Study Notes on Pancreatic Hormones, Insulin, and Glucagon

1–2%.

What percentage of the pancreas is endocrine tissue?

~98–99%.

What percentage of the pancreas is exocrine tissue?

Insulin, glucagon, somatostatin, pancreatic polypeptide (PP), gastrin.

Which pancreatic hormones are secreted by endocrine tissue?

\beta (B) cells.

Which cell type secretes insulin?

\alpha (A) cells.

Which cell type secretes glucagon?

\delta (D) cells.

Which cell type secretes somatostatin?

F (PP) cells.

Which cell type secretes pancreatic polypeptide (PP)?

G cells.

Which cell type secretes gastrin?

Chymotrypsin, trypsin, amylase, lipase.

Which digestive enzymes are produced by the exocrine pancreas?

Bicarbonate.

What additional important component does the exocrine pancreas secrete?

Neutralize gastric acid in the duodenum.

What is the role of bicarbonate released by the pancreas?

Pancreas, liver, gallbladder, bile ducts, duodenum.

What organs form the hepatopancreatic complex?

Integration of digestion and nutrient processing.

What is the functional role of the hepatopancreatic complex?

~60%.

What percentage of islet cells are \beta (B) cells?

Center of the islet.

Where are \beta (B) cells located in the islet?

~25%.

What percentage of islet cells are \alpha (A) cells?

Periphery of the islet.

Where are \alpha (A) cells located in the islet?

~10%.

What percentage of islet cells are \delta (D) cells?

Near \alpha-cells.

Where are \delta (D) cells located in the islet?

Pancreatic polypeptide (PP).

What stimulates gastric acid secretion in the stomach?

A peptide co-secreted with insulin from \beta-cells in a 1:100 ratio.

What is amylin (IAPP)?

Inhibits glucagon secretion, slows gastric emptying, increases satiety.

Name three functions of amylin.

Occurs in diabetes; contributes to impaired glucagon regulation and satiety.

What is the consequence of amylin deficiency?

Capillaries \to arterioles \to venules \to systemic circulation.

Describe the blood flow pathway inside pancreatic islets.

Adrenergic (SNS) and cholinergic (PNS) fibers.

What types of nerve fibers innervate pancreatic islets?

Increases insulin secretion.

What is the effect of parasympathetic stimulation on insulin secretion?

Decreases glucagon secretion.

What is the effect of parasympathetic stimulation on glucagon secretion?

Increases glucagon secretion.

What is the effect of sympathetic stimulation on glucagon secretion?

Decreases insulin secretion.

What is the effect of sympathetic stimulation on insulin secretion?

The hypothalamus.

What brain structure regulates SNS and PNS influence on islets?

110 amino acids.

What is the amino acid length of preproinsulin?

C-peptide.

What molecule links the A and B chains of insulin before cleavage?

21 amino acids.

What is the amino acid length of the A-chain?

30 amino acids.

What is the amino acid length of the B-chain?

21 amino acids.

What is the amino acid length of C-peptide?

Three.

How many disulfide bonds exist in mature insulin?

Two.

How many disulfide bonds link the A and B chains?

One.

How many disulfide bonds are internal to the A chain?

Neonatal diabetes, hyperinsulinemia, hyperproinsulinemia, MODY, Type 1b diabetes.

What disorders result from mutations that disrupt insulin folding or disulfide bond formation?

PC1/PC3 + CPE.

Which enzymes drive the major pathway of proinsulin processing?

PC2 + CPE.

Which enzymes drive the slower minor pathway?

Adjacent Lys/Arg residues.

What type of amino acid residues define cleavage sites in proinsulin?

Mature insulin (A + B chains) and free C-peptide.

What are the final products of proinsulin processing?

The three disulfide bond positions, A-chain N- and C-termini, hydrophobic B-chain C-terminus.

Which insulin structural features are evolutionarily conserved?

The monomer.

What is the active form of insulin?

Hexamer.

In what form is insulin stored in pancreatic \beta-cells?

Zn^{2+} ions and histidines.

What stabilizes the insulin hexamer?

Tetramer of 2 \alpha-subunits + 2 \beta-subunits.

What is the structural composition of the insulin receptor?

Bind insulin extracellularly.

What is the function of the \alpha-subunits?

Contain tyrosine kinase domain; undergo autophosphorylation.

What is the function of the \beta-subunits?

Two (one per \alpha-subunit).

How many insulin molecules must bind to activate the receptor?

A conformational change in \beta-subunits induced by insulin binding.

What initiates insulin receptor autophosphorylation?

SHC \to GRB2 \to SOS \to RAS \to RAF \to MEK \to MAPK.

What proteins initiate the P1a/P1b (MAPK) pathway?

Regulation of gene expression and cell growth.

What is the function of the MAPK pathway?

eNOS.

Which enzyme initiates pathway P2?

Nitric oxide (NO).

What molecule does eNOS produce?

Vasodilation.

What is the function of the P2 pathway?

PI3K.

Which kinase initiates pathway P3?

PI3K \to PDK \to Akt \to aPKC \to FOXO1 \to GSK-3.

What are the sequential steps of the P3 pathway?

Glycogen synthesis.

What metabolic process is promoted by inhibiting GSK-3?

P4.

Which pathway controls GLUT4 translocation?

CAP \to Cbl \to Crk \to C3G \to TC10.

What is the sequence of proteins in pathway P4?

Translocation of GLUT4 to the plasma membrane.

What is the final cellular effect of the P4 pathway?

Sodium-independent facilitated diffusion transporter.

What type of transporter is GLUT4?

Insulin signaling via the P4 pathway.

What triggers GLUT4 vesicle fusion with the plasma membrane?

Class I.

Which GLUT class includes glucose transporters 1–4?

Fructose.

What molecules do Class II GLUTs transport?

Structurally atypical with not fully defined functions.

What characterizes Class III GLUTs?

12.

How many transmembrane helices does each GLUT contain?

Cytosolic.

Are the N- and C-termini of GLUT proteins cytosolic or extracellular?

Pancreatic \alpha-cells.

What tissue primarily produces glucagon?

Glycogenolysis and gluconeogenesis.

Which physiological process does glucagon stimulate in the liver?

Lipolysis.

Which physiological process does glucagon stimulate in adipose tissue?

The proglucagon gene.

All glucagon and GLP-related peptides originate from what gene?

Amino acids (Arg, Ala, Gln), epinephrine, neuropeptides.

What stimulates glucagon release?

Glucose and somatostatin.

What inhibits glucagon release?

Full-length glucagon.

What does pancreatic proglucagon predominantly yield?

GLP-1, GLP-2, oxyntomodulin.

What peptides are produced from intestinal proglucagon?

Stimulates glucose-dependent insulin secretion and suppresses glucagon.

What is the primary role of GLP-1?

Antihyperglycemic.

What is GLP-1’s classification as a hormone?

GI growth and nutrient absorption.

What is the primary role of GLP-2?

Oxyntomodulin.

Which peptide activates GLP-1 receptors besides GLP-1 itself?

GPCRs (G-protein–coupled receptors).

What type of receptors mediate glucagon, GLP-1, and GLP-2 actions?

80–110 mg/dL.

What is the normal fasting blood glucose range?

130 mg/dL.

What glucose level is associated with Type 2 diabetes?

50–60 mg/dL.

What blood glucose range indicates hypoglycemia?

~5 g.

How much glucose is in total blood at 100 mg/dL?

~90 g.

How much glucose does an average meal provide?

~50%.

What percentage of post-meal glucose is stored as glycogen?

~50%.

What percentage is metabolized for ATP?

\uparrow GLUT4-mediated glucose uptake, \uparrow glycogenesis, \uparrow lipogenesis, \downarrow gluconeogenesis.

What are the major post-meal effects of insulin?

\uparrow glycogenolysis, \uparrow gluconeogenesis, \uparrow lipolysis.

What are the major effects of glucagon during fasting?

Via phosphorylation.

How does glucagon activate hepatic enzymes?

Via dephosphorylation of enzymes.

How does insulin inhibit hepatic glycogen breakdown?

Pyruvate, lactate, alanine, glycerol.

What substrates does glucagon stimulate conversion of into glucose?

It lacks glucose-6-phosphatase.

Why can’t muscle export glucose into the bloodstream?