Glucose Homeostasis Flashcards
Where is insulin stored?
in dense-core granules within pancreatic beta cell
Insulin Synthesis Process
- proinsulin synthesized on rough ER
- proinsulin travels to Golgi, then secretory granules
- PC 1/3 cleaves proinsulin at amino acids 32-33
- PC2 cleaves proinsulin at amino acids 65-66
- carboxypeptidase E (CPE) removes remaining basic residues
result: mature insulin and C-peptide
What are the two prohormone convertase enzymes?
PC 1/3
PC 2
Does proinsulin have any bioactivity?
has 5-10% of the bioactivity of insulin
What is the function of C-peptide?
- biological action is still not clear – maybe because it is not highly conserved
- measured as marker for insulin secretion from beta cells in diabetic patients
Regulation of Insulin Secretion
How is insulin stimulated by glucose?
in a concentration-dependent manner
- steep dose response between 5 and 10 mM
- beta cells are attuned to be sensitive in range where it is needed
Does blood insulin levels increase or decrease after eating a meal?
increase
How many phases of insulin release are there?
2
Insulin is secreted in what pattern?
oscillatory manner
- initial spike within first 5 minutes
- beta cells are stressed out or at risk if not oscillating properly
Intracellular Mechanisms Involved in Insulin Secretion by Beta Cells
Steps
- glucose enters beta cells via GLUT1 glucose transporters
- glucose is phosphorylated to glucose-6-phosphate
- glucose-6-phosphate is metabolized to produce ATP (glycolysis in mitochondria)
- rate-limiting step: glucokinase
- majority of ATP produced by OxPhos in mitochondria - increased ATP:ADP ratio triggers closing of ATP-sensitiive K+ channels
- causes membrane depolarization
- opens voltage-dependent Ca2+ channels
- increased intracellular Ca2+ triggers exocytosis of insulin secretory granules
What ispersistent hyperinsulinemia and hypoglycemia in infants (PHHI) caused by?
mutations in ATP-sensitive K+ channel
What does Ca2+ response in a single human beta-cell exposed to high glucose look like on a graph?
- initially basal level of Ca2+
- huge spike in Ca2+
- slow oscillating decrease in Ca2+
- delay from 3 to 15 mM glucose – how long it takes cell to generate ATP to close K+ channel, then Ca2+ channel opens almost instantaneously
What happens in exocytosis of insulin secretory granules?
dense-core insulin granules fuse with plasma membrane and release insulin – mediated by SNARE proteins
What are the 2 phases of insulin release (exocytosis)?
- 1st phase: thought to correspond to fusion of ‘docked’ granules
- 2nd phase: requires mobilization from a reserve pool
Does insulin last a long time in the blood?
no – very short half-life, lasting only 4 minutes in bloodstream
Where does insulin clearance occur?
at liver and kidney
What happens to insulin released by beta cells?
1/2 taken up by liver on the first pass
- insulin receptors in liver
- insulin goes through liver, but doesn’t get absorbed by liver
- too much insulin coming through, would oversaturate
What factors increase stimulation to islet beta cells to secrete insulin? (4)
- increase in GI hormones (by food intake)
- increase in parasympathetic stimulation (by food intake)
- increase in blood amino acid concentration
- increase in blood glucose concentration (major control)
What factors decrease stimulation to islet beta cells to secrete insulin? (1)
sympathetic stimulation (and epinephrine)
What does insulin secretion do to:
- blood glucose
- blood fatty acids
- blood amino acids
- protein synthesis
- fuel storage
- decrease blood glucose
- decrease blood fatty acids
- decrease blood amino acids
- increase protein synthesis
- increase fuel storage
What is insulin secretion tightly regulated by? (3)
- nutrients
- neural
- hormonal
How do nutrients tightly regulate insulin secretion?
glucose (most important), amino acids (ie. arginine) and fatty acids stimulate insulin secretion
How does neural control tightly regulate insulin secretion?
increased sympathetic activity (epinephrine) inhibits insulin secretion
increased parasympathetic activity (ie. response to food intake) stimulates insulin secretion
How does hormonal control tightly regulate insulin secretion?
GI hormones stimulate insulin secretion – ie. glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide 1 (GLP-1)
- only WITH GLUCOSE can they release insulin secretion
- release twice as much insulin
- more insulin to drive glucose
islet hormones also regulate insulin secretion (ie. somatostatin inhibits insulin secretion)
What are incretins?
group of metabolic hormones that stimulate a decrease in blood glucose level
Incretin Concept
- intravenous is more glucose intolerant
- intrajejunal glucose returns quicker to baseline due to greater glucose response (hormonal regulation)
What is the insulin receptor composed of?
glycoprotein composed of two extracellular 𝛼-subunits and two 𝛽-subunits which span cell’s plasma membrane
What are alpha and beta-subunits of insulin receptors joined by?
disulfide bonds
What are insulin receptors?
kinase that phosphorylates scaffold proteins (ie. IRS-1, IRS-2)
What are the short-term effects of increased insulin?
glucose transport (immediate) metabolic enzymes (minutes to hours)
What are the longer-term effects of increased insulin?
cell differentiation/growth (many hours to days)
What is GLUT4 for?
- for tissues that are independent for glucose uptake
- stimulation of GLUT4 translocation is one of the best studied effects of insulin
- beta cells and many cells in brain are not glucose-independent
Glucagon Synthesis
- proglucagon synthesized in alpha cells
- proglucagon cleaved in…
- pancreas in alpha cells by PC2
- OR in intestinal L cells by PC1/3
result: glucagon and other protein fragments
What is glucagon secretion regulated by? (3)
- nutrients
- hormonal
- neural
How do nutrients regulated glucagon secretion?
- low glucose (post-absorptive state) and amino acids (arginine – most important) stimulate glucagon secretion
- high glucose (absorptive state) and fatty acids inhibits glucagon secretion (in presence of insulin)
How does hormonal control regulate glucagon secretion?
GI hormones
- GIP, CCK (stimulatory)
- GLP-1, somatostatin (inhibitory)
How does neural control regulate glucagon secretion?
activation of both sympathetic and parasympathetic (vagus) nerves stimulate glucagon secretion
In general, how do regulators of insulin secretion compare to regulators of glucagon secretion
opposite to one another
What is the role of glucagon in glucose metabolism?
opposes the effects of insulin on glucose metabolism
Where is the major site of action of glucagon?
liver
What are the important metabolic effects of glucagon in the liver for carbohydrates? (3)
- increase gluconeogenesis (glucose production from amino acids and fatty acids)
- increase glycogenolysis (glycogen breakdown)
- decrease glycogen synthesis
What are the important metabolic effects of glucagon in the liver for fat? (1)
increase ketogenesis (ketone production) – fatty acids turn into ketone bodies
What are the important metabolic effects of glucagon in the liver for protein? (2)
- decrease hepatic protein synthesis
- increase protein catabolism in liver
When does glucagon increase glycogenolysis?
during exercise or fasting
Glucagon Receptor Signalling
- binding of glucagon to its receptor causes conformational change in G-protein (hydrolyzes GTP)
- activation of adenylate cyclase increases cAMP via cAMP-dependent protein kinase A
