Control of BGL and Endocrine Pancreas

Question 1

How is glucose transported into cells?

Answer 1

Sodium-glucose co-transporters (SGLTs) transport glucose into cells via secondary active transport (co-transport)

Question 2

What are the 2 major glucose receptors responsible for glucose transport around the body?

Answer 2

SGLT1: glucose absorption from gut

SGLT1, SGLT2: glucose reabsorption from kidney (PCT)

Question 3

Describe the family of glucose transporters

Answer 3

GLUT 1
(brain, erythrocytes)
– high glucose affinity: constant glucose uptake 2-6 mM

GLUT 2
(liver, kidney, pancreas, gut)
– low affinity: glucose equilibrates across membrane
Glucose-dependent insulin release in pancreas

GLUT 3
(brain)
– high affinity

GLUT 4
(muscle and adipose tissue)
– medium affinity; Insulin recruits transporters
– Insulin-dependent glucose uptake into cells

Question 4

What are the Islets of Langerhans?

Answer 4

Clusters of endocrine cells surrounded by exocrine pancreas

Question 5

Which cells of the Islets of Langerhans secrete which hormone?

Answer 5

α-cells (A cells): glucagon
β-cells (B cells): insulin
δ-cells: somatostatin

Question 6

Describe the process of insulin synthesis

Answer 6

1. Original transcript: pre-pro insulin
2. Signal sequence cleaved: proinsulin (in RER)
3. Transfer to Golgi apparatus
4. Peptidases break off C peptide leaving A and B chain
   linked by disulphide bonds
5. One mole of C-peptide secreted for each mole of
   insulin

Question 7

What can we use to measure insulin secretion?

Answer 7

C-peptide is inert, so is a good index of insulin secretion

Question 8

Which vessels supply the pancreas?

Answer 8

Pancreas supplied by branches of coeliac, superior mesenteric, and splenic arteries

Question 9

Describe the venous drainage of the pancreas

Answer 9

The venous drainage of the pancreas is into portal system

Question 10

Why is circulating insulin not a better determinant of insulin secretion levels?

Answer 10

50% secreted insulin is metabolised by liver in its first pass; remainder is diluted in peripheral circulation
Hepatic portal vein is only a fraction of CO, so insulin levels in peripheral circulation (where you can easily sample) are much diluted

Question 11

Which factors increase insulin secretion?

Answer 11

• Rise in plasma [glucose]
• Incretin hormones
• Parasympathetic system
• a.a. (esp. arginine)
• Glucagon secretion from nearby ꭤ cells stimulates insulin
  secretion

Question 12

Which factors decrease insulin secretion?

Answer 12

• hormonal/neuronal effects via ꭤ-adrenergic receptors
  (counter-regulatory)
• Somatostatin (paracrine)

Question 13

What increases glucagon secretion?

Answer 13

• Amino acids counteracts ↑insulin secretion
• Parasympathetic system
• Βeta-adrenergic receptors

Question 14

What causes a decrease in glucagon secretion?

Answer 14

• Increased Plasma [glucose]
• Somatostatin
• Insulin secretion

Question 15

What is the main determinant of insulin/glucagon secretions?

Answer 15

Insulin and glucagon secretion are very sensitive to BGL

Insulin : glucagon ratio varies over physiologically significant range of glucose concentrations

Question 16

How do β cells respond to an increase in BGL?

Answer 16

β cells sense ↑[glucose] directly
Glucose enters pancreas via GLUT2 and is metabolised and oxidised to ATP
ATP interacts with the ATP-sensitive K channel (closing channel) = depolarisation

Question 17

How does glucose move into β cells when BGL is high?

Answer 17

GLUT2 has a low affinity for glucose so as EF [glucose] rises rate of entry into cell will also increase

Question 18

What is the fate of glucose entering Pancreatic β cells?

Answer 18

Glucose → G6P via glucokinase
Oxidised further to form ATP
ATP binds to ATP-sensitive K channel to close it
=> consequent membrane depolarization
leads to ↑Ca entry - triggers insulin exocytosis

Question 19

What causes β cells to stimulate insulin release?

Answer 19

Anything that can depolarize the B cell, or raise intracellular Ca, will also lead to insulin release
e.g. [Ca]i

Question 20

Which family of receptors does the insulin receptor belong to?

Answer 20

The insulin receptor is a member of the tyrosine kinase superfamily

Question 21

Describe the events that follow insulin binding to its receptor

Answer 21

1. Insulin binds to its receptor
2. Initiates many protein activation cascades

• e.g: translocation of GLUT4 transporter to plasma
  membrane and influx of glucose

3. Glycogen synthesis occurs
4. Glycolysis also occurs
5. As well as fatty acid synthesis

Question 22

How does insulin binding to its receptor, activate protein cascades?

Answer 22

Activates cascade of protein phosphorylation, which stimulate or inhibit specific metabolic enzymes by modulating enzyme phosphorylation
Modulates activity of metabolic enzymes by regulating gene transcription

Question 23

Describe the structure of the insulin receptor

Answer 23

The insulin receptor is a disulfide-linked tetramer with the β-subunits spanning the membrane and the α-subunits located on the exterior surface

Question 24

Which enzyme initiates lipogenesis?

Answer 24

Acetyl-CoA carboxylase (ACC), is the enzyme that starts off lipogenesis, by converting acetyl CoA → malonyl CoA

Question 25

explain how PKA has an inhibitory role to ACC

Answer 25

ACC under inhibitory PKA control, which in turn depends on cAMP for its activity

Insulin binding leads to ↓ cAMP levels, ↓ PKA activity, releasing ACC from inhibition, thereby promoting lipogenesis

Question 26

Which enzymes are involved in glucagon receptor action?

Answer 26

• glycogen synthase

- glycogen phosphorylase

Question 27

How is glycogen synthase activated?

Answer 27

glycogen synthase is activated by dephosphorylation

Question 28

What activates glycogen phosphorylase?

Answer 28

glycogen phosphorylase is activated by phosphorylation