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Molecular Endocrinology > The Pancreas (4-6) > Flashcards

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
Q

What are the hormones of the islet of Langerhans?

A

Beta-cell → insulin
Alpha-cell → glucagon
Delta-cell → somatostatin

→ islets are vascularised for secretion of hormones into blood

26
Q

What is ‘intra-islet’ regulation?

A

Islet cells don’t only do endocrine signalling
→ beta cell - autocrine, paracrine etc

27
Q

How is glucagon synthesised?

A

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
Q

How does insulin and glucagon interact within the islet?

A

There is blood flow through the islet
→ can go through the venules and signal to other side of islet

29
Q

What affect does somatostatin have on insulin?

A

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
Q

What is the effect of insulin on metabolism?

A

Anabolic (fed state)

Amino acids → protein biosynthesis
Glucose → glycogenesis
Fatty acids → lipogenesis

31
Q

What is the effect of glucagon on metabolism?

A

Catabolic (starved state)

Glycogenolysis, lipolysis, ketogenesis, gluconeogenesis → fuel production

32
Q

What effect does insulin have on amino acid metabolism?

A

High presence of insulin drives uptake of amino acids in the liver
→ increases protein synthesis
→ decreases protein breakdown

33
Q

What is glycogen?

A

Stored form of glucose
→ made from glucose-1-p by glycogen synthase
→ glycogen phosphorylase converts glycogen back to glucose-1-p

34
Q

How does insulin regulate glycogen synthesis?

A

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
Q

How does glucagon regulate glycogen synthesis?

A

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
Q

What insulin signalling is involved in glycogen metabolism?

A

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
Q

How does insulin regulate fat metabolism?

A

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
Q

How does glycogen regulate fat metabolism?

A

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
Q

How does insulin act on glycolysis?

A

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
Q

How does insulin act on gluconeogenesis?

A

Gluconeogenesis → allows formation of glucose from e.g. pyruvate, glycerol

Down regulated by insulin

41
Q

What occurs to the body if there’s a lack of insulin?

A

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
Q

Why do diabetics have different pH of blood?

A

Insulin deficiency → causes increased ketone bodies - diabetic ketoacidosis

43
Q

What is type 1 diabetes?

A

Insulin dependant - insufficient production of insulin
→ usually <30yrs, juvenile onset
→ 10% of diabetics

44
Q

What is type 2 diabetes?

A

Non-insulin dependent
→ pancreas functions normally, but there is insulin resistance
→ its an epidemic
→ closely linked with obesity

45
Q

What might cause obesity driven insulin resistance?

A

A decrease in receptors/receptor binding
→ 90% develop compensatory increases in beta-cell mass and hyperinsulinemia
→ 10% develop beta-cell failure and diabetes

46
Q

What is maturity-onset diabetes of the young?

A

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
Q

What is gestational diabetes mellitus?

A

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
Q

What are the symptoms of diabetes?

A

→ 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
Q

What are some consequences of diabetes?

A

→ blindess - diabetic retinopathy
→ kidney failure
→ nerve damage
→ atherosclerosis
→ stroke
→ coronary heart disease
→ coma

50
Q

How is diabetes treated?

A

Diet, weight reduction and exercise, increase body’s sensitivity to insulin, insulin

Medication

Transplantation

51
Q

When was insulin discovered?

A

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

Molecular Endocrinology (7 decks)

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