance of venous blood from one islet cell type bathing other cell types?

Gap junctions

What structures interconnect islet cells allowing for cell-to-cell communication?

Paracrine modulation

What does cell-to-cell communication in islets allow?

Insulin inhibits glucagon secretion, Amylin inhibits insulin secretion, Somatostatin inhibits insulin and glucagon secretion

Give examples of autocrine and paracrine effects within the islets of Langerhans that regulate blood glucose levels.

Decrease blood glucose concentration

What is the main goal of insulin?

Excess energy to be stored

During what period is insulin secreted?

Preproinsulin

What is the initial translation product of RNA when a signal comes to make more insulin?

Endoplasmic reticulum

Where does the cleavage of the signal peptide from preproinsulin occur?

Proinsulin

What molecule is formed after the signal peptide is cleaved from preproinsulin?

Golgi apparatus

Where does the cleavage of C-peptide from proinsulin occur?

Insulin (A and B chains) and C-peptide

What are the products of proinsulin cleavage?

Secretory granule

In what structure are insulin and C-peptide packaged before secretion?

Portal circulation

Into what circulatory system are insulin and C-peptide secreted?

Mainly insulin, 5-10% proinsulin

What does beta cell secretion mainly consist of?

No insulin activity

What is the insulin activity of proinsulin and C-peptide?

Measure endogenous insulin function through radioimmunoassay

What is the clinical significance of C-peptide?

Equimolar amount with insulin, not extracted by the liver, constant kidney clearance

Why is C-peptide used to measure endogenous insulin production instead of insulin itself?

Exogenous insulin will not have C-peptide

How can C-peptide levels differentiate between exogenous and endogenous insulin sources?

Insulinoma

What is a pancreatic mass producing lots of insulin called?

Two amino acid chains (A and B) connected by disulfide linkages

What is the structure of insulin?

Loss of functional activity

What happens if the disulfide linkages in insulin break?

Unbound form

How does insulin circulate in the blood?

6 minutes

What is the plasma half-life of insulin?

Insulinase (mainly in the liver, kidneys, and muscles)

What enzyme degrades insulin?

Breaks disulfide bonds, inactive A and B chains excreted in urine

How does insulinase degrade insulin?

Quality of beta cell mass, architecture and structural integrity, ability to sense ambient glucose concentration

What are the requirements for insulin secretion?

Glucose concentration > 70 mg/dL (3.9 mmol/L)

At what glucose concentration is insulin synthesis stimulated?

200-250 units

What is the functional reserve of beta cells in terms of insulin secretion?

Islet neogenesis, beta cell proliferation, beta cell hyperplasia, beta cell apoptosis, beta cell dedifferentiation

What factors influence beta cell mass?

Abundant GLUT2 transporters, rich islet cell vascularization (fenestrated vessels)

How does the pancreas sense ambient glucose?

Glucose, Leucine, Parasympathetic (M3 acetylcholine), Sulfonylureas, Enteric hormones (GLP, GIP, CCK, Secretin, gastrin), Neural (β-adrenergic), Amino acids (Arginine)

List some stimulants of insulin release.

Neural (α2-adrenergic norepinephrine), Humoral (somatostatin), Drugs (Diazoxide, Phenytoin, Vinblastine, Colchicine)

List some inhibitors of insulin release.

Glucose transporter 2 (GLUT2)

Through which glucose transporter does glucose enter the beta cell?

Glucose-6-phosphate (G6P)

What is glucose phosphorylated into inside the beta cell?

ATP

What molecule is produced when glucose-6-phosphate is oxidized in the beta cell?

Closes ATP-sensitive K+ channels

What is the effect of ATP on potassium channels in the beta cell?

Depolarization

What electrical change occurs in the beta cell membrane due to the closure of potassium channels?

Voltage-sensitive Ca2+ channels

What type of ion channels open in response to beta cell depolarization?

Exocytosis of secretory vesicles containing insulin

What does the increase in intracellular calcium in the beta cell lead to?

Glucokinase

What is the rate-limiting enzyme in glucose metabolism in the beta cell?

SUR1 and KIR6.2

What are the subunits of KATP channels?

Basal (50%) and postprandial (50%)

What are the two main kinds of insulin secretion?

Rapid increase (5x baseline) peaking within 60 minutes

Describe postprandial insulin secretion.

Sharp and short-lived peak (3-5 minutes, max 10 minutes)

Describe the 1st phase of insulin secretion.

Release of preformed insulin, suppresses hepatic glucose production, primes the 2nd phase

What is the significance of the 1st phase of insulin secretion?

15 minutes to 2 hours, directly related to glucose elevation, covers mealtime carbohydrates

Describe the 2nd phase of insulin secretion.

1.5 to 3 hours after glucose exposure, spontaneous decline of insulin levels

Describe the 3rd phase of insulin secretion.

Higher insulin level for oral glucose load compared to IV glucose infusion despite similar blood glucose levels

What is the incretin effect?

Gut hormones released in response to ingestion of a meal

What are incretins?

Glucagon-like Peptide 1 (GLP-1) and Glucose-Dependent Insulinotropic Polypeptide (GIP)

What are the two major types of incretins?

Inhibits glucagon secretion, increases insulin, inhibits gastric emptying, enhances beta cell proliferation and survival (animal models)

What are the functions of GLP-1?

Increases insulin

What is a function of GIP?

Tyrosine kinase-linked receptor

What type of receptor is the insulin receptor?

α subunit (extracellular membrane)

Which subunit of the insulin receptor is the insulin binding site?

β subunit (embedded in the cell membrane)

Which subunit of the insulin receptor translates the signal produced by insulin binding?

Autophosphorylation of the beta subunit

What is the first step in the mechanism of insulin receptor action after insulin binds?

Activation of tyrosine kinase

What happens after the autophosphorylation of the insulin receptor's beta subunit?

Increase in insulin receptor substrates and phosphorylation of enzymes

What are the downstream effects of tyrosine kinase activation in insulin signaling?

Carbohydrate, fat, and protein metabolism

On which metabolic processes does insulin have significant effects?

Anabolic

Is insulin considered an anabolic or catabolic hormone?

Increased permeability to glucose

What is an immediate effect of insulin on glucose uptake?

Translocation of glucose transporters

What cellular mechanism mediates insulin's effect on glucose permeability in muscle and adipose cells?

Increased permeability to amino acids, potassium, phosphate ions

Besides glucose, what other substances does insulin increase cell permeability to?

Increased enzyme activity (slower effect via changed phosphorylation states), increased protein synthesis (much slower effect via translation and transcription)

What are the slower effects of insulin on enzyme activity and protein synthesis?

Muscle and adipose cells

In which cell types does insulin increase glucose permeability significantly?

Most cells and tissues, transports glucose into the cell

Where is GLUT1 located and what is its function?

Liver and pancreatic beta cells, low affinity & high capacity, first step in glucose detection for insulin stimulation

Where is GLUT2 located and what is its function?

CNS, high affinity, allows brain cells to use glucose without insulin

Where is GLUT3 located and what is its function?

Adipose and muscle tissue, principal insulin-responsive glucose transporter

Where is GLUT4 located and what is its function?

Pancreatic beta cell

In which specific cell type is GLUT2 crucial for glucose sensing?

High transport capacity, low affinity for glucose

What are the key characteristics of GLUT2's affinity and capacity?

High affinity for glucose

What is a key characteristic of GLUT3's affinity?

Adipose tissue and resting skeletal muscle

In which tissues is glucose transport insulin-dependent?

Exercising skeletal muscle, nervous tissue, kidney tubules, intestinal mucosa, RBCs, beta cells of the pancreas, liver

In which tissues can glucose transport occur independently of insulin?

Increase glucose utilization in adipose tissue and muscle (GLUT4 insertion)

How does insulin increase glucose utilization?

Promotes glycogenesis (glycogen formation) and inhibits glycogenolysis (glycogen breakdown)

How does insulin regulate glycogen metabolism?

Inactivates liver phosphorylase, increases glucokinase, activates glycogen synthase

List the specific enzymatic effects of insulin that promote glycogen formation and inhibit breakdown.

Decreases gluconeogenesis (glucose synthesis mainly in the liver and kidney)

How does insulin affect gluconeogenesis?

Activates phosphofructokinase, decreased precursor release from extrahepatic tissues

List the mechanisms by which insulin decreases gluconeogenesis.

Decreases lipolysis (by decreasing hormone-sensitive lipase and increasing glucose transport)

How does insulin decrease blood fatty acids?

Increases fat storage (mainly in the liver then adipose tissue)

How does insulin affect fat storage?

Activates Acetyl-CoA carboxylase, activates lipoprotein lipase, inhibits ketoacid formation

List the specific mechanisms by which insulin increases fat storage and inhibits ketone body formation.