The endocrine pancreas: alpha and beta cell functions Flashcards
What is the pancreas and the 2 functions it can be broken down into?
- Pancreas develops as an outgrowth of the gut tube
- Closely associated with the development of the gall bladders
- Ducts join before emptying in the duodenum
Exocrine: Pancreatic Acini secrete enzymes active in protein, fat and carbo digestion (typist, lipase, amylase) - Neutralises contents of stomach and helps digestion
Endocrine: Pancreatic islets (Islets of Langerhans) produce hormones (1% of all cells in pancreas)
What are the features of the Endocrine Pancreas, and what cells do they contain and their function?
Endocrine Pancreas;
- 1-2% of the total mass of pancreas
Various cell types - Islets of Langerhans;
- Alpha (A) Cells - Glucagon
(controls blood glucose in absorptive and post absorptive state) - Beta (B) Cells - Insulin & Amylin (100:1)
- Delta (D) Cells - Somatostatin
(Stimulates enzymes + bicarb secretions) - Epsilon (E) Cells - Grhelin (Less than 1% islet)
(Stimulates enzymes + bicarb secretions - feedback on hypothalamus ) - PP (F) Cells - Pancreatic Polypeptide
(Inhibit enzymes + bicarb secretions)
Main functions;
- Control of blood glucose in absorptive (digesting food) and post-absorptive (fasting) states - Glucagon and Insulin, Cells A + B
- Stimulate/inhibit digestive enzymes and bicarbonate (HCO3-) secretion in GI tract
Bicarb = neutralise stomach acid
Give a summary of each Cell, its percentage in the islet, hormone secreted and hormone structure ?
A Cell - 20% islet - Secretes Glucagon - 29 amino acid linear peptide
B cell - 65% (Most abundant and in centre) - Secretes Insulin and Amylin -
Insulin - 21 amino acid and 30 amino acid peptides linked by 2 disulphide bonds (When insulin produced it folds up into most energetically favourable conformation and forms disulphide bonds)
Amylin - 37 amino acid peptide
Delta/D Cell - <10% - Secretes Somatostatin - 14 amino acid cyclic peptide (Ring structure which protects hormone from degradation from exogenous enzymes and increases biological half life)
Epsilon/E Cell - <1% - Produces Ghrelin - 28 amino acid peptide
PP/F Cell - <5% - Produced Pancreatic polypeptide - 36 amino acid linear peptide
Note - D, E and PP/F cells are between beta and alpha cells
Describe the synthesis and processing of insulin ?
1). Transcription of the insulin gene occurs, producing mRNA encoding Preproinsulin (5’ linked exons helps directs MRNA out of nucleus to ribosome to begin translation)
2). Prepropinsulin is translated which produces a signal sequence to directs growing of the protein into the ER and into secretory granule where cleavage and disulphide bond formation occurs (most energy favourable)
3) Converting enzymes in Trans-Golgi network work by cleaving off the C-peptide/chain in insulin resulting in a secretory granule with mature insulin inside. Waits in the Beta pancreatic cell on stimulus to be released
Active Insulin form - 95 % of all insulin form in secretory granule
What is unique about the structure of insulin that is formed ?
Insulin is so densely packed that it forms a crystalline structure. In high osmotic gradients, high concentrations of proteins will exclude water, but the structure of insulin prevents them being damaged by osmotic stress or swelling of the granules. Insulin also has Chromogranins and Zinc in it which helps the crystallisation in the secretory granule
What are the features of the Microvasculature & Innervation of the endocrine pancreas ?
Microvasculature & Innervation of the endocrine pancreas;
- Islets use approx 15% of the pancreatic blood supply
- Each islet is encapsulated and innervated with a capillary bed
- Facillitates rapid delivery of pancreatic hormones in to the circulation
- Insulin secretion is stimulated by activation of parasympathetic nerves (not main action, main is glucose)
- Insulin secretion cam be inhibited by action of sympathetic nerves
- “Rest and digest”
What factors regulate insulin secretion?
1). Glucose is absorbed from digested food into the blood and it strongly stimulates B cells to secrete insulin in order to store the glucose away by triggering glycogen storage and lipid synthesis
2). Amino acids and free fatty acids are also absorbed from digested food into the blood and it weakly stimulates B cells to act with glucose and stimulate/potentiate the secretion of insulin in the presence of high glucose, but cannot do this without glucose stimulation
3). Brain-Gut hormones like GLP-1+ CIP (stimulated by glucose in gut) and CCK (stimulated by fatty acids) from the digestive system stimulate/potentiate B cells via incretin receptors in the presence of high glucose to secrete insulin, but cannot do this without glucose stimulation
4). Parasympathetic nerves: ACh on muscarinic receptors and some Sympathetic nerves ; Norepinephrine on B2 adorenoreceptors stimulate/potentiate B cells in the presence of high glucose to secrete insulin, but cannot do this without glucose stimulation
5). Sympathetic nerves: Norepinephrine on A2-adrenoreceptors inhibit B cells from secreting insulin (glucose will majorly over power this)
Paracrine effects from adjacent cells;
6). D cells produce Somatostatin which inhibits B cells from secreting insulin (glucose will majorly over power this) and also negatively inhibits A cells
7). A cells produce Glucagon which stimulate/potentiate B cells in the presence of high glucose to secrete insulin (cannot do this without glucose stimulation)
How were incretins and their affect discovered and how does this vary in diabetic patients?
Incretin effect discovered, how brain gut hormones were regulating insulin release
When gave a patient an oral glucose challenge in a healthy response the oral would spike but in IV infusion the spike is not seen
Difference is to do with meal/glucose going through their GI and releasing those incretins affecting how much insulin is being secreted
Type 2 diabetics have a suppressed insulin response and are largely insensitive to insulin, so not only reduced insulin secretion but are compounded by insulin sensitivity meaning they have a much harder time clearing glucose after a meal
What happens cellularly for Glucose to release Insulin from Beta cells?
1). Glucose enters the cell via a GLUT2 transporter (across lots of cells and shuttle when there is high glucose), which mediated facilitated diffusion of glucose into the cell
2). The increased glucose influx stimulates glucose metabolism, leading to an increased in ATP:
Glucose undergoes Glycolysis where Glucokinase converts it into Glucose-6-phosphate by phosphorylation (trapping it in the cell) then it the undergoes a series of reactions to produce ATP and Pyruvate which will enter into the citric acid cycle to make even more ATP
3). The increased ATP inhibits an ATP-sensitive K+ channel
4). Inhibition of this K+ channel causes Vm to become more positive (depolarisation)
5). The depolarisation activates a voltage-gated Ca2+ channel in the plasma membrane
6). The activation of this Ca2+ channel promotes Ca2+ influx thus increasing Ca2+ which also evokes Ca2+ induced Ca2+ release
7). The elevated Ca2+ activates Ryanodine receptors on the ER which leads exocytosis and release into the blood of insulin contained within the secretory granules
What are the cellular mechanisms of Brain-Gut hormones to stimulate release Insulin from Beta cells?
Other modulators of secretion act via the adenylyl cyclase-cAMP protein kinase A (PKA) pathway and the phospholipase C - phosphoinositide pathway;
1). Brain gut hormones like CCK from fatty acids works by binding to its cognate receptor, GCPR (Gq-coupled receptor) which activates phospholipase C enzyme generating IP3 and DAG (secondary messengers).
- IP3 goes on to induce the release of calcium and stimulating the secretory granules to fuse with the membrane to cause insulin release.
- DAG stimulates PKC (protein kinase C) enzyme which phosphorylates a number of proteins involved in secretion of insulin, further stimulating insulin secretion
What are the cellular mechanisms of Glucagon and Somatostatin to stimulate/inhibit release Insulin from Beta cells?
2). Glucagon or B-adrenergic agonists bind to Gs coupled receptors activating adenylate cyclase producing secondary messenger cAMP which goes on to activate protein kinase A which phosphorylated a number of proteins involved in secretion of insulin, Further stimulates insulin secretion
3). Somatostatin or A-adrenergic agonists bind to Gi coupled receptors compete and suppress adenylate cyclase reducing the amount secondary messenger cAMP which is made and suppressing the activity of protein kinase A and suppressing the phosphorylation of the proteins involved in secretion of insulin
What are the cellular mechanisms of Leucine to help the production of Insulin?
Leucine is a transporter for amino acids into the B cell and augments this response. They can be deaminated or oxidised and be fed into glycolysis or citric acid cycle increasing amounts of ATP and augmenting the metabolic processes - blocking potassium channel and producing this downstream cascade, feeding into the metabolism of the B cell
Give a fully summary of all of the Cellular pathways to produce Insulin?
1). Glucose enters the cell via a GLUT2 transporter (across lots of cells and shuttle when there is high glucose), which mediated facilitated diffusion of glucose into the cell
2). The increased glucose influx stimulates glucose metabolism, leading to an increased in ATP:
Glucose undergoes Glycolysis where Glucokinase converts it into Glucose-6-phosphate by phosphorylation (trapping it in the cell) then it the undergoes a series of reactions to produce ATP and Pyruvate which will enter into the citric acid cycle to make even more ATP
3). The increased ATP inhibits an ATP-sensitive K+ channel
4). Inhibition of this K+ channel causes Vm to become more positive (depolarisation)
5). The depolarisation activates a voltage-gated Ca2+ channel in the plasma membrane
6). The activation of this Ca2+ channel promotes Ca2+ influx thus increasing Ca2+ which also evokes Ca2+ induced Ca2+ release
7). The elevated Ca2+ activates Ryanodine receptors on the ER which leads exocytosis and release into the blood of insulin contained within the secretory granules
Other modulators of secretion act via the adenylyl cyclase-cAMP protein kinase A (PKA) pathway and the phospholipase C - phosphoinositide pathway;
1). Brain gut hormones like CCK from fatty acids works by binding to its cognate receptor, GCPR (Gq-coupled receptor) which activates phospholipase C enzyme generating IP3 and DAG (secondary messengers).
- IP3 goes on to induce the release of calcium and stimulating the secretory granules to fuse with the membrane to cause insulin release.
- DAG stimulates PKC (protein kinase C) enzyme which phosphorylates a number of proteins involved in secretion of insulin, further stimulating insulin secretion
2). Glucagon or B-adrenergic agonists bind to Gs coupled receptors activating adenylate cyclase producing secondary messenger cAMP which goes on to activate protein kinase A which phosphorylated a number of proteins involved in secretion of insulin, Further stimulates insulin secretion
3). Somatostatin or A-adrenergic agonists bind to Gi coupled receptors compete and suppress adenylate cyclase reducing the amount secondary messenger cAMP which is made and suppressing the activity of protein kinase A and suppressing the phosphorylation of the proteins involved in secretion of insulin
Leucine is a transporter for amino acids into the B cell and augments this response. They can be deaminated or oxidised and be fed into glycolysis or citric acid cycle increasing amounts of ATP and augmenting the metabolic processes - blocking potassium channel and producing this downstream cascade, feeding into the metabolism of the B cell
What are the Physiological actions of Insulin ?
Insulin will circulate through the systemic circulation;
- Increased glucose transport into the cells
- Increased glycogenesis
- Increase in Protein Synthesis
- Increased Lipogenesis;
Increased glucose transport into the cells;
In the muscle and adipose tissue insulin stimulates glucose uptake by recruiting glucose transporter GLUT4 which will embed into them membrane and facilitate glucose entry into the cells trapping it inside to start glycolysis.
Increased glycogenesis
Glucose enters the Liver using GLUT2 transporter (always there, concentration gradient), high glucose outside liver then liver will facilitate glucose in and down concentration gradient and store it as glycogen. If glucose is low glucose will be released by breaking down glycogen, diffusing down concentration gradient out of cell. Insulin also causes skeletal muscle to increase glycogenesis (glucose storage)
These decrease your blood glucose overall by moving into cells and storing glucose away.
Increase in Protein Synthesis;
- Mediated through binding insulin receptor on target tissues. Can bind to insulin growth factor receptor if concentrations are high enough, stimulating growth and anabolic processes, similar to growth hormone stimulating muscle and bone growth, essential for maintenance of most tissues
Increased Lipogenesis;
- Inhibits action of hormone sensitive lipase (enzyme that causes hydrolysis of those triglycerides stored in fat cells), so release fatty acids inhibited
- Insulin promotes glucose transport in adipose tissue, but some of this glucose is used to synthesis fatty acids directly
What are the factors mediating Glucagon release?
1). Amino acids and Low glucose;
If you are fasting or are eating a meal with high protein and low carbs these will both stimulate Glucagon release from A cell
A cell is not being regulated by glucose itself !
2). Both Parasympathetic and Sympathetic nerves have a stimulatory effect on A cells encouraging Glucagon release
3). D cells producing Somatostatin and B cells producing Insulin both inhibit the release of glucagon
4). Some gut hormones stimulate or inhibit
What are the Physiological actions of Glucagon ?
Glucagon binds to its G-coupled protein receptor and activate a Gs stimulatory protein which stimulates adenylate cyclase which produces cAMP and this causes the following effects;
- Increased Glycogenolysis (presence no glucose)
- Decreased Lipogenesis (presence no glucose)
- Increased Gluconeogenesis (With Cortisol present)
With no insulin;
- Increased Glycogenolysis - Increased blood glucose
- Decreased Lipogenesis and Increased Lipolysis - More fatty acids and glycerol released
- Glycogen is broken down (glycogenolysis) into glucose-6-phosphate and is dephosphorylated and glucose is released from hepatocytes into blood causing increased blood glucose
- Actions in adipose due to lack of insulin as it’s a potent stimulator of lipogenesis in liver and adipose (causing lipolysis)
- Adrenoceptors on Beta adrenergic receptor in adipose tissue so nerves releasing catecholamines to the adipose will stimulate lipolysis there as well, increase and rise in fatty acids and glycerol which can be used by other metabolic pathways
With Cortisol present;
Increased Gluconeogenesis - Increased blood glucose
Gluconeogenesis - Makes glucose from non carbohydrate precursor like glycerol and some amino acids, stimulate in presence cortisol (glucocorticoid produced from adrenal cortex - stress hormone)
Contains enzymes allowing to make glucose in times of fight or flight (stater activated when levels glucose drop to low)
