Lecture 6 Flashcards
What is the pancreas?
It is an endocrine and exocrine gland
Produce digestive enzymes and HCO3 which flow into the GI tract via a network of exocrine ducts
Almost all pancreatic cells found in clusters called acini, among acini are millions of islets of langerhans which make 1-2% of pancreatic mass
Each islet contains ~2500 cells
Slides 1-2
What are the 3 ways pancreatic islets communicate with eachother?
Humoral communication- blood supply of islets courses outward from the center of the Islet toward the periphery, carrying glucose and stuff
Cell-cell communication- cells within an islet can communicate through gap junctions, which may be important for the regulation of both insulin and glucagon secretion
Neural communication- islets are innervated by sympathetic and parasympathetic nerves, cholinergic stimulation enhance insulin secretion, adrenergic stim can either stim or inhibit depending on α (inhibit) or β (stim) dominates
Slide 3
What are the 4 types of cells of the pancreatic islets?
α cells- secrete glucagon (during hypoglycemia and caused liver to convert stored glycogen to glucose) glucagon also stims release of insulin to enhance glucose reuptake
β cells- secrete insulin, proinsulin, C peptide, and amylin in the plasma
δ cells- secrete somatostatin (inhibitory hormone that regulates the endocrine system)
F cells- secrete pancreatic polypeptide (this inhibits secretion of somatostatin)
Islets are 20% α, 70% β, 7% δ, 3% F
Slides 4-8
What are the 2 factors affecting the secretion of glucagon?
- Reduced level of glucose in the blood, exercise and protein rich meals
- Inhibition of glucagon secretion is by somatostatin and insulin
What are the 3 functions of insulin?
Functions of insulin:
- Lowers blood glucose by increasing transport of glucose into cells via GLUT
- Glycogenesis: converting glucose into glycogen
- Increases lipogenesis and protein synthesis
What is the biosynthesis of insulin?
Full length mRNA That encodes pre-isoinsulin is formed in beta cells. Ribosomes synthesize pre-proinsulin
Pro insulin is shuttled into ER where disulphide bridges are formed giving rise to a folded insulin structure
Trans Golgi package the proinsulin and create secretory granules while the proteases cleave the proinsulin generating mature insulin linked by 2 disulphide bonds
Insulin and free C peptide are packaged in the Golgi into secretory granules which accumulate in the cytoplasm
Slide 10-11
What are glucose transporters and the 3 types?
Glucose transporters (GLUT) transport glucose
GLUT1- expressed in red blood cells and endothelial cells
GLUT2- found in renal tubular cells, hepatic cells, and pancreatic beta cells
GLUT4- expresses in adipose tissue, skeletal muscles, and cardiac tissue
What are the 7 steps of insulin release?
- Glucose enters cell via GLUT2 which mediates facilitated diffusion of glucose into cell
- Increased glucose influx stims glucose metabolism, increase ATPi
- Increased ATPi inhibits ATP-sensitive K channel (these channels usually open)
- Inhibition of K channel causes Vm to depolarize (more positive)
- Depolarization activates voltage gated Ca channel in plasma membrane
- Activation of Ca channel promotes Ca influx which evokes Ca induced Ca release
- Elevated [Ca]i leads to exocytosis and release into the blood of insulin contained within secretory granules
Slide 12-14
Can proinsulin be secreted with insulin?
What about c-peptide
Yes, in β cells, 5% of the secretion is proinsulin (with mild insulin like activities)
C peptide is secreted in equimolar amounts with insulin (no biological effect)
What are the 10 factors that stimulate insulin release?
What are the 5 factors that inhibit insulin release?
Stim: Elevated glucose concentration Increased levels of amino acids Increased levels of fatty acid/ketoacid Glucagon Growth hormone Cortisol Vagal stimulation (ACh) Gastric inhibitory peptide (GIP) Obesity Drugs like sulfonylureas that inhibit ATP dependant K channels
Inhibit: Low glucose conc Fasting Exercise Somatostatin α-adrenergic agonists
Slides 15-17
Which is a more powerful stimulant for insulin secretion;
Oral glucose or IV infusion?
Oral glucose is a more powerful stimulant for insulin secretion because it involves the gastric inhibitory peptide (GIP) hormone with an independent additive stimulators effect on insulin secretion
Slide 17-19
What is the insulin receptor?
Catalytic receptor
Associated with enzymatic activity following its binding with a Logan
Also known as a receptor tyrosine kinase (RTK) because it phosphorylates tyrosine residues on itself and other proteins
Made up of 2 extracellular α-chains and 2 membrane spanning β chains
Extracellular domain is the ligand binding part of receptor, insulin binding takes place on cysteine rich region of α chains
Slides 20-21!!
Slide 23
What are the 3 determining factors of the number of insulin receptors present on a target cell?
What are the 3 things the ability of insulin to act on a target cell is dependant on?
Insulin receptor presence:
1. Receptor synthesis
2. Endocytosis of receptors followed by recycling of receptors back to the cell surface
3. Endocytosis by degradation
Cells chronically exposed to high levels of insulin have fewer receptors because downregulation
Insulin ability:
- # of receptors present on the target cell
- Receptors affinity for insulin
- Receptors ability to transduce the insulin signal
In normal individual, the glucose response to insulin is max when ~5% of the receptors are occupied
Slide 22-23
What is insulin signalling?
3 ways of insulin receptor transmitting signals?
Insulin initiates it’s metabolic effects by binding to its receptor
- SH2 containing proteins bind and phosphorylate tyrosine groups on the insulin receptor
- Receptor can tyrosine phosphorylate and activate different cytoplasmic proteins
- Insulin receptor phosphorylates at tyrosine residues, family of cytosolic proteins known as insulin-receptor substrates (IRS) which are important link in insulin signal transduction path
IRS has 4 members (IRS1, IRS2, IRS3, IRS4)
What do defects in IRS1 been linked to?
IRS-1 has its major role in skeletal muscle whereas IRS-2 regulates hepatic insulin action as well as pancreatic beta-cell development and survival
Defects in IRS-1 have been reported in insulin resistant type 2 diabetes
Slide 24
