Control of Blood Glucose Flashcards
How does glucose get into cells?
→ Secondary active transport
→ SGLT 1
→ Sodium transports glucose into the cell
How does glucose get reabsorbed in the kidney?
→ SGLT 1 and SGLT2(PCT)
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
→ Insulin recruits transporters
What does high affinity mean?
→ rate of transport does not depend on the concentration
What are the islets of Langerhans?
→ Clusters of endocrine cells surrounded by an exocrine pancreas
what do alpha cells in the pancreas produce?
→ Glucagon
What do beta cells in the pancreas produce?
→ Insulin
What do the delta cells in the pancreas produce?
→ Somatostatin
has no systemic endocrine effect, to my knowledge
What are the steps for insulin production?
1) original transcript is pre-pro insulin
2) Signal sequence is removed ( in RER)
3) Transferred to Golgi apparatus
4) Peptidases break off the C peptide leaving an A and B chain linked by disulfide bonds
For every mole that is secreted of insulin how many C peptides do you get?
one
What is the clinical significance of C peptide
→ It is inert
→ good index of insulin circulation
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 path insulin takes
→ Insulin is secreted in circulation
→ drained into portal vein so high conc in portal vein initially
→Half of the secreted insulin is metabolized by the liver
→ remainder is diluted in circulation
Where is the insulin most concentrated?
→ in the portal vein
Why is C peptide a more accurate index of insulin secretion?
→ It is not metabolized by the liver
What stimulates the secretion of insulin from Beta cells ?
→ rise in plasma glucose → amino acids - arginine → Glucagon → Parasympathetic effects → Incretin hormones
What inhibits insulin?
→ Alpha adrenergic receptors
→ somatostatin
What stimulates glucagon secretion from alpha cells?
→ Amino acids
→ beta adrenergic
→ parasympathetic
What inhibits glucagon secretion?
→ Plasma glucose
→ Somatostatin
→ Insulin
How do beta cells sense a rise in glucose?
→ Increase in glucose through the GLUT 2 → glucose is metabolized into ATP → ATP closes a K+/ATP channel → Depolarized the cell → Activates VG calcium channels → rise in iCa stimulates vesicular release of insulin
What family is the insulin receptor a part of?
→ Tyrosine Kinase
How does the insulin receptor work?
→ Insulin binds
→ Starts many protein activation cascades
→PKA→ HSL→ lipolysis
What are the protein cascades activated by the insulin receptor?
→ Translocation of the GLUT 4 transporter to plasma membrane and influx of glucose
→ Glycogen synthesis
→ Glyolysis
→ Fatty acid synthesis
What enzyme starts lipogenesis and how?
→ACC starts lipogenesis- acetylCoa carboxylase
→ Insulin reduces PKA which inhibits ACC
Why is insulin resistance not down to one reason?
→ could be something highly selective
→ because there are many intracellular pathways
How does the glucagon receptor work?
→ Glucagon binds to its receptor
→ Adenylate cyclase converts ATP to cAMP
→ PKA is activated
How do insulin counter regulatory hormones work?
→ phosphorylation of enzymes
How should we think about insulin and glucagon secretion balance?
the continual balance between these opposing hormones that maintains glucose homeostasis.
The ratio of insulin/glucagon increases as plasma glucose increases, and decreases as it decreases
What is metformins?
→ a common class of insulin-potentiating drugs, act to directly close the K/ATP channel, → increasing insulin release by-passing the normal mechanisms
What does sympathetic stimulation of B-cells do?
→ via alpha receptors, leads to a reduced sensitivity of the channel,
→ leading to reduced likelihood of closure, → decreased insulin release
What does incretin stimulation of GLP-1 result in?
→GLP-1 R activates adelylate cyclase, ↑cAMP,
→amplifies glucose-induced insulin release
→unlikely to promote hypoglycaemia because its mechanism is dependent on high glucose
What do sulfonylurea drugs do?
bind to a subunit on the K+ATP closing it so they directly depolarise the beta cells to release insulin
What are the incretin hormones?
GLP-1
GIP
They boost insulin output on beta cells.
Explain the incretin effect
the increased stimulation of insulin secretion elicited by oral as compared with intravenous administration of glucose under similar plasma glucose levels
Something in the GI tract must potentiate insulin release in response to glucose
Importance of glycaemic control
→Glycosylated Hb (A1C) levels are good indicator of glycaemic control- Less than 6.5% is good
→Every 1% fall in A1C results in 20-30% relative risk reduction in microvascular complications
But …
→Glycaemic control is hard because of insulin release and difficulties with distributing.
Classification for diabetes in fasting plasma glucose and oral glucose tolerance test…
→Random plasma glucose ≥ 11.1 mmol L-1
→Fasting plasma glucose ≥ 7.0 mmol L-1
→Oral glucose tolerance test (OGTT) ≥ 11.1 mmol L-1
