Glucose Homeostasis Flashcards
What is glucose homeostasis?
Maintaining constant level of glucose in the blood
Why is blood glucose regulation important
- Blood glucose is tightly regulated
- All cells in our body depends on glucose as a source of energy (ATP)
- Brain is dependent on glucose for energy
- Low blood glucose = neurological symptoms
What is the normal range for blood glucose?
Held in a tight range, wi a mM 3;9-5.5 mM
How do we maintain blood glucose?
Intercellular metabolic homeostasis - balance of fuels and different needs between organs and tissues (brain, RBC, muscle liver, adipose)
This balance of maintaining these fuels to meet the needs of the tissues is regulated by amount of nutrients in blood an metabolic hormones
Where does insulin promote glucose uptake?
Adipose, muscle
Cortisol and GH _____ glucose output by acting on the adipose and muscle
Inhibits
After a high carbohydrate meal, what happens to blood glucose, insulin and glucagon?
Rises
Rises
Suppressed/lowered
What type of hormones are insulin and hormones?
Where are they secreted from?
Are they active when synthesized?
Peptide hormones Pancreatic islets (insulin = beta cells, glucagon = alpha cells) No, they are sensitized as inactive pre-prohormones and are processed into active forms
What is the C-peptide?
What is it function?
- Peptide that comes from processing insulin we make in beta cells
- Marker of beta cell function bc only through insulin processing our bodies can make it
- A decrease in C-peptide is associated with loss of beta cell mass (type 1 diabetes)
- It increases with insulin resistance (where beta cells trying to make more insulin bc tissues aren’t responding)
If pancreatic beta cells are destroyed or impaired in their function, the C peptide levels in the blood be?
lower than normal
Elevated glucose _____ insulin exocytosis and _____ glucagon exocytosis
stimulates
inhibits
High protein meal (with high amino acid levels) ________ glucagon
potently stimulates
we will see a huge rise in glucagon, more than we would see in fasting
What does high protein meal do to insulin levels?
insulin levels increases but not as much as they do after a high carb meal because glucose is the most potent stimulator of insulin
glucose regulation of insulin release
- glucose enters b-cells through GLUT2 transporters
- ATP generated from catabolism closes Katp channels
- reduced K+ efflux (less K+ leaving cell) depolarizes membrane
- depolarization opens Cav (Ca2+ comes into the cell)
- Increase in cytosolic Ca2+ stimulates exocytosis of insulin containing secretory granules
What is one thing that cortisol does that other hormones do not?
stimulate mobilization of AA from muscle protein (stimulates break down of AA)
What type of cell surface receptor does insulin bind to?
tyrosine kinase receptor
- insulin binding activates the tyrosine kinase which phosphorylates intracellular proteins
Describe insulin signaling pathways
- insulin binds to cell surface receptor on the outside which causes formation of a dimer
- induces phosphorylation of tyrosine residues on the receptor itself
- The phosphotyrosine residues recruit and phosphorylate different adaptor proteins
- The adaptor proteins activate different pathways which:
- stimulate cell growth
- Increase synthesis of glycogen, lipid and protein
- Increase GLUT4 trafficking
The energy needed to make new glucose in the liver is provided primarily by oxidation of which fuel?
glucose, pyruvate, fatty acids
Fatty acids
Which of the following statements best describes glucagon?
A. It acts as an anabolic hormone promoting synthesis and storage of fuel
B. It acts on skeletal muscle, liver and adipose tissue
C. It acts primarily on liver and adipose tissue
D, Its concentration in the blood increases after a high carb meal
E. Its concentration increases in the blood when insulin levels increase
C
Why do we have effects of hypoglycemia in the brain?
Glucose transport
Blood brain barrier - endothelial cells lining blood vessels of the CNS
GLUT1 is found in the cells which allows glucose to come from blood vessels across the BBB
GLUT1 transporters - low kT of 1.5 (so that glucose transport into the brain is as fast as it can be)
If glucose gets below 1.5 mM = neurological symptoms of convulsions, coma
We know GLUT1 is responsible bc GLUT1 deficiency also = convulsion, coma
In uncontrolled diabetes, the actions of glucagon predominate. Besides glucose, what other fuel will be elevated in the blood of a patient with uncontrolled diabetes ?
Fatty acid
wo insulin, lipolysis is unopposed
both type 1 and type 2 uncontrolled diabetes can lead to
hyperglycemia
Type 1 - little to no insulin being produced and muscle cell cant get GLUT4 to plasma membrane
Type 2 - problems with signaling pathway. Insulin is there and binds, but muscle cant respond
What happen to diabetics whose blood glucose gets too high?
Can lead to coma, death.
When there is high glucose in the blood, water in the neurons leak by osmosis. This hinders the neurons from working as they should
Insulin ______ glucose output in the liver
inhibits
Glucagon, epinephrine, cortisol ______ glucose output by acting on the liver
increases
Why does glucagon go down after a high carb meal?
insulin potently inhibits glucagon
After a high carb meal, why does blood glucose eventually go down?
Insulin promotes uptake of glucose and fuel utilization
What is insulin vs glucagon response to release in response to glucose?
increased
decreased
What is insulin vs glucagon response to hepatic glucose output?
decreased
increased
What is insulin vs glucagon response to glucose utilization?
increased
decreased
What is insulin vs glucagon response to glucose storage as glycogen and at?
increased
decreased
What is insulin vs glucagon response to growth and protein synthesis?
increased
decreased
How is insulin vs glucagon controlled after meals?
- Insulin rises in response to a glucose/protein meal
- Glucagon decreases in response to a carb mean and rises in response to a protein meal
- after mixed meals of carbs and proteins glucagon stays relatively constant but caries in relation to insulin
- ration of insulin/glucagon determines their effects on fuel metabolism
Proteolytic processing of insulin
- Starts of with pre-pro-hormone with signal sequence at amino terminus
- ribosome recognizes sequence to target it to ER
- Signal peptidase in lumen of ER that removes the signal sequence
- Now have pro-hormone which is still inactive
- Has disulfide bonds
- There is processing of the pro-hormone:
- piece of peptide is removed is removed (C-peptide) to make active insulin
Insulin Regulators:
+ = stimulates/- = inhibits
Glucose ++ (most potent)
AA +
Glucagon regulators:
+ = stimulates/- = inhibits
Glucose –
Insulin – (potently acts on a- cell to inhibit glucagon release)
AA ++ (very focused stimulator of glucagon release)
After high protein meal, what does the ratio of insulin/glucagon means
More gluconeogenesis being promoted than protein synthesis
Insulin regulation of fuel metabolism
- promotes fuel storage and growth
- stimulates glucose storage as glycogen (muscle and liver)
- stimulates fatty acid synthesis and storage after a high carbohydrate meal
- Stimulates AA uptake and protein synthesis
Glucagon regulation of fuel metabolism
- Mobilizes fuels and maintains blood glucose levels between meals
- activates gluconeogenesis and glycogenolysis (liver) during fasting
- activates fatty acid release from adipose tissue
Epinephrine regulation of fuel metabolism
- Mobilizes fuels from acute stress
- Stimulates glucose production from glycogen (muscle and liver)
- Stimulates fatty acid release from adipose tissue
Cortisol regulation of fuel metabolism
- Provides for changing requirements over the long term
- Stimulates AA mobilization from muscle protein
- Stimulates gluconeogenesis
- Stimulates fatty acid release from adipose tissue
What type of cell surface receptor does Glucagon bind to?
GCPR
- Glucagon binding leads to increase in cAMP which activates protein kinase A an phosphorylation of intracellular proteins
Describe the glucagon signaling pathway
- glucagon bind to receptor and activates adenylate cyclase which converts ATP into cAMP
- cAMP activates protein kinase A which phosphorylates lots of different proteins
- In the liver, PKA:
activates glycogen phosphorylase (rate limiting step in glycogenolysis) - inhibits glycogen synthase
- increases expression of PEPCK
What are the major sites of insulin action on fuel metabolism
Insulin Promotes:
- fuel utilization in liver and muscle
- glycogen synthesis and storage in liver and muscle
- fatty acid synthesis in liver
- triacylglycerol synthesis in adipose
- protein synthesis in liver and muscle
It inhibits fuel mobilization
What are the major sites of glucagon action on fuel metabolism
Promotes fuel mobilization by:
- increasing glycogenolysis (liver)
- increasing gluconeogenesis (liver)
- increasing lipolysis in adipose in concert with low insulin
It has no effect on muscle
After a meal, what happens to blood glucose concentrations over time
- Blood glucose levels increase
- Levels don’t cross a certain point in a healthy person because tissues take up and utilize glucose
- levels decline as cells continue to metabolize glucose
Which hormones and pathways increase in the fed state
blood glucose blood insulin F-2,6-bisP Glycogenesis Glycolysis
Which hormones and pathways decrease in the fed state
Blood glucagon
Liver cAMP
Liver glycogenolysis
Liver gluconeogenesis
Which hormones and pathways increase in the fasting state
Blood glucagon
Liver cAMP
Glycogenolysis
Gluconeogenesis
Which hormones and pathways decrease in the fasting state
blood glucose blood insulin Liver F-2,6-bisP Glycogenesis Glycolysis
Symptoms of hypoglycemia
sweating, light-headedness
slurring of speech
brain damage
coma, death
Symptoms of hyperglycemia
Hyperosmolarity (can lead to coma and death)
Insufficient glucose in muscle
Glycation of proteins
Ketoacidosis
What is the hypoglycemic response?
Purpose of cortisol and epinephrine
- release of glucagon, epinephrine, norepinephrine, cortisol
Cortisol:
- increases release of fatty acids and glycerol from adipose
- activates muscle proteolysis
- induces hepatic enzymes like PEPCK
Epinephrine:
- increase release of fatty acids and glycerol from adipose
- increases glycogenolysis
What is the hyperglycemic response in healthy and non-healthy individuals?
Healthy:
- Stimulates an increase in insulin and suppression of glucagon.
- the increased insulin promotes glucose uptake and utilization
Unhealthy:
- Insulin secretion is impaired and glucagon secretion is not suppressed
- the impaired insulin impairs glucose uptake and utilization
- The glucagon promotes hepatic glucose output and lipolysis in adipose
How insulin regulates glucose transport in adipose and muscle
- during fasting, GLUT4 is sequestered in vesicles in the cell
- Insulin stimulates GLUT4 vesicles to insert in the plasma membrane
- Impaired insulin results in less GLUT4 at the surface and reduced glucose uptake
Diabetes Mellitus
“Sugar Diabetes”
Characterized by excess urine production or polyuria that is sugar laden
Type 1 diabetes
primarily caused by autoimmune destruction of pancreatic beta cells
-characterized by the absence of insulin, prone to ketoacidosis
Type 2 diabetes
most prevalent
- characterized by both insulin secretion defect and insulin resistance (tissues do not respond to insulin present)
- obesity is a contributing factor
