Glucagon and other Diabetogenic Hormones Flashcards
Glucagon is what type of molecule?
a linear polypeptide
glucagon is produced in what type of cell?
alpha cells of the pancreatic islets
what percent of islet cells do alpha cells make up?
about 10% of islet cells
what is the precursor to glucagon?
preproglucagon
how does preproglucagon synthesize glucagon?
preproglucagon has 6 exons, and one encodes for the glucagon precursor - the other exons encode precursors for GLP 1 and GLP 2
what are the actions of glucagon?
it is generally a ‘counterregulatory’ hormone- antagonising the effects of insulin and maintaining blood glucose levels
- Glucagon Receptor
- Also linked to phospholipase C
- Increases intracellular calcium [Ca2+]i
- [Ca2+]i stimulates glycogenolysis
- Glucagon also stimulates gluconeogenesis from available amino acids in the liver
- Increases ketone body formation by the liver
- Stimulates hormone sensitive lipase in adipocytes via cAMP/Protein kinase A pathway – catalyses the breakdown of stored triglycerides into glycerol and fatty acids
what are some other counter regulatory hormones other than glucagon?
–Catecholamines
–Growth Hormone
–Cortisol
–Thyroid Hormone
What type of receptor is the glucagon receptor?
it is a G protein receptor - activates adenylate cyclase - increases intracellular cAMP conc.- protein Kinase A activates phosphorylase which results in glycogen breakdown
where is the main site of glucagon function?
the liver
what is the half life of glucagon?
5-10 min
where is glucagon secreted into?
the portal vein •so liver is exposed to levels 2-3 times higher than other organs
where is glucagon degraded?
many tissues, but particularly the liver
does glucagon have any appreciable effect on muscle glycogenolysiis?
no. •Glucagon has no appreciable effect on muscle glycogenolysis
basal glucagon release acounts for what percent of fasting hepatic glucose production?
75%
what determines glycogenolysis vs. gluconeogensis?
depends on insulin being low
- Glucagon does increase gluconeogenic enzymes but the contribution of this to basal glucose production is minor
- Only with prolonged fasting does gluconeogenesis contribute significantly
–Mobilization of glycerol and amino acids is due to low insulin levels rather than a direct effect of glucagon
what else does an increase of endogenous glucagon above basal level stimulate?
it stimulates hepatic glucose production mostly through glycogen breakdown
what are the stimulators of glucagon secretion?
- Hypoglycemia
- Amino acids
- CCK, gastrin
- Cortisol
- Exercise
- Infections/stresses
- b-adrenergic receptors
- Theophylline
- Acetylcholine
what are the inhibitors of glucagon secretion?
- Glucose
- Insulin- Increased insulin release associated with increased GABA which may inhibit glucagon
- Somatostatin
- Secretin
- FFA
- Ketones
- a-adrenergic receptors
- GABA
- Phenytoin
what is the effect of the sympathetic nervous system on the beta and alpha receptors?
inhibits via alpha receptors and stimulates via beta receptrs
what happens to glucagon levels during starvation?
it increases- maximal about day 3 when gluconeogenesis is maximal
what is the effect of the parasympathetic nervous system on glucagon release?
stimulates it (Acetylcholine)
increased glucose production is due to what?
due to increased glucagon and reduced insulin level
what sort of administration does glucagon respond to more?
•Glucagon response to oral administration of amino acids is greater than intravenous
glucagon stimulating factor is released from what organ?
•Glucagon stimulating factor released from gut
what is the glucagon response to hypoglycemia?
- Direct effect of low glucose
- Release of tonic inhibitory effect of beta cells on alpha cells (insulin, GABA, zinc)
- Autonomic nervous system
FFA effect to decrease glucagon can be overridden with what?
DKA
What are the effects of catecholamines?
glycogen breakdown - •Catechols activate phosphorylase by beta receptors which increase cAMP and a receptors which increase [Ca2+]- more of an effect on muscle phosphorylaase
what is a huge danger of pheochromocytomas?
extremely high blood pressure due to increase in epinephrine
what is the main effect of thyrotoxicosis?
- Main effect is to increase absorption of glucose from the gut
- Also some degree of hepatic glycogen depletion due to potentiation of effect of catecholamines
- Glycogen depleted liver cells are easily damaged and this can result in abnormal glucose tolerance as the liver can take up less glucose
- Thyroid hormone may accelerate insulin degradation
- Decrease insulin content of pancreas
- Slight inhibition of insulin release
- All of these actions have a hyperglycemic effect
what are the effects of adrenal glucocorticoids?
- Indirectly increase insulin secretion–Increased glucose–Antagonism of insulin action
- Glucocorticoids increase blood glucose
- Diabetes may develop in those who are genetically predisposed
- Glucose tolerance reduced in 80% of patients with Cushing’s syndrome, 20% have diabetes
- Glucocorticoids are necessary for glucagon to exert is gluconeogenic action
- Actions include:
–Increased peripheral protein catabolism resulting in increased circulating amino acids
–Increased hepatic uptake of amino acids
–Increased deamination and transamination of amino acids
–Increased activity of enzymes of gluconeogenesis in the liver:
•Fructose diphosphatase, Glucose-6-phosphatase, phosphoenolpyruvate carboxykinase
–Decreased peripheral glucose utilisation (inhibition of phosphorylation)-
–Increased blood lactate and pyruvate
–Decreased hepatic lipogenesis
–Increased plasma FFA (free fatty acid) levels and increased ketone formation (when pancreatic reserve is low)
Can adrenal glucocorticoids cause diabetes?
yes! it may develop in those who are genetically predisposed
in adrenal insufficiency, is it more dangerous to fast or eat?
eating is fine, but fasting is very dangerous and could precipitate hypoglycemia
if you take out the pituitary, what is the procedure called?
•Hypophysectomy improves diabetes by reducing growth hormone
how does growth hormone influence a diabetic activity ?
- Growth Hormone reduces peripheral insulin sensitivity
- Human growth hormone makes clinical diabetes worse
what are the two receptors for growth hormone ?
IGF 1
and
growth hormone receptor
what are the effects of Growth Hormone?
–Mobilizes FFA from adipose tissue, favouring ketogenesis
–Decreases glucose uptake into tissues
–Increases hepatic glucose output
–May decrease tissue binding of insulin
–Does not stimulate insulin release directly but the hyperglycemia it produces secondarily stimulates the pancreas and may eventually lead to beta cell exhaustion
–Growth hormone may reduce the number of insulin receptors whereas glucocorticoids reduce receptor affinity
–However the decrease in glucose utilization produced by these hormones is probably due to reduced phosphorylation rather than to reduced entry into cells
–Entry into cells is usually the rate limiting step but when adequate insulin is present a decline in phosphorylation can decrease utilization
where is glucagon secreted into from the cells?
it is secreted directly into the portal vein- so the liver is exposed to level 2-3 times higher than other organs -
it’s degraded in the liver as well though
What is shown here?
endocrine pancreatic tissue is visible surrounded by dark-staining exocrine acini
what is shown here?
what type of cell is found here?
They are Leydig Cells
Identify the areas lablled in the picture
The adrenal gland consists of the adrenal medulla and the adrenal cortex, which is made up of:
the zona reticularis, the thin, innermost zone
the zona fasciculata, the middle and largest zone
the zona glomerulosa, the outermost zone, immediately inside the capsule
