Control of BGL and Endocrine Pancreas Flashcards
How is glucose transported into cells?
Sodium-glucose co-transporters (SGLTs) transport glucose into cells via secondary active transport (co-transport)
What are the 2 major glucose receptors responsible for glucose transport around the body?
SGLT1: glucose absorption from gut
SGLT1, SGLT2: glucose reabsorption from kidney (PCT)
Describe the family of glucose transporters
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
What are the Islets of Langerhans?
Clusters of endocrine cells surrounded by exocrine pancreas
Which cells of the Islets of Langerhans secrete which hormone?
α-cells (A cells): glucagon
β-cells (B cells): insulin
δ-cells: somatostatin
Describe the process of insulin synthesis
- Original transcript: pre-pro insulin
- Signal sequence cleaved: proinsulin (in RER)
- Transfer to Golgi apparatus
- Peptidases break off C peptide leaving A and B chain
linked by disulphide bonds - One mole of C-peptide secreted for each mole of
insulin
What can we use to measure insulin secretion?
C-peptide is inert, so is a good index of insulin secretion
Which vessels supply the pancreas?
Pancreas supplied by branches of coeliac, superior mesenteric, and splenic arteries
Describe the venous drainage of the pancreas
The venous drainage of the pancreas is into portal system
Why is circulating insulin not a better determinant of insulin secretion levels?
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
Which factors increase insulin secretion?
- Rise in plasma [glucose]
- Incretin hormones
- Parasympathetic system
- a.a. (esp. arginine)
- Glucagon secretion from nearby ꭤ cells stimulates insulin
secretion
Which factors decrease insulin secretion?
- hormonal/neuronal effects via ꭤ-adrenergic receptors
(counter-regulatory) - Somatostatin (paracrine)
What increases glucagon secretion?
- Amino acids counteracts ↑insulin secretion
- Parasympathetic system
- Βeta-adrenergic receptors
What causes a decrease in glucagon secretion?
- Increased Plasma [glucose]
- Somatostatin
- Insulin secretion
What is the main determinant of insulin/glucagon secretions?
Insulin and glucagon secretion are very sensitive to BGL
Insulin : glucagon ratio varies over physiologically significant range of glucose concentrations
How do β cells respond to an increase in BGL?
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
How does glucose move into β cells when BGL is high?
GLUT2 has a low affinity for glucose so as EF [glucose] rises rate of entry into cell will also increase
What is the fate of glucose entering Pancreatic β cells?
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
What causes β cells to stimulate insulin release?
Anything that can depolarize the B cell, or raise intracellular Ca, will also lead to insulin release
e.g. [Ca]i
Which family of receptors does the insulin receptor belong to?
The insulin receptor is a member of the tyrosine kinase superfamily
Describe the events that follow insulin binding to its receptor
- Insulin binds to its receptor
- Initiates many protein activation cascades
- e.g: translocation of GLUT4 transporter to plasma
membrane and influx of glucose
- Glycogen synthesis occurs
- Glycolysis also occurs
- As well as fatty acid synthesis
How does insulin binding to its receptor, activate protein cascades?
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
Describe the structure of the insulin receptor
The insulin receptor is a disulfide-linked tetramer with the β-subunits spanning the membrane and the α-subunits located on the exterior surface
Which enzyme initiates lipogenesis?
Acetyl-CoA carboxylase (ACC), is the enzyme that starts off lipogenesis, by converting acetyl CoA → malonyl CoA
