Control of Blood Glucose & Endocrine Pancreas Flashcards
How does glucose get into cells in the gut?
- Secondary active transport
- SGLT 1
- Sodium transports glucose into the cell
How does glucose get reabsorbed in the PCT?
SGLT 1 and SGLT2
Where is GLUT 1 found and in what ranges does it work?
- In the brain + erythrocytes
- High affinity for glucose
- Constant uptake at 2-6mM
Where is GLUT 2 found and what is the affinity like?
- Liver, kidney, pancreas, gut
- Low affinity
- Transport rate increases with glucose concentration
Where is GLUT 3 found and what is its affinity?
- Brain
- High affinity
Where is GLUT 4 found and what is its affinity?
- Muscle and adipose tissue
- Medium affinity
- Glucose uptake is insulin dependent
What are the islets of Langerhans?
Clusters of endocrine cells surrounded by an exocrine pancreas where hormones are synthesised
What do the following secrete?
α-cells (A cells)
β-cells (B cells)
δ-cells
α-cells (A cells) - glucagon
β-cells (B cells) - insulin
δ-cells - somatostatin
How do we get mature insulin from the precursor? PART 1
- Formed from preproinsulin by proteolytic processing.
- Removal of signal sequence at the amino acid terminus of preproinsulin and the formation of 3 disulphide bonds produces proinsulin.
How do we get mature insulin from the precursor? PART 2
- Further proteolytic cuts remove the C peptide from proinsulin to produce mature insulin, composed of A and B chains.
What is the blood supply of the pancreas?
Branches of celiac, superior mesenteric and splenic arteries
What is the venous drainage of the pancreas?
Into the portal system
Describe the release of insulin into the circulation.
- Half of the secreted insulin is metabolised by the liver in its first pass
- Remainder is diluted into peripheral circulation.
What is the clinical significance of C peptide?
- Not metabolised by the liver
- Good index of insulin circulation
List some factors stimulating insulin secretion (ie. affecting B-cells).
- plasma glucose
- incretin hormones
- alpha adrenergic
- parasympathetic
List some factors inhibiting insulin secretion.
Somatostatin
List some factors stimulating glucagon secretion.
- beta-adrenergic
- parasympathetic
List some factors inhibiting glucagon secretion.
insulin
plasma glucose
somatostatin
How do β-cells sense a rise in glucose? PART 1
- Glucose uptake via GLUT2 transporter.
- Glucose metabolised to G6P, which generates ATP.
- ATP stimulates an ATP-sensitive K+ channel, so K+ efflux is stopped.
How do β-cells sense a rise in glucose? PART 2
- Cell depolarisation, which activates VGCCs.
- Ca2+ influx signals vesicle mobilisation (the vesicles contain insulin).
Describe the glucagon receptor action pathway.
- Binds to its receptor, activating αGs subunit.
- Stimulates Adenylate Cyclase, which generates cAMP
- Activates PKA
What type of receptor are insulin receptors?
Tyrosine kinase
What are the general effects of insulin binding to its receptor?
- Activates cascade of protein phosphorylation, which stimulates or inhibits specific metabolic enzymes
- Modulates activity of metabolic enzymes by regulating gene transcription
What are the specific effects of insulin binding to its receptor?
- Translocation of GLUT4 transporters to plasma membrane ∴ influx of glucose
- Glycogenesis
- Glycolysis
- Fatty acid synthesis
How do insulin and glucagon act together?
- Counter-regulatory hormones that act principally through PKA activity
- Glucagon phosphorylates key enzymes in metabolic pathways.
- Insulin action leads to dephosphorylation of these same enzymes.
Describe Type 1 Diabetes Mellitus.
Absolute insulin deficiency (due to destruction of pancreatic β-cells)
Describe Type 2 Diabetes Mellitus
Combination of insulin resistance and insulin deficiency
How do we diagnose diabetes mellitus?
- Random plasma glucose would be ≥11.1 mmol/L
- Fasting plasma glucose would be ≥7.0 mmol/L
- Oral glucose tolerance test (OGT) would be ≥11.1 mmol/L
How does insulin affect plasma glucose?
- Plasma glucose is kept within constant limits by insulin and glucagon
- Insulin is released in response to high plasma glucose, acting to lower it to within a suitable range.
What is the importance of glycaemic control?
- Reduces macrovascular complications (increased risk of CVD and stroke, etc.)
- Reduces microvascular complications (damage to capillary beds in retina, kidney, etc.)
What would be a good indicator of glycaemic control?
- HbA1C (glycosylated Hb) - ideally found in low levels
- Less than 6.5% is good
- With every 1% fall in A1C, there is a 20-30% relative risk reduction in microvascular complications.
Why would a doctor not administer an injection to maintain glycaemic control?
- Accidental overdoses can occur
- Patient may become hypoglycaemic
Give examples of incretin hormones and where they are released from.
- GLP-1 and GIP.
- Released by gut endocrine cells in response to nutrients in the gut.
What is the general mechanism of action of incretin hormones?
- Circulate in bloodstream until they reach the pancreas
- Potentiate production of insulin from β-cells ∴ blood glucose decreases
How does GLP-1 work?
- Activates adenylate cyclases
- Increases cAMP ∴ increases PKA
- Increased release of insulin-rich secretory granules.
What are some drug treatments for Type 2 Diabetes Mellitus? PART 1
- Metformin: decreases gluconeogenesis
- Sulfonylureas: bind and close ATP-sensitive K channels, depolarising β-cells and releasing insulin
What are some drug treatments for Type 2 Diabetes Mellitus? PART 2
- Thiazolidinediones: activate PPARγ receptors (controllers of lipid metabolism), which reduces insulin resistance
- SGLT2 inhibitors: promote glucose excretion via the kidney
What are some drug treatments for Type 2 Diabetes Mellitus? PART 3
- Incretin-targeting drugs: potentiate insulin release in response to rising plasma glucose (such as synthetic GLP-1 analogues)
Why is insulin resistance not down to one reason?
Many intracellular pathways
What enzyme starts lipogenesis and how?
- ACC(Acetyl CoA-carboxylase)
- Insulin reduces PKA which inhibits ACC
