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
What happens when insulin binds it’s receptor?
When insulin binds, the insulin receptor phosphorylate itself and other cytoplasmic proteins including IRS
The binding activated the insulin signal transduction cascade
Phosphorylated IRS act as docking proteins between the insulin receptor and a complex network of intracellular signalling molecules
Slide 25-27
What are the 3 major sites where insulin exerts it’s effects?
- Liver- promotes storage of glucose as glycogen, lipogenesis, stimulate protein metabolism
- In muscles- uptake of glucose via GLUT4, enhance conversion of glucose glycogen, increase glucose breakdown, promotes synthesis of proteins in skeleton muscles
- In adipose tissue- increase uptake of glucose via GLUT4, stimulates breakdown of glucose, promotes formation of triglycerides, indices the synthesis of lipoprotein lipase
Slide 28
What are the 4 major effects of insulin on hepatocytes (liver cells)?
- Insulin promotes glycogen synthesis from glucose by enhancing the transcription of glucokinase and by activating glycogen synthase
- Insulting promotes glycolysis and carbohydrate oxidation by increasing activity of glucokinase, phosphofructokinase, and pyruvate kinase
- Insulin promotes oxidation of pyruvate by stimulating pyruvate dehydrogenase, also inhibits gluconeogenesis by inhibiting activity of PEPCK
- Insulin promotes the synthesis and storage of fats by increasing the activity of Acetyl CoA carboxylase and fatty acid synthase
Slide 29!!
What are the 4 major effects insulin has on muscle?
- Insulin promotes glucose uptake by recruiting GLUT4
- Insulin promotes glycogen synthesis from glucose by enhancing transcription of hexokinase and by activating glycogen synthase
- Insulin promotes glycolysis and carbohydrate oxidation by increasing the activity of hexokinase, phosphofructokinase, and pyruvate dehydrogenase
- Insulin promotes protein synthesis and inhibits protein degradation
Slide 30!!
What are the 4 major effects of insulin on adipocytes?
- Insulin promotes glucose uptake by recruiting GLUT4
- Insulin promotes glycolysis, leading to the formation of α-glycerol phosphate, also converts Pyruvate to fatty acids
- Insulin promotes the esterification of α-glycerol phosphate with fatty acids to form triglycerides
- Insulin promotes the synthesis of LPL in the adipocyte, then adipocyte exports this enzyme to the endothelial cell where it breaks down the triglycerides contained
Slide 31!!
How can insulin also release notice oxide and what are it’s effects?
Insulin enhances endothelial nitric oxide production by stimulating nitric oxide synthase
C-peptide and pro-insulin also stim nitric oxide
Nitric oxide plays a role in glucose metabolism and diabetes by increasing vasodilation and thus enhancing glucose uptake and can cause erectile dysfunction
Slide 32
What is the effects of hypoglycemia and hyperglycemia?
Hypoglycemia- (low blood glucose) early manifestations include palpitations, tachycardia, anxiety, hyperventilation, shakiness, weakness, hunger, nausea, can cause seizures n stuff too
During hypoglycemia, glucagon is important in stimming glycogenolysis, gluconeogenesis, and ketogenesis
Hyperglycemia- (high blood glucose) early manifestations include weakness, polyuria, polydipsia, altered vision, weight loss, mild dehydration, long term can cause hyperventilation, coma, hypotension
Slide 33-34
What is glucagon signal transduction?
Glucagon antagonizes the effects of insulin in the liver
Glucagon binds to galpha s-coupled receptor which activates the adenylyl cyclase/cAMP/PKA cascade
- Glucagon promotes net glycogen breakdown by inhibiting glycogen synthesis by reducing activity of glucokinase and glycogen synthase
- Glucagon promotes net gluconeogenesis by inhibiting glycolysis and carbohydrate oxidation by reducing activity of glucokinase, phosphofructokinase, and pyruvate kinase
- Glucagon promotes the oxidation of fats by inhibiting the activity of acetyl CoA carboxylase
Slide 35
How is glucose metabolism affected during pregnancy?
The placenta makes many peptide hormones (including hCG and hCS- which convert glucose to fatty acids and ketones)
hPL to facilitate the energy supply of the developing fetus, but also has anti-insulin effects and causes carbohydrate intolerance (reduces maternal insulin causing hyperglycemia and gestational diabetes)
Slide 36
