Week 9: Hormonal Regulation Flashcards
What is endocrine signaling?
Hormones that are carried by blood stream to nearby cells or other organs
Where are insulin and glucagon produced?
Islets of Langerhans in pancreas
What are the major tissues of fuel metabolism?
- Liver
- Adipose
- Muscles
- Brain
What are the important hormones for fuel metabolism?
- Insulin
- Glucagon
- Catecholamines
What is insulin?
- Anabolic peptide secreted by the pancreatic b-cels
- Promote the storage of glucose, fat, and aa
- Stimulates the synthesis of macromolecules and inhibits breakdown
When is insulin secreted?
Increased blood glucose, aa, and fats
Where does insulin bind to?
Insulin receptors in brain, liver, adipose, and other fuel-metabolizing tissues
Describe the formation of insulin
- Insulin is formed as preproinsulin consisting of A and B chain with a C-peptide segment
- Preproinsulin is cleaved to proinsulin in the RER
- In the Golgi, proinsulin is cleaved into insulin and C-peptide
- Insulin and c-peptide is stored in secretory granules (vesicles) in the cytoplasm
- Secreted by exocytosis releasing insulin and C-peptide
- Insulin is inhibited by epinephrine during periods of physiologic stress
Describe the formation of insulin
- Insulin is formed as preproinsulin consisting of A and B chain with a C-peptide segment
- Preproinsulin is cleaved to proinsulin in the RER
- In the Golgi, proinsulin is cleaved into insulin and C-peptide
- Insulin and c-peptide is stored in secretory granules (vesicles) in the cytoplasm
- Secreted by exocytosis releasing insulin and C-peptide
- Insulin is inhibited by epinephrine during periods of physiologic stress
Describe the signaling of insulin
- Glucose enters the pancreatic b cells through GLUT2 transporter and enters glycolysis to generate ATP
- Increased ATP levels cause inhibition of ATP-sensitive K+ channels leading to membrane depolarization
- This triggers the activation of voltage gated Ca2+ channels
- Intracellular Ca2+ triggers fusion of insulin vesicles with the plasma membrane where they are released.
Where is GLUT2 located?
Cells in the liver, pancreatic, renal proximal tube and small intestine
What occurs during insulin-mediated glucose transport?
- Insulin binds to insulin receptor (tyrosine kinase receptor)
- Binding leads to a signaling cascade that promotes recruitment of glucose transporters (GLUT4) from the cytosol to cell membrane.
- GLUT4 increases insulin-mediated uptake
- When glucose levels decrease, GLUT4 moves back to the cytosol into intracellular storage vesicles.
Where is GLUT4 located?
Skeletal muscle, adipose tissue and cardiac muscle
What is glucagon?
- Catabolic peptide hormone that is secreted by the pancreatic a-cells
- Promotes the usage of glucose and alternative fuels
- Stimulates degradation of macromolecules
- Inhibits synthetic pathways
What stimulates glucagon release?
- Decrease in blood glucose
- Amino acids stimulate glucagon release to counteract insulin release after protein-rich meal
- Catecholamines (E or NE) can stimulate glucagon release
Where is catecholamines secreted?
E: Adrenal medula
NE: Sympathetic innervation of pancreas
What is the function of epinephrine?
Stimulates glycogen phosphorylase to break down glycogen in the muscle and liver to generate glucose
What happens to E and NE under physiologic stress?
Override the control of glucagon release by the a cell and cause increased release of glucagon
What is glucose homeostasis?
Maintenance of blood glucose within a narrow concentration range is critical for proper bodily function
What are the main organs that regulate blood glucose?
Liver and kidneys
What is the stimuli of liver and kidney cells?
- Hormones
- Increase and decrease of blood glucose
How is the regulation of blood glucose preformed?
Uptake and phosphorylation of glucose
Which glucose transported is insulin dependent?
GLUT4
What can be converted in G6P?
- Glucose
- Fructose
- Galactose
- Mannose
Why is G6P the transfer station of the liver?
- Can be made by multiple pathways
- Has multiple metabolic fates
What is the purpose hepatocytes having GLUT2 transporters?
Allows passive diffusion of glucose in and out
What is the purpose hepatocytes having glucokinase?
- has a lower affinity for glucose than hexokinase
- When [blood glucose] is high, readily binds glucose
- When [blood glucose] is low, reverts to T state
What are the fates of G6P in the liver?
- Dephosphorylate to yield free glucose to send to other tissues (glc-6-phosphatase) through GLUT2
- Make into liver glycogen stores
- Enter glycolysis, make acetyl CoA and then ATP for hepatocytes themselves
- Enter glycolysis, make acetyl CoA to be made into fatty acids and then TAGs
- Enter pentose phosphate pathway to yield NADPH and ribose-5-phosphate
Describe the metabolism in a fed state
- Digestive enzymes in the GI breakdown protein, fat, and carbohydrates into their building blocks
- Intestinal epithelial cells take up these building blocks and move them into the blood.
- Increased blood levels of these nutrients (especially glucose and amino acids) stimulates the pancreas to secrete insulin and suppress glucagon release.
- All tissues use glucose for energy during this time
- High insulin/glucagon ratio stimulates anabolic processes
What occurs when the insulin/glucagon ratio is high in liver?
- Increase glycolysis and clc uptake
- Inhibits gluconeogenesis
- Inhibits glycogenolysis
- Inhibits ketogenesis, lipolysis
- Increase glycogen synthesis
- Increased fatty acid synthesis
What occurs when the insulin/glucagon ratio is high in muscles?
- Increases uptake of glucose by GLUT4 (INSULIN DEPENDENT)
- Inhibits protein degradation
What occurs when the insulin/glucagon ratio is high in adipose?
- Increase glucose uptake by GLUT4
- Increases glycolysis
- Increased PPP to produce NADPH for lipid synthesis
- Increases TAG storage
- Inhibits TAG breakdown
What occurs when the insulin/glucagon ratio is high in brain?
- Enters through GLUT1 (insulin-independent)
- The brain has no stores of glycogen or TAG to use for energy.
- FA cannot cross BBB.
- Fuel needs for the brain are large and easily met during the fed state
What occurs immediately after a meal?
Insulin stimulates glycolysis and glycogen synthesis
What occurs 2-4 hrs of eating?
- Glucagon is secreted causing a switch over from anabolic to catabolic processes
- Biosynthetic pathways slow down
- Gluconeogenesis is stimulated
- Glycogenolysis is increased
What occurs 4 or more hrs of eating?
Glucagon is released, more TAGs hydrolyzed, and FA’s become fuel for muscle and the liver.
How are ketones used as an alternative fuel?
- Ketone bodies are made in the liver and transferred to extrahepatic tissues
- Extrahepatic tissues break down ketone bodies into 2 Acetyl-CoA
- Acetyl-CoA can be used to run the CAC
What occurs when the insulin/glucagon ratio is low in liver?
- Increased gluconeolysis
- Inhibits glycogen synthase and activates glycogen phosphorylase
- Decreases glycolysis and increases gluconeogenesis
- Energy for the liver is supplied by fatty acid catabolism (b-oxidation)
- TAGs are broken down to acetyl-CoA
- Glycerol feeds into gluconeogenesis
- Glucogenic amino acids are broken down and converted to glucose
What occurs when the insulin/glucagon ratio is low in muscles?
- Only have epinephrine receptors
- Cells obtain energy from the b-oxidation
- Increased acetyl CoA inhibits glycolysis
- Muscle protein is broken down into amino acids
- Lactate is released from muscle and sent to liver for gluconeogenesis
- Glycogen stores are rapidly depleted
What occurs when the insulin/glucagon ratio is low in adipose?
- Activates HS-lipase to breakdown TAGs into fatty acids and glycerol
- Fatty acids are released by the adipose tissue, travel to the liver, and undergo b-oxidation to produce acetyl-CoA needed for ketone body production
- Glycerol is sent to the liver for gluconeogenesis
What occurs when the insulin/glucagon ratio is low in brain?
- Glucose is provided from the liver
- Ketone bodies can also be used as an alternative fuel source for the brain
What does insulin bind to to decrease blood glucose?
Tyrosine kinase receptor
What does glucagon bind to to raise blood glucose?
Signals via Gas-protein coupled receptors and the secondary messenger molecule cAMP
What does epinephrine bind to to raise blood glucose?
Signals via Gas-protein coupled receptors and the secondary messenger molecule cAMP
What occurs during prolonged fasting?
- Proteins in the muscle begin to be used for fuel
- Amino acids are used for gluconeogenesis and ketone body formation and provides glucose for brain
- Increased breakdown of FA’s which are oxidized to acetyl-CoA, then used to form ketone bodies
What occurs when there is a high fasting blood glucose level?
Diabetes
What occurs when there is a low fasting blood glucose level?
Hypoglycemic
What is the standard glucose level after a meal?
145mg/100mL
How is protein affected by Long-Term Effects of Elevated Blood Sugar?
- Proteins lining the blood vessels
- Could lead to protein dysfunction
- Degradation products cause oxidant damage to the kidney
- Can cause increased permeability of blood vessels due to cytokine and oxidative damage
How is Hb affected by Long-Term Effects of Elevated Blood Sugar?
Hb is easily glycosylated and can be measured by determine HbA1c levels
Glycosylation of Hb does not affect its function
What is Type I Diabetes mellitus?
Insufficient production of insulin by pancreatic beta cells
What causes Type 1 diabetes?
- due to autoimmune destruction of beta cells
- usually develops early in life
- used to be called insulin-dependent or juvenile diabetes
What is Type 2 diabetes?
Insulin resistance
What causes type 2 diabetes?
- usually develops in adulthood
- associated with weight gain
- cells do not respond appropriately to insulin due to insulin receptor signaling desensititization
What is the fuel metabolism of Type 1?
- No insulin is produced
- Glucagon has unopposed action in muscle, liver, and adipose tissue
- Decreased uptake of blood glucose Gluconeogenesis leads to overproduction of new glucose
- Adipose tissue: Increased TAG degradation causing increasing FA’s in the blood
- Increased FA’s lead to ketone body production
- Mimics a person in starved state
What are the symptoms of Type 2?
- High levels of free FA
- Dyslipidemia
- Hyperglycemia
What can cause insulin resistance?
- Resistance increases with weight gain
- Adipocytes secrete proinflammatory cytokines
