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Physiology 1 > 58) Control of blood glucose & the endocrine pancreas > Flashcards

58) Control of blood glucose & the endocrine pancreas Flashcards

1
Q

How does Glucose get into cells?

A
  • Glucose is polar and so is unable to simply diffuse across the lipid bilayer
  • There are two families of transporters that aid with glucose transport: SGLTs and GLUTs
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2
Q

What are Sodium-Glucose Cotransporters (SGLTs)?

A
  • They are a family of cotransporters that rely on secondary active transport
  • Its movement is coupled to the movement of Na+ down its electrochemical gradient (into the cell).
  • SGLT1 is present lining the gut (on the epithelial cells) and lining the kidney (on the epithelial cells). It is responsible for absorbing glucose from the gut and for the reabsorption of glucose in the PCT of the kidneys
  • SGLT2 is only present lining the kidney (on the epithelial cells). It is responsible for the reabsorption of glucose in the PCT of the kidneys
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3
Q

How are SGLTs targeted when treating diabetes?

A
  • We can prescribe SGLT2 inhibitors to reduce plasma glucose concentration (found in diabetes)
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4
Q

What are Glucose Transporters (GLUTs)?

A
  • A family of glucose transporters that allows glucose to diffuse across a membrane
  • GLUT 1: Found in the brain and red blood cells. They have a high affinity for glucose
  • GLUT 2: Found in the liver, kidney, pancreas and gut. They have a low affinity for glucose
  • GLUT 3: Found in the brain. It has a high affinity for glucose
  • GLUT 4: Found in muscle and adipose tissue. It has a medium affinity and is insulin dependent
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5
Q

How does affinity of a transporter affect the rate of transport?

A
  • At low affinity the movement of nutrients (e.g. glucose) will not be saturated (i.e. nutrient will not be transported at a maximum rate)
  • At high affinity there will be a constant/saturated uptake of nutrients (glucose) at a low extracellular concentration (i.e. nutrients will always be transported at a maximum rate)
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6
Q

What are the endocrine cells found within the pancreas that secrete insulin and glucagon?

A
  • Alpha-cells: Secrete glucagon
  • Beta-cells: Secrete insulin
  • Delta-cells: Secrete somatostatin
  • These endocrine cells are found in clusters in the pancreas called Islets of Langerhans
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7
Q

What is the function of somatostatin that is secreted by the Delta-cells within the pancreas?

A
  • It inhibits the secretion of insulin and glucagon from Alpha-cells and Beta-cells however it has no systemic effects
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8
Q

How is insulin made?

A
  • The original transcript of insulin is called the pre-proinsulin
  • The signal sequence is removed ( in the RER) and is then transferred to the Golgi apparatus
  • This leaves us with a molecule containing an A chain, B chain and C chain bonded together with disulphide bonds between them. This is called proinsulin
  • Peptidases break off the C-chain leaving us with an A and B chain bonded together by disulphide bridges
  • This is mature insulin and so one mole of C-peptide is released for every mole of insulin secreted (which is metabolically inert)
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9
Q

What can we use as a marker to determine if insulin secretion occurs in a perso?

A
  • C-peptide levels
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10
Q

How is insulin secreted into circulation?

A
  • The insulin flows in the blood which is drained into branches of the coeliac artery, superior mesenteric artery and splenic artery
  • This drainage leads to the portal system where it enters the liver
  • Half of the secreted insulin is metabolised by the liver in its first pass
  • The remainder of the insulin from the liver (into the hepatic veins) is diluted in peripheral circulation as it travels back to the heart and out into systemic circulation
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11
Q

What factors regulate insulin secretion?

A
  • Plasma glucose: An increase in plasma glucose causes an increase in insulin secretion
  • Incretin hormone: An increase in incretin hormone causes an increase in insulin secretion
  • Amino acid: An increase in amino acid levels causes an increase in insulin secretion
  • Glucagon: An increase in glucagon levels causes an increase in insulin secretion
  • Parasympathetic activity: An increase in parasympathetic stimulations (through muscarinic receptors) causes an increase in insulin secretion
  • Somatostatin: An increase in somatostatin inhibits insulin secretion
  • Alpha adrenergic receptors: An increase in stimulation of alpha adrenergic receptors inhibits insulin secretion
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12
Q

What factors regulate glucagon secretion?

A
  • Amino acid: An increase in amino acid levels causes an increase in glucagon secretion
  • Beta adrenergic receptors: An increase in stimulation of beta adrenergic receptors causes an increase in glucagon secretion
  • Parasympathetic activity: An increase in parasympathetic stimulations causes an increase in glucagon secretion
  • Somatostatin: An increase in somatostatin inhibits glucagon secretion
  • Plasma glucose: An increase in plasma glucose causes a decrease in glucagon secretion
  • Insulin: An increase in insulin levels causes an decrease in glucagon secretion
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13
Q

How do levels of glucose in the blood affect insulin and glucagon secretion?

A
  • Within the physiological range of glucose concentration we have insulin and glucagon secretion that react to changes in opposite direction
  • As we increase glucose concentration insulin secretion increases and glucagon secretion decreases
  • As we decrease glucose concentration insulin secretion decreases and glucagon secretion increases
    (Secretions are never switched off!!! Rather at different blood glucose concentrations we have a different ratio of insulin : glucose)
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14
Q

How do Beta-cells sense a rise in glucose?

A
  • Beta cells have no glucose receptor
  • Sensing depends on the GLUT2 transporter and glucokinase (converts glucose to G-6-P) enzyme present
  • The effector is a rise in intracellular ATP due to the oxidation of glucose
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15
Q

What are KATP channels?

A
  • They are ATP-dependent Potassium channels that are located on the Beta cell.
  • These are K+ channels that are sensitive to ATP
  • Upon binding of ATP to the ATP binding site the channel closes
  • The proportion of KATP channels within a beta cell closed is proportional to the amount of ATP within the cell
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16
Q

Explain the mechanism of glucose sensing by Beta-cells.

A
  • As extracellular glucose rises more glucose enters the Beta-cell via the GLUT2 transporter
  • As it enters it is converted to Glucose-6-Phosphate via the glucokinase enzyme
  • G-6-P goes into glycolysis and undergoes full oxidative phosphorylation (via the Krebs cycle) which generates more ATP
  • This increase in ATP binds to the KATP channels and so less K+ efflux from the cell
  • This means the cell will be depolarised (extent of depolarisation depends on the proportion of KATP channels that are closed) which activates VGCCs
  • This results in an influx of Ca2+ into the cell which triggers a biochemical cascade resulting in exocytosis of secretory granules which store insulin
17
Q

How do amino acids and free fatty acid increase insulin secretion?

A
  • Amino acids and free fatty acids can be metabolised to generate ATP
  • This increase in ATP binds to the KATP channels and so we see the same mechanism occuring
18
Q

How do neurones increase insulin secretion?

A
  • There are muscarinic GPCRs located on Beta cells
  • Acetylcholine released by parasympathetic nerves binds to these receptors which triggers the Gq protein
  • This Gq protein activates phospholipase C which phosphorylates and opens up Ca2+ channels
  • This increases intracellular Ca2+ and so triggers the exocytosis of the insulin-rich secretory granules
  • There are A2-adrenergic GPCRs which can be stimulated by adrenergic neurones
  • Upon binding of adrenaline/noradrenaline it activates Gi protein which in turn activates Adenylate cyclase
  • Adenylate cyclase converts ATP into cAMP which activates Protein Kinase A
  • PKA strengthens the mobilisation of insulin-rich secretory granules in response to Ca2+ influx
19
Q

How do neurones decrease insulin secretion?

A
  • There are A2-adrenergic GPCRs which can be stimulated by adrenergic neurones
  • Upon binding of adrenaline/noradrenaline it activates Gi protein which in turn deactivates Adenylate cyclase
  • Adenylate cyclase converts ATP into cAMP which activates Protein Kinase A
  • PKA strengthens the mobilisation of insulin-rich secretory granules in response to Ca2+ influx
  • Hence by blocking adenylate cyclase we are inhibiting the production of PKA
20
Q

Describe the insulin receptor.

A
  • The insulin receptor is a member of the tyrosine kinase superfamily
  • Upon binding of insulin to its receptor it activates a cascade of protein phosphorylation which stimulate or inhibit certain metabolic enzymes by modulating enzyme phosphorylation
  • It also leads to modulation of metabolic enzymes by regulating gene transcription
21
Q

Explain the action of a glucagon receptor

A
  • It is a G-Protein Coupled Receptor (GPCR)
  • Upon binding of glucagon it activates Gs which activates adenylate cyclase which converts ATP into cAMP
  • cAMP activates Protein Kinase A which leads to many substrates being phosphorylated
22
Q

How does insulin and glucagon affect enzymes within a target cell?

A
  • Glucagon acts principally through activity of Protein Kinase A which phosphorylates key enzymes in metabolic pathways
  • Insulin action leads to dephosphorylation of these same enzymes
23
Q

What are the different types of diabetes mellitus?

A
  • Type 1: Absolute insulin deficiency due to destruction of pancreatic beta cells
  • Type 2: Variable combination of insulin resistance and insulin insufficiency
24
Q

What are the three ways to diagnose diabetes?

A
  • Random plasma glucose samples
  • Fasting plasma glucose samples
  • Oral glucose tolerance test
25
Q

What happens when glycaemic control is poor?

A
  • When there are higher than normal levels of glucose in circulation it will react with plasma proteins and proteins on the endothelial layer of the vasculature
  • This can lead to macrovascular and microvascular complications
  • Microvascular complications are damages to capillary beds within the body
26
Q

How can we measure glycaemic control?

A
  • By measuring the amount of glycosylation in the haemoglobin we have a good indicator of the average glucose levels over the life time of a red blood cell and hence glycaemic control
27
Q

What is the incretin effect?

A
  • The effect by which glucose taken orally causes the body to produce more insulin in comparison to glucose glucose given intravenously
28
Q

What are incretin hormones?

A
  • Hormones that syncing insulin secretion to food intake
  • Their main role is to boost insulin output from the beta cells
  • Gastric Inhibitory Peptides (GIP) and Glucagon-Like Peptide 1 (GLP1) are two incretin hormones
29
Q

How is the incretin effect impaired?

A
  • It is impaired by Type 2 Diabetes Mellitus which accounts for some of the insulin insufficiency that is observed
30
Q

Describe the mechanism of incretin hormone action.

A
  • After ingesting food it travels down our GI tract.
  • As it reaches the gut, the gut hormones/incretin hormones are released
  • They enter circulation where they bind to receptors on beta and alpha cells
  • GLP-1 and GIP increases insulin secretion from the beta cells
  • This causes increased glucose uptake by skeletal muscles
  • GLP-1 will also inhibit glucagon secretion from alpha cells
  • As a result this will decrease hepatic production of glucose
  • Overall there is a decrease in blood glucose levels
31
Q

How long do incretin hormones stay active?

A
  • Incretin hormones have a very short half life

- This is because they are rapidly degraded by the enzyme DPP-4 which cleaves and inactivates them

32
Q

How do incretins increase insulin secretion from beta cells?

A
  • The incretins bind to a GPCR which activates Gs.
  • Activated Gs stimulates adenylate cyclase which converts ATP to cAMP
  • This increase in cAMP increases activity of PKA which potentiates (strengthens) the secretion of insulin secretor granules in response to Ca2+
33
Q

What are the treatments to the different types of diabetes?

A
  • Type 1: Lifelong insulin therapy

- Type 2: Drugs of lower power/severity than insulin (e.g. incretin drugs and sulfonylurea drugs)

34
Q

What are sulfonylurea drugs?

A
  • They are drugs used to treat type 2 diabetes
  • They do this by binding to a subunit on the KATP channel (in beta cells) causing it to close
  • They are directly depolarising the beta cell by bypassing the normal glucose dependent depolarisation

Physiology 1 (64 decks)

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