Control of Blood Glucose & the Endocrine Pancreas Flashcards
(17 cards)
Describe the islet of Langerhans, the cell types and their secretions
Islet of Langerhans - Clusters of endocrine cells surrounded by exocrine pancreas
- Alpha cells (A cells) - Secrete glucagon
- Beta cells (B cells) - Secrete insulin
- Delta cells (δ) - Secrete somatostatin
How do B cells sense rises in glucose?
- No glucose receptor
- GLUT 2/glucokinase can be thought of as sensor
- Effector is rise in ATP due to glucose oxidation
2 step process:
Glucose entry:
- Glucose enters cell via GLUT2
Glucose metabolism:
- Once inside the beta cell, glucose is metabolised (mainly through glycolysis). Glucokinase phosphorylates glucose, converting it into G6P (rate limiting step in B-cell glucose metabolism)
- ATP increase as glucose metabolised. This leads to closure of a special K channel (which is blocked by intracellular ATP) leading to membrane depolarisation
- This leads to increased Ca entry, and intracellular Ca is the signal that triggers insulin exocytosis.
Sympathetic stimulation, via alpha receptors, leads to a reduced sensitivity of the Ca signalling, and hence decreases insulin release
Describe the importance of glycaemic control
Reduce macro- and microvascular complication:
- Glycosylated Hb (A1C) lvls good indicator of glycaemic control
- Less than 6.5% = Good
- Every 1 % fall in A1C results in 20-30% relative risk reduction in microvascular complications
How does GLP-1 stimulate insulin release?
- GLP-1 binds to GLP-1 receptor
- Activates adelylate cyclase
- Increase cAMP
- Amplifies glucose-induced insulin release
Outline the actions of insulin and glucagon
- Counter-regulatory hormones act principally (not exclusively) through activity of PKA, which phosphorylates key enzymes in metabolic pathways
- Insulin action leads to dephosphorylation of these same enzymes
- Insulin keeps plasma glucose within constant limits, despite periodic intake of sugar and burst of exercise requiring fuels
What are the factors regulating insulin secretion?
Positive factors inducing insulin secretion:
- Plasma glucose (when high)
- Incretin hormones - Hormones released into circulation of feeding, serve to enhance glucose-induced insulin secretion
- Amino acids
- Glucagon
- Parasympathetic
Negative factors inhibiting insulin secretion:
- Somatostaitn
- Alpha adrenergic stimulation
What are the factors regulating glucagon secretion?
Positve factors inducing glucagon secretion:
- Amino acids
- Beta adrenergic stimulation
- Parasympathetic
Negative factors inhibiting glucagon secretion:
- Plasma glucose (when high)
- Somatostatin
- Insulin
How is insulin synthesised?
- Transcription of mRNA will form pre-pro insulin, this is the original transcript
- The signal sequence is removed in the rER, this forms proinsulin
- Proinsulin is transferred to the Golgi apparatus
- Peptidases break off the C peptide insulin, leaving an A and b chain which is insulin, linked by disulphidebonds
- One mole of C-peptide is secreted for each mole of insulin. C-peptide is inert, and is thus a good index of insulin secretion
How is glucose released into circulation?
- Pancreas supplied by branches of coeliac, superior mesenteric and splenic arteries
- Venous drainage of pancreas is into portal system, hepatic vein then drains into IVC for systemic circulation
- Half of secreted insulin is metabolised by liver in it’s first pass; remainder is diluted in peripheral circulation
- C-peptide more accurate index of insulin secretion in peripheral circulation (not metabolised by liver) as it’s inert meaning it doesn’t get metabolised. One mole of C-peptide is secreted for each mole of insulin
How does glucose get into cells?
SGLTs:
- Secondary active transport
- SGLT1 - Glucose absorption from ugt
- SGLT1, SGLT2- Glucose reabsorption from kidney (PCT)
GLUTs: Affinity determines the rate at which glucose is transported into cells
- Facilitated diffusion
- GLUT 1 (brain, eythrocytes)- High affinity for glucose: constant uptake at 2-6mM
- 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 uptake of glucose into cells
What family of receptor does the insulin receptor belong to?
The insulin receptor is a member of the tyrosine kinase superfamily
Describe the mode of action of the insulin receptor
Insulin binds to its receptor:
- The insulin receptor is a disulfide-linked tetramer with the B-subunits spanning the membrane and the alpha subunits located on the exterior surface
- 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
What type of receptor is the glucagon receptor?
Gs
Define type 1 diabetes mellitus
Absolute insulin deficiency due to destruction of insulin-producing pancreatic beta cells
Define type 2 diabetes mellitus
Variable combination of insulin resistance and insulin insufficiency
How is diabetes mellitus diagnosed?
Hyperglycaeamia is central to DM diagnosis:
- Random plasma glucose ≥ 11.1 mmol per litre
- Fasting plasma glucose ≥ 7.0 mmol per litre
- Oral glucose tolerance test (OGTT) > 11.1 mmol per litre
Explain the incretin effect
- Plasma insulin lvls following oral intake of glucose greater than those observed when glucose given via IV.
- Conclusion is that the oral route stimulates greater insulin secretion than when you bypass GIT and infuse glucose directly into circulation
- Therefore, presence of glucose in GIT stimulates factors that enhance insulin release from the pancreas. These factors are now known to be the incretin hormones, GLP-1 and GIP. Released in response to presence of nutrients within gut, coupling potentiation of insulin secretion with rising glucose from the gut
- GLP-1 also has an inhibitory effect on glucagon
- These factors are broken down by DPP-4 enzymes, many diabetic medications prevent the action of this enzyme to prevent breakdown
- They are secreted by gut endocrine cells in response to presence of nutrients in gut
