The Pancreas (4-6) Flashcards
Where does the pancreas sit in situ?
Posterior to the stomach
→ head of the pancreas lies in the curve of the duodenum
How is the pancreas structured?
Exocrine tissue - contains acinar cells
→ site of enzyme production
→ feed into pancreatic ducts - joins the bile duct and connects to the duodenum
Contains islet (of Lagerhans) cells
→ alpha, beta, delta
What is the major stimulator for insulin secretion?
Glucose
→ (not the complete driver)
How was it discovered that pancreatic islets cells are synchronised?
Used Ca2+ sensitive dye to monitor the fluctuations of Ca2+ in and out of islet cells
→ found oscillations that start at different times become synchronised and linked
→ interplay of cell-cell contact, cell coupling, cell-cell communication - co-ordination is important
How can Ca2+ move between beta cells in pancreatic islets?
Via connections - gap junctions proteins
→ connexion 36
→ discovered using heptagon as an uncoupler
What are the two aspects to pancreatic islet beta cell coupling?
Movement of Ca2+
ATP secretion
→ help with synchronisation - regulating K+
How does low glucose affect pancreatic islet beta cells?
- Low glucose in blood (GLUT 2 transporter)
- Metabolism slows → decrease in ATP
- Katp channels open → K+ leaks out - membrane potential changes
- Voltage-gated Ca2+ channels closed → can’ dock vesicles
- No insulin secretion
How does high glucose affect pancreatic islet beta cells?
- High glucose in blood (GLUT 2 transporter)
- More metabolism → increase in ATP
- Katp channels (sensitive to [ATP]) close → K+ leaves - cell depolarises
- Voltage-gated Ca2+ channels open
- Entry of Ca2+ triggers exocytosis and insulin is secreted → vesicles can dock
How to secretory cells reset membrane potential?
Calcium dependant K+ channels
How can Katp channels be used as a drug target?
Sulphonylureas → increase insulin secretion
→ stop K+ moving in from cytoplasm
Diaxzoxide, cromakalin, pinacidil → decrease insulin secretion
→ encourage K+ moving in from cytoplasm
How does somatostatin affect insulin secretion?
Somatostatin from the HPA axis shuts down insulin secretion by closing K+ channels
How does the parasympathetic nervous system input insulin secretion?
Insulin secretion is stimulated in anticipation of blood glucose rise
→ parasympathetic NS inputs into beta cells - cephalic phase
→ sensory stimuli and neural input activated when food is first eaten
→ activated parasympathetic preganglion neurons - axons to vagus nerve activate post ganglion neurones - stimulates insulin secretion
How does the sympathetic nervous system input in insulin secretion?
Sympathetic input is important during exercise
→ muscle cells using glucose at much higher rates
→ need to prevent glucose uptake by non-muscle cells - so insulin secretion inhibited
What is the basic structure of insulin?
A-chain and B-chain linked by 2 disulphide bridges
What does the insulin prepro hormone consist of?
Signal peptide
B chain
C-peptide
A chain
→ with basic residues that are cleavage sites for conversion from proinsulin to insulin
What is a sign that insulin has been made correctly?
Identification of the cleaved C-peptide
What is the structure of the insulin receptor?
Transmembrane receptor tyrosine kinase
→ extracellular alpha subunits - insulin binding domain
→ transmembrane domain
→ intracellular beta subunits - tyrosines become phosphorylated after dimerisation due to change in structure allowing kinase activity
What does insulin mainly work on?
Insulin (secreted from the pancreas)
Liver → decreases glucose synthesis, increases glycogen synthesis
Fat → increases glucose metabolism and lipogenesis, decreases lipolysis
Muscle → increases glucose metabolism, increases glycogen synthesis
What are the main effects of insulin receptor binding ligand?
- Moving glucose transporter to membrane → vesicles dock - more glucose
- Signal transduction → effects proteins (bit slower)
→ changes gene expression (even slower)
What are the molecules involved in insulin signal transduction?
Insulin receptor undergoes autophosphorylation
→ catalyses phosphorylation of members of the IRS family (inc. Shc, CbI)
→ these interact with signalling pathways involving PI(3)K, MAPK, TC10
→ coordinate regulation of vesicle trafficking, protein synthesis, enzyme activation, gene expression
→ regulation of glucose, lipid and protein metabolism
What happens to GLUT4 with an insulin burst?
Signal transduction from insulin causes GLUT4 translocation from vesicles
→ in preparation to move glucose
No insulin → returns to basal levels, with little GLUT4 on membrane
How can insulin-receptor regulate gene expression?
Via signal transduction with
→ IRS and AKT - phos. of FOXOs
→ Shc and ERK - TF processing
Receptor can be retrafficked into nucleus
How does the insulin receptor cluster in low and high conc of insulin?
Low [insulin] → receptor affinity for second insulin molecule is higher
→ positive cooperativity
High [insulin] → receptor affinity for second insulin lower than first
→ negative cooperativty
→ receptors cluster
What are insulin degrading enzymes?
Enzymes that degrade hormones involved in glucose homeostasis
→ potential therapeutic targets for type 2 diabetes
→ however bad off target side effects
What are the hormones of the islet of Langerhans?
Beta-cell → insulin
Alpha-cell → glucagon
Delta-cell → somatostatin
→ islets are vascularised for secretion of hormones into blood
What is ‘intra-islet’ regulation?
Islet cells don’t only do endocrine signalling
→ beta cell - autocrine, paracrine etc
How is glucagon synthesised?
Preprohormone → processed differently in islet alpha cells in the gut and brain
→ only a small part makes glucagon
→ mediated by enzymes that cleave at particular sites
How does insulin and glucagon interact within the islet?
There is blood flow through the islet
→ can go through the venules and signal to other side of islet
What affect does somatostatin have on insulin?
Inhibitory
via activation of SSTR2 and 5
→ inhibits adenylate cyclase and reduce cAMP
→ open K+atp and hyper polarise the membrane - can’t get Ca2+ in, prevents vesicles of insulin docking
What is the effect of insulin on metabolism?
Anabolic (fed state)
Amino acids → protein biosynthesis
Glucose → glycogenesis
Fatty acids → lipogenesis
What is the effect of glucagon on metabolism?
Catabolic (starved state)
Glycogenolysis, lipolysis, ketogenesis, gluconeogenesis → fuel production
What effect does insulin have on amino acid metabolism?
High presence of insulin drives uptake of amino acids in the liver
→ increases protein synthesis
→ decreases protein breakdown
What is glycogen?
Stored form of glucose
→ made from glucose-1-p by glycogen synthase
→ glycogen phosphorylase converts glycogen back to glucose-1-p
How does insulin regulate glycogen synthesis?
Drives formation of glycogen
Synthase phosphate can activate glycogen synthase → insulin up regulates synthase phosphatase
→ also removes phosphate from glycogen phosphorylase promoting glycogen formation
Protein kinase can remove active part of glycogen synthase → insulin down regulates protein kinase
How does glucagon regulate glycogen synthesis?
Inhibits formation of glycogen
Glucagon/epinephrine increases cAMP
cAMP stimulates phosphorylase kinase which activates glycogen phosphorylase → promoting conversion of glycogen to glucose-1-phosphate
cAMP stimulates protein kinase A which inactivates glycogen synthase → inhibiting glycogen synthesis, promoting glucose-1-p
What insulin signalling is involved in glycogen metabolism?
Insulin binds its receptor in plasma membrane
→ IRS-1 binds the phosphorylated tyrosines of the activated receptor
→ activates the PKB/Akt pathway
Signal cascades leads to:
→ activating glycogen synthase - activate the activator
→ inhibiting glycogen phosphorylase - inactivates the inactivator
→ inhibiting of a glycogen synthase inhibitor
Drives glycogen synthesis
How does insulin regulate fat metabolism?
Fat cell lipoprotein lipase actively promoted by insulin → fat synthesis
Insulin also up regulates formation go glucose into pentose shunt and alpha-glycerophosphate for fat synthesis
Insulin enables triglyceride formation
How does glycogen regulate fat metabolism?
Glucagon down-regulates fat cell lipoprotein lipase → inhibiting fat synthesis
→ in a starved state you don’t want to store fat in adipose tissue
Glucagon up regulates hormone sensitive lipase → drives freeing of fatty acids
How does insulin act on glycolysis?
Glycolysis flux is controlled by:
→ availability of substrate
→ conc of enzymes responsible for rate-limiting steps
→ allosteric regulation of enzymes
→ covalent modification of enzymes
Insulin up regulates glycolysis
How does insulin act on gluconeogenesis?
Gluconeogenesis → allows formation of glucose from e.g. pyruvate, glycerol
Down regulated by insulin
What occurs to the body if there’s a lack of insulin?
Lack of insulin means you can’t move glucose in
→ decreases glucose utilisation
→ increases protein catabolism - aminoacidaemia
→ increases gluconeogenesis - hyperglycaemia
→ increases urinary nitrogen
→ causes intracellular dehydration - thirst, coma, death
→ K+ is lost from cells - increases K+ loss from body - hyper polarisation of cells
Why do diabetics have different pH of blood?
Insulin deficiency → causes increased ketone bodies - diabetic ketoacidosis
What is type 1 diabetes?
Insulin dependant - insufficient production of insulin
→ usually <30yrs, juvenile onset
→ 10% of diabetics
What is type 2 diabetes?
Non-insulin dependent
→ pancreas functions normally, but there is insulin resistance
→ its an epidemic
→ closely linked with obesity
What might cause obesity driven insulin resistance?
A decrease in receptors/receptor binding
→ 90% develop compensatory increases in beta-cell mass and hyperinsulinemia
→ 10% develop beta-cell failure and diabetes
What is maturity-onset diabetes of the young?
Atypical form of type II diabetes
→ usually develops before the age of 25
→ inherited in an autosomal dominant fashion (unlike type II)
→ several genetic defects described
What is gestational diabetes mellitus?
Pregnancy related diabetes
→ caused by placental normal interference (human placental lactose, growth hormone)
→ progesterone indirect effects
→ insulin resistance - reduce Tyr-P, increased Ser-P - results in reduces insulin signals
can lead to abnormally large foetus, increased rate of spontaneous abortion, increased risk of congenital abnormalities, neonatal hypoglycaemia
What are the symptoms of diabetes?
→ elevated blood glucose, loss of glucose in urine
→ dehydration, increased thirst
→ inability to use glucose energy - fatigue, nausea
→ more prone to infection
→ blurred vision
→ extreme - diabetic coma
What are some consequences of diabetes?
→ blindess - diabetic retinopathy
→ kidney failure
→ nerve damage
→ atherosclerosis
→ stroke
→ coronary heart disease
→ coma
How is diabetes treated?
Diet, weight reduction and exercise, increase body’s sensitivity to insulin, insulin
Medication
Transplantation
When was insulin discovered?
1921 - Banting and Best isolated insulin
Isolated ‘isletin’ from degenerating ligated pancreas - reinjected into diabetic dogs
- enzymes don’t go into duodenum, stay in pancreas - degrade - secretion of islet enough to replace pancreas function
