Endocrinology: Physiology - Endocrine functions of the pancreas Flashcards
How many total islets of Langerhans are in the human pancreas?
1 million
In what part of the pancreas are the most islet of Langerhans found?
Tail
What % of the pancreas does the endocrine portion constitute? What makes up the remainder?
2% endocrine pancreas
80% exocrine
Remainder ducts and blood vessels
Four islet cell types, their % distribution, and their secretions
B cells (60-75%): insulin
A cells (20%): glucagon
D cells (10%): somatostatin
F cells (2%): pancreatic polypeptide
Which of the four cell types in the islets of Langerhans are usually found in the centre of the islet?
B cells
A-cell rich islets arise from which portion of the pancreas?
Dorsal pancreatic bud
F-cell rich islets arise from which portion of the pancreas?
Ventral pancreatic bud
Describe the chemical structure of insulin
Polypeptide containing two chains of amino acid linked by disulfide bridges
Describe the synthesis and secretion of insulin?
Produced in rough endoplasmic reticulum as prohormone preproinsulin
Packaged in granules in Golgi apparatus
Folded to make proinsulin (folding facilitated by C peptide, which is then detached prior to secretion)
Granules transported via microtubules to membrane then exocytosed
What % of product exocytosed in insulin-containing granules is insulin? What makes up the remainder?
90-97% insulin (with equimolar amounts C peptide)
Remainder is proinsulin
What is the significance of serum C peptide level?
Can be measured to provide an indication of B cell function in patients receiving exogenous insulin
What non-insulin factors have weak insulin activity?
IGF-I
IGF-II
Half-life of insulin
5 mins
How is insulin metabolised?
By proteases in endosomes
Describe the rapid, intermediate, and delayed effects of insulin
RAPID (secs):
- Increased glucose, AA and K+ transport into insulin-sensitive cells
INTERMEDIATE (mins):
- Activation of protein synthesis
- Inhibition of protein degradation
- Activation of glycolytic enzymes and glycogen synthase
- Inhibition of phosphorylase and gluconeogenic enzymes
DELAYED (hours):
- Increased mRNA for lipogenic and other enzymes
What time post IV insulin administration does maximal decline in glucose level occur?
30mins post
Seven effects of insulin on adipose tissue
- Increased glucose entry via GLUT4
- Increased FA synthesis
- Increased glycerol phosphate synthesis
- Increased triglyceride deposition
- Lipoprotein lipase activation
- Hormone-sensitive lipase inhibition
- Increased K+ uptake (unclear mechanism - but increased Na+/K+ ATPase activity)
Eight effects of insulin on skeletal muscle
- Increased glucose entry via GLUT4
- Increased glycogen synthesis
- Increased AA uptake
- Increased protein synthesis
- Decreased protein catabolism
- Decreased release of gluconeogenic AAs
- Increased K+ uptake (unclear mechanism - but increased Na+/K+ ATPase activity)
- Increased ketone uptake
Seven effects of insulin on liver
- Decreased ketogenesis
- Increased protein synthesis
- Increased lipid synthesis
- Decreased gluconeogenesis
- Increased glycogen synthesis
- Increased glycolysis (promotes lipogenesis)
- Increase glucose entry indirectly, via induction of glucokinase (phosphorylates glucose, decreased intracellular concentration then drives entry of more glucose)
General effect of insulin on tissues
Increased cell growth
Describe the structure of the insulin receptor
Tyrosine kinase receptor
Tetramer:
- 2x a subunits: extracellular, insulin-binding
- 2x B subunits: membrane-spanning, intracellular portion has tyrosine kinase activity
Half life of insulin receptor
7hrs
Describe the mechanism of action of insulin binding to its receptor
Insulin binding triggers tyrosine kinase activity of B subunit -> autophosphorylation of subunit -> phosphorylation of some cytoplasmic proteins, dephosphorylation of others (including IRS-1)
Which enzyme mediates the growth-promoting protein anabolic effects of insulin?
P13K
What is the most common cause of early death in diabetics?
Acidosis
Describe the fate of a glucose load. How does this differ in a diabetic?
In normal circumstances:
- 50% burned to CO2 and H2O
- 5% converted to glycogen
- 30-40% converted to fat
In diabetic:
- Decreased amount burned to CO2 and H2O
- 5% converted to glucogen
- <5% converted to fat
- Glucose accumulates in bloodstream and spills over into urine (glycosuria)
Describe the pathway of changes in insulin deficiency leading to dehydration and acidosis
At what glucose level is insulin secretion inhibited?
4.6 (80mg/dL)
At what glucose level is glucagon, epinephrine, and GH secretion stimulated?
3.8
At what glucose level is cortisol secretion stimulated?
3.2
At what glucose level does cognitive dysfunction (neuroglycopenic symptoms) occur?
2.8
At what glucose level does lethargy occur?
2.2
At what glucose level do convulsions occur?
1.1
At what glucose level do permanent brain damage and death occur?
0.6
What is the normal fasting insulin level in adults?
0-70uU/mL (0-502pmol/L)
How much insulin is secreted per hour in basal state? How does this change after food ingestion?
1U/hr
Increased 5-10x following food
What is the average amount of insulin secreted in a day?
40U (287nmol)
Describe the biphasic response of insulin secretion to glucose load
Initial spike within 5mins:
- Glucose enters B cells via GLUT2 transporter and is phosphorylated by glucokinase
- Glycolysis occurs resulting in ATP formation via oxidative phosphorylation
- ATP inhibits ATP-sensitive K+ channels, reducing K+ efflux and resulting in B cell depolarisation
- Ca2+ enters B cell via voltage-gated Ca2+ channels, stimulating exocytosis of insulin-containing secretory granules
Prolonged plateau phase within 2-3hrs:
- Pyruvate metabolism increases intracellular glutamate level
- Intracellular glutamate acts on different type of insulin-containing secretory granule and stimulates its exocytosis
Describe the effect of protein and fat derivatives on insulin secretion
Certain AAs and ketones increased insulin secretion by generating ATP during their metabolism (inhibits ATP-sensitive K+ channels in B cells -> decreased K+ efflux -> B cell depolarisation -> Ca2+ influx via voltage-gated Ca2+ channels -> exocytosis of insulin-containing secretory granules)
How do sulfonylureas increase insulin secretion?
Bind to ATP-inhibited K+ channels in B cells and inhibit their activity (requires functioning B cells for effect)
How do biguanides (e.g. metformin) lower blood sugar?
Decrease gluconeogenesis
How do thiazolidinediones lower blood sugar?
Bind and activate peroxisome proliferator-activated receptor y (PPAR-y), a nuclear transcription factor that increases synthesis of proteins which increase peripheral glucose utilisation
What is the first effect of cAMP of insulin secretion? What are three factors that increase cAMP in B cells?
Stimuli that increase cAMP in B cells increase insulin secretion
Includes B-adrenergic agonists, glucagon, theophylline
What is the effect of catecholamines on insulin secretion?
Inhibit release via a2-receptors
Stimulate release via B-receptors
Net effect of adrenaline and NA is usually inhibition (however in presence of a blockade will stimulate)
What is the effect of autonomic nerves on insulin secretion?
R vagus nerve innervates pancreatic islets, and stimulation causes increased insulin secretion via M4 (atropine therefore inhibits release, and ACh stimulates)
Sympathetic nerve stimulation inhibits insulin secretion via net effect of a2-receptors
What is the effect of intestinal hormones on insulin secretion?
Gastric inhibitory peptide is the only intestinal hormone which stimulates insulin release at blood levels reflective of in vivo pathways
Other hormones which stimulate include glucagon, glucagon derivatives, secretin, CCK and gastrin
What is the effect of hypokalaemia on insulin secretion?
Decreases
10 stimulators of insulin secretion
- Glucose, mannose
- AAs (leucine, arginine, others)
- Intestinal hormones (GIP, GLP-1, gastrin, secretin, CCK)
- B-ketoacids
- ACh
- Glucagon
- cAMP
- B-adrenergic stimulators
- Theophylline
- Sulfonylureas
13 inhibitors of insulin release
- Somatostatin
- 2-deoxyglucose
- Mannoheptulose
- a-adrenergic stimulators (adrenaline, NA)
- B-blockers (e.g. propranolol)
- Galanin
- Diazoxide
- Thiazide diuretics
- K+ depletion
- Phenytoin
- Alloxan
- Microtubule inhibitors
- Insulin
Where is glucagon formed?
In pancreatic A cells
In upper GIT
How is glucagon synthesis in pancreatic A cells?
As prohormone preproglucagon
Later cleaved to glucagon and major proglucagon
What additional peptides are generated during the process of glucagon synthesis in L cells of the lower GIT? What is the effect of these hormones on glucose homeostasis?
GLP-1: stimulates insulin secretion, increases glucose utilisation
GLP-2: weak activity
Describe the mechanism of activity of glucagon binding to receptors
Binds to glucagon GPCR
Activates adenylyl cyclase
Increased intracellular Ca2+
Increased protein kinase A activity, phospholipase C activation (further increases Ca2+ and leads to glycogenolysis)
Six metabolic effects of glucagon
- Increased hepatic glycogenolysis (not in skeletal muscle)
- Increased gluconeogenesis
- Increased lipolysis
- Increased ketogenesis
- Positive inotrope in large doses (without increasing myocardial excitability)
- Stimulates secretion of insulin, GH, and pancreatic somatostatin
Half-life of glucagon
5-10mins
Where is glucagon metabolised?
By many tissues but particularly liver (therefore increased peripheral glucagon levels in cirrhosis)
11 stimulators of glucagon secretion. Which of these are mediated at least in part by sympathetic nervous system activity?
- AAs (especially Ala, Ser, Gly, Cys, Thr), protein meal
- Starvation up to day 3 of fasting (after this glucagon level falls)
- CCK, gastrin
- Cortisol
- Exercise*
- Infections*
- Other stresses*
- B-adrenergic stimulators
- Theophylline
- ACh
- Hypoglycaemia
- mediated at least in part by sympathetic nervous system activity
What is the effect of sympathetic nervous system stimulation on glucagon synthesis?
B-adrenergic receptors increase glucagon secretion
a-adrenergic stimulators inhibit glucagon secretion
Net effect (unlike for insulin) is increased secretion (except in B-blockade where secretion is inhibited)
Nine inhibitors of glucagon secretion
- Glucose
- Phenytoin
- Secretin
- FFA
- Somatostatin
- Insulin
- Ketones
- a-adrenergic stimulators
- GABA
What is the effect of phenytoin on insulin and glucagon secretion?
Decreases both
What is the effect of CCK and gastrin on insulin and glucagon secretion?
Increases both
What is the effect of secretin on insulin and glucagon secretion?
Increases insulin
Decreases glucagon
What is the effect of somatostatin on insulin and glucagon secretion?
Decreases both
What happens to the insulin-glucagon molar ratio during starvation?
Decreases
What kinds of situations increase the insulin-glucagon molar ratio?
When need for energy mobilisation is low
What is the effect of pancreatic somatostatin?
Inhibits insulin, glucagon and pancreatic polypeptide release
What are the two forms of pancreatic somatostatin? Which of these is more active and what is its receptor?
SS14 and SS28
SS28 more active: acts via SSTR5
Four effects of somatostatinomas
- Hyperglycaemia
- Slowed gastric emptying*
- Decreased gastric acid secretion*
- Gallstones (due to inhibition of CCK secretion causing decreased gall bladder contraction)
- cause dyspepsia
Three stimulators of somatostatin release
Glucose
AAs (especially arginine, leucine)
CCK
What are two polypeptides related to pancreatic polypeptide?
Polypeptide YY (GI peptide)
Neuropeptide Y (CNS peptide)
What is the function of pancreatic polypeptide?
Uncertain
Slows absorption of food
May regulate ion transport in intestine
Five factors that stimulate pancreatic polypeptide secretion
- Protein meal
- Fasting
- Exercise
- Hypoglycaemia
- ACh
Two factors that inhibit pancreatic polypeptide secretion
- Somatostatin
- IV glucose
Effect of insulin on glucagon secretion
Inhibits
Effect of glucagon on insulin secretion
Stimulates
Effects of glucagon on somatostatin secretion
Stimulates
What is the effect of exercise on peripheral glucose utilisation? What does this mean for insulin-dependent diabetics when exercising?
Increases glucose uptake into skeletal muscle via GLUT4 transporter in insulin-independent fashion
Diabetics should increase their calorie load or decrease insulin dose prior to exercising to reduce risk of hypoglycaemia
What is the initial and late effect of catecholamines on carbohydrate metabolism? What is the effect on FFA metabolism?
B-adrenoceptors increase cAMP
a-adrenoceptors increase Ca2+
Initial effect is to increase hepatic glucose output causing hyperglycaemia
Adrenaline also specifically decreases peripheral glucose utilisation
Late effect is increased glycogen synthesis due to increased lactate (liver oxidises lactate to pyruvate, then converted to glycogen)
Increases FFA release
What is the effect of adrenaline on peripheral glucose utilisation?
Decreases
What are the three effects of thyroid hormones on carbohydrate metabolism?
- Increase glucose absorption from GIT
- Hepatic glycogen depletion
- May also accelerate insulin degradation
Five diabetogenic effects of adrenal glucocorticoids
- Increased protein catabolism
- Increased hepatic gluconeogenesis
- Increased hepatic glycogenesis
- Increased hepatic ketogenesis
- Decreased peripheral blood glucose utilisation (insulin-independent)
What is the effect of glucocorticoids on carbohydrate metabolism?
Permissive effect: needed for glucagon to exert gluconeogenic effect during fasting (so glucocorticoid deficiency precipitates hypoglycaemia during fasting)
Glucocorticoids also gluconeogenic themselves but main role is this permissive effect
What % of patients with GH-secreting anterior pituitary tumours have DM?
25%
What is the effect of GH on carbohydrate and FFA metabolism?
Worsens diabetes partly due to direct effects and partly mediated by IGF-1:
- Decreased glucose uptake into some tissues
- Increased hepatic glucose output
- May decrease insulin binding
- Mobilises FFA (favouring ketogenesis)
When are symptoms of insulinoma most prominent and why?
In the morning due to overnight fasting depleting hepatic glycogen reserves
Four features of metabolic syndrome
Obesity
Hyperinsulinaemia
Dyslipidaemia
Accelerated development of atherosclerosis
