The Pancreas (4-6) Flashcards

1
Q

Where does the pancreas sit in situ?

A

Posterior to the stomach
→ head of the pancreas lies in the curve of the duodenum

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2
Q

How is the pancreas structured?

A

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

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3
Q

What is the major stimulator for insulin secretion?

A

Glucose
→ (not the complete driver)

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4
Q

How was it discovered that pancreatic islets cells are synchronised?

A

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

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5
Q

How can Ca2+ move between beta cells in pancreatic islets?

A

Via connections - gap junctions proteins
→ connexion 36
→ discovered using heptagon as an uncoupler

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6
Q

What are the two aspects to pancreatic islet beta cell coupling?

A

Movement of Ca2+
ATP secretion
→ help with synchronisation - regulating K+

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7
Q

How does low glucose affect pancreatic islet beta cells?

A
  1. Low glucose in blood (GLUT 2 transporter)
  2. Metabolism slows → decrease in ATP
  3. Katp channels open → K+ leaks out - membrane potential changes
  4. Voltage-gated Ca2+ channels closed → can’ dock vesicles
  5. No insulin secretion
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8
Q

How does high glucose affect pancreatic islet beta cells?

A
  1. High glucose in blood (GLUT 2 transporter)
  2. More metabolism → increase in ATP
  3. Katp channels (sensitive to [ATP]) close → K+ leaves - cell depolarises
  4. Voltage-gated Ca2+ channels open
  5. Entry of Ca2+ triggers exocytosis and insulin is secreted → vesicles can dock
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9
Q

How to secretory cells reset membrane potential?

A

Calcium dependant K+ channels

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10
Q

How can Katp channels be used as a drug target?

A

Sulphonylureas → increase insulin secretion
→ stop K+ moving in from cytoplasm

Diaxzoxide, cromakalin, pinacidil → decrease insulin secretion
→ encourage K+ moving in from cytoplasm

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11
Q

How does somatostatin affect insulin secretion?

A

Somatostatin from the HPA axis shuts down insulin secretion by closing K+ channels

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12
Q

How does the parasympathetic nervous system input insulin secretion?

A

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

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13
Q

How does the sympathetic nervous system input in insulin secretion?

A

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

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14
Q

What is the basic structure of insulin?

A

A-chain and B-chain linked by 2 disulphide bridges

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15
Q

What does the insulin prepro hormone consist of?

A

Signal peptide
B chain
C-peptide
A chain

→ with basic residues that are cleavage sites for conversion from proinsulin to insulin

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16
Q

What is a sign that insulin has been made correctly?

A

Identification of the cleaved C-peptide

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17
Q

What is the structure of the insulin receptor?

A

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

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18
Q

What does insulin mainly work on?

A

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

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19
Q

What are the main effects of insulin receptor binding ligand?

A
  1. Moving glucose transporter to membrane → vesicles dock - more glucose
  2. Signal transduction → effects proteins (bit slower)
    → changes gene expression (even slower)
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20
Q

What are the molecules involved in insulin signal transduction?

A

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

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21
Q

What happens to GLUT4 with an insulin burst?

A

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

22
Q

How can insulin-receptor regulate gene expression?

A

Via signal transduction with
→ IRS and AKT - phos. of FOXOs
→ Shc and ERK - TF processing

Receptor can be retrafficked into nucleus

23
Q

How does the insulin receptor cluster in low and high conc of insulin?

A

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

24
Q

What are insulin degrading enzymes?

A

Enzymes that degrade hormones involved in glucose homeostasis
→ potential therapeutic targets for type 2 diabetes
→ however bad off target side effects

25
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
26
What is 'intra-islet' regulation?
Islet cells don't only do endocrine signalling → beta cell - autocrine, paracrine etc
27
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
28
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
29
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
30
What is the effect of insulin on metabolism?
Anabolic (fed state) Amino acids → protein biosynthesis Glucose → glycogenesis Fatty acids → lipogenesis
31
What is the effect of glucagon on metabolism?
Catabolic (starved state) Glycogenolysis, lipolysis, ketogenesis, gluconeogenesis → fuel production
32
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
33
What is glycogen?
Stored form of glucose → made from glucose-1-p by glycogen synthase → glycogen phosphorylase converts glycogen back to glucose-1-p
34
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
35
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
36
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
37
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
38
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
39
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
40
How does insulin act on gluconeogenesis?
Gluconeogenesis → allows formation of glucose from e.g. pyruvate, glycerol Down regulated by insulin
41
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
42
Why do diabetics have different pH of blood?
Insulin deficiency → causes increased ketone bodies - diabetic ketoacidosis
43
What is type 1 diabetes?
Insulin dependant - insufficient production of insulin → usually <30yrs, juvenile onset → 10% of diabetics
44
What is type 2 diabetes?
Non-insulin dependent → pancreas functions normally, but there is insulin resistance → its an epidemic → closely linked with obesity
45
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
46
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
47
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
48
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
49
What are some consequences of diabetes?
→ blindess - diabetic retinopathy → kidney failure → nerve damage → atherosclerosis → stroke → coronary heart disease → coma
50
How is diabetes treated?
Diet, weight reduction and exercise, increase body's sensitivity to insulin, insulin Medication Transplantation
51
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