hormonal regulation of blood glucose levels (insulin and glucagon) Flashcards
What are the different cells in the pancreatic islet?
• Beta cells (60%) ○ Insulin ○ Arranged in a central core • Alpha cells (25%) ○ Secrete glucagon ○ Sit next to insulin secreting cells • D or delta cells ○ somatostatin • PP cells ○ Pancreatic polypeptide
Describe the blood flow to the pancreatic islet
• Fenestrated capillaries, moves from the central core out to the periphery, and thus the cells secreting somatostatin and pancreatic polypeptide are bathed in insulin rich blood
Describe the structure of insulin
- Derived from pro-insulin by cleavage of the connecting peptide
- “c peptide”
- Leaving the A and B chains joined by disulfide bonds
Why might you measure C peptide levels in a diabetic?
• Exogenous insulin does not have C peptide, so checking C peptide levels is a way to distinguish between exogenous and native insulin release
Describe the synthesis and secretion of insulin
• Pre-pro-insulin is synthesized by the usual pathway for synthesis of secreted proteins
○ Nascent peptide is inserted across the RER membrane where the signal peptide is cleaved
○ Transferred to golgi for packaging into secretory granules
○ C peptide cleaved in secretory vesicles
• Mature secretory vesicles are called secretory GRANULES
○ Insulin is in a crystalline structure made up of insulin hexamers containing Zn atoms
○ Also contain tons of other regulatory proteins
• After secretory vesicle release, the dilution of the insulin crystals will result in crystal degradation release of free insulin
What is meant by ‘biphasic’ response of the islet to glucose?
- When islet cells are exposed to high glucose concentrations for 20 minutes or longer, there is an initial surge in insulin release followed by a second phase of prolonged release
- The prolonged release goes until glucose levels drop
- The initial phase is thought to be from pre-formed and docked vesicles
What is the stimulus for insulin secretion?
• Initiators
○ Stimulate insulin release on their own and include glucose, amino acids and drugs like sulfonylureas
§ Glipizide and glyburide
• Potentiators
○ Increase insulin secretion only in the presence of glucose
○ Incretin peptides such as
§ GLP-1 and ach
• Inhibitors
○ Include the drug diazoxide, somatostatin and alpha-adrenergic agents
○ Longstanding hyperglycemia results in a reversible reduction in insulin secretory capacity, or glucose toxicity
How does glucose affect insulin release?
- Most important stimulus
- Taken up by beta cell, metabolized via glycolysis and TCA cycle
- Increases ATP levels which generates the intracellular signal that starts the cascade
- Increased intracellular calcium will lead to docking of secretory vesicles
- Anything that results in increased intracellular calcium will result in insulin release
- Glucose enters through GLUT2, an insulin INDEPENDENT glucose transporter
- Glucokinase traps it in the cell
- The cell is depolarized by closing ATP regulated potassium channels
- Sulfonylureas act directly by blocking the ATP regulated potassium channels
How do sulfonylureas mess with insulin release?
- Sulfonylureas act directly by blocking the ATP regulated potassium channels
- Depolarizes the beta cell and leads to increased intracellular calcium and secretory vesicle docking
Do amino acids and fats stimulate insulin secretion?
- Just amino acids, not fat
* The amino acids get metabolized and those metabolite intermediates are what stimulates insulin secretion
Describe the nervous system regulation of insulin release
- Stimulation of splanchnic nerves inhibits insulin secretion as the catecholamines liberated interact with alpha receptors on the beta cell
- Stimulation of vagal nerve with attendant release of ach increases insulin secretion
- Modest increase in insulin during the cephalic phase
What “other hormones” affect insulin release?
- Somatostatin from the delta or D cells decrease insulin release in a paracrine fashion
- Catecholamines also have effects on insulin secretion
- Epinephrin inhibits secretion by binding alpha-adrenergic receptors on the beta cells
- Important during exercise and stress
When you see alloxan and streptozotocin what should you think?
- Experimental destruction of islet cells
* Creation of experimental diabetes
In general, what does insulin do to the liver, muscle and fat tissue in terms of glucose handling?
• Liver
○ GLUT2 is the transporter and that is insulin independent so nothing as far as uptake
○ It does however inhibit gluconeogenesis while stimulating glycogen syntheisis and fat synthesis
• Muscle
○ Increases uptake and glycogen synthesis
○ GLUT4 transporter
• Fat
○ Stimulates glucose uptake and fat synthesis and inhibits fat breakdown
○ Inhibits lipolysis
Describe the insulin receptor
- Part of the EGF (epidermal growth factor) family of membrane associated receptors
- Hetero-tetramer with two extracellular alpha chains and two membrane spanning Beta chains
- Alpha and beta chains are synthesized as one chain then cleaved and reconnected by disulfide bridge
- Insulin binding happens on the alpha chains
What are the “other” or “global” effects of insulin?
• It reduces food intake at the brain level
• Regulates blood flow in vessels
• Regulates salt and water reuptake in kidneys
• Stimulates overall growth in tissues (mitogenic effects)
○ This can be involved in the development of cancer during hyperinsulinemia
*beta chains have inherent tyrosine kinase activity
*insulin binding leads to autophosphorylation and other protein mediators being phosphorylated
What role do SH2 domains play in insulin signaling?
• SH2 domains are the particular domains that dock to and are phosphorylated by RTKs
• Since the insulin receptor phosphorylates SH2 domains on tyrosine residues, it is these domains that are important for insulin signaling
• In particular the IRS proteins are impoartant
○ Insulin receptor substrates
○ 1-4
What are the key intermediates in the metabolic pathway?
• The second messengers:
○ PI3K - phosphoinositol 3 kinase
○ AKT
• Also, remember the IRS proteins are adapter proteins and provide a docking site for all the SH2-domain containing proteins in the cell
What is a key intermediate in the mitogenic pathway?
- MAP kinase
- Also, remember the IRS proteins are adapter proteins and provide a docking site for all the SH2-domain containing proteins in the cell
Describe the pathway that ends up putting GLUT4 in the membrane of insulin sensitive tissues
- Insulin stimulates the phosphorylation of IRS1
- This stimulates PI3K activation
- PI3K causes rapid translocation to the plasma membrane and probably an activation of these GLUT4 transporters as well
- When insulin is removed the glut-4 transporters are re-endocytosed
The mitogenic actions of insulin are carried out by the action of what kinase pathway?
• MAP kinase pathway
Does insulin resistance usually involve the insulin receptor?
• NOPE. Only in rare genetic diseases
What, if not the receptor, is implicated in most cases of insulin resistance?
- Most insulin resistance is due to problems in the insulin signaling pathways
- Genetic and lifestyle factors combine to change cellular metabolism in a way that favors phosphorylation of serine and threonine residues on signaling molecules which make signaling less effective
- Serine and threonine phosphorylation reduces insulin signaling while tyrosine phosphorylation increases it
Describe the structure of glucagon
- Synthesized in the alpha cells of the pancreatic islets
- Pro-hormone that is cleaved prior to secretion by exocytosis
- Like insulin, glucagon is secreted into the protal circulation where it’s first target is liver
