Acute Regulation of Glucose Flashcards
What does plasma glucose conc need to stay between?
3 and 10 mM
After a meal, what can portal vein glucose reach?
20mM (between meals it can decline to almost 0)
What can the liver make ketone bodies from?
Lipid
How can the liver make glucose?
- From glycogen (glycogenolysis)
- From amino acids (gluconeogenesis)
What is glycogenolysis?
Breakdown of glycogen into glucose
What is gluconeogenesis?
Forming glucose from non-carbohydrate molecules (e.g. amino acids)
What is glycogenesis?
Forming glycogen from glucose
What are the sodium/glucose co-transporters?
SGLT1 and SGLT2 (active carrier transport)
What do SGLT1 and SGLT2 take up?
Glucose at the apical brush border
Where does SGLT1 work?
Small intestine, kidney tubules
Where does SGLT2 work?
Kidney proximal tubule
What do SGLT1 and SGLT2 transport along with glucose?
Sodium
What is an enterocyte?
A cell of the intestinal lining
What does SGLT1 pick up at the brush border?
Glucose or galactose
What picks up fructose at the brush border?
GLUT5
What then transports glucose/galactose/fructose from inside the enterocyte (or other tissues) into the capillary?
GLUT2
What are the glucose transporters?
GLUT1-12 (all use facilitated diffusion to transport monosaccharides)
Allow glucose across membranes
Where does GLUT2 work?
Kidney, ileum, liver, pancreatic beta cells
Does GLUT2 have a low or high affinity?
Low (as glucose levels rise, it will very effectively transport more glucose)
Where is GLUT4 found?
Skeletal muscle, heart, adipocytes
What is job of GLUT2?
Takes sugar that has been taken up by gut and transports it out of cells and into circulation
Where does GLUT1 work?
Brain, red cells, endothelium, beta cells (a transporter we use where we always need some uptake of glucose)
What is GLUT4 induced by?
Insulin (when insulin levels are high, cells put this transporter into the membrane so they can take up glucose)
Where does GLUT3 work?
Neurones, placenta
Where does GLUT5 work?
Widely distributed (picks up fructose)
Are the Islets of Langerhans exocrine or endocrine glands? Why?
Endocrine as secreting directly into bloodstream
Describe the blood supply to the Islets of Langerhans?
Arterioles run into the centre of these Islets and then the blood passes through capillaries into the periphery (middle to outside)
What do the beta cells of the pancreas produce?
Insulin
What do the alpha cells of the pancreas produce?
Glucagon
What do the delta cells of the pancreas produce?
Somatostatin
Where are beta cells of the pancreas found?
Mainly central, most abundant
Where are alpha cells of the pancreas found?
At the periphery (i.e. blood picks up insulin at centre then glucagon)
What is a key element of the beta cells of the pancreas regarding insulin secretion?
Have an ATP gated K+ channel in the cell membrane
What happens when lots of ATP is around the beta cells of the pancreas?
K+ channel is not open –> cell depolarises (K+ does not flow out) –> secretes insulin
How does glucose enter the beta cells of the pancreas?
GLUT2 transporter (mediates facilitated diffusion of glucose into cell)
As glucose levels rise, they will transport more glucose in
As glucose is transported into the beta cells of the pancreas, what happen?
Glucose –> ATP (and NADH) (glycolysis and TCA)
What does this increase in ATP (and NADH) inhibit in the beta cells of the pancreas?
Inhibits the K+ channel which causes Vm (membrane potential) to become more positive –> depolarisation
What does the depolarisation (beta cells of the pancreas) activate?
A voltage gated Ca2+ channel in the plasma membrane –> Ca2+ influx
What does Ca2+ influx cause (beta cells of the pancreas)?
Secretion of insulin (by exocytosis)
How do insulin levels differ between oral glucose and injection of glucose?
Much higher spike in insulin if oral, despite lower plasma [glucose]
How do other modulators of secretion of glucose (in beta cells of pancreas) act?
Act via the adenylyl cyclase-cAMP-protein kinase A pathway and phospholipase C-phosphoinositide (PLC) pathway
These increase exocytosis of insulin
How does the parasympathetic NS affect insulin secretion?
Increases
How does the sympathetic NS affect insulin secretion?
Inhibits
What are incretins?
Gut hormones that stimulate insulin secretion (along with high glucose)
What is insulin produced as?
A preprohormone which is quickly cleaved to the prohormone
Internal disulphide bonds fold it up (due to cysteine)
During processing in the Golgi, what is insulin cleaved to give?
A and B chains, which are linked, and a free C peptide
What is the free C peptide a marker of?
Inactive peptide but is a useful marker of endogenous insulin production
What is the insulin receptor?
Tyrosine kinase receptor (enzyme linked)
- Insulin binds to receptor
- Turns on tyrosine kinase
- These start to phosphorylate lots of things
What are the 2 main pathways for insulin signalling?
- Fast pathway –> PI3K and PKB phosphorylate proteins, altering activity (and inserting GLUT4)
- Slow pathway –> MAPK pathway alters gene expression
What are both insulin signalling pathways mediated by?
Insulin Receptor Substrates (IRS)
What does the fast insulin pathway control?
Controls metabolism
What does the slow insulin pathway control?
Longer term growth type changes
Does the liver have insulin receptor?
Yes
Why is the liver always permeable to glucose?
Due to GLUT2
Is there GLUT4 in the liver?
No
What is effect of insulin on the liver?
Increased uptake of glucose:
- Movement of glucose down glycolysis pathway and then into mitochondria favoured
- Glycogen storage increased
- VLDL production increased
- Gluconeogenesis inhibited
- Ketone body production inhibited
What happens when glucose is moved down glycolysis pathway and then into mitochondria in the liver? What then happens?
Acetyl CoA is made –> make it into fatty acids and triglycerides
Liver then packages those as VLDL (storing energy in form of fat)
Is GLUT4 present in muscle?
Yes –> insulin receptors trigger insertion of GLUT4 into membrane and favours use of glucose
Are insulin receptors present in muscle?
Yes
What is effect of insulin on muscle?
Favours glucose over using fatty acids as foodstuff
- Used in TCA to make lots of ATP
- Glycogen, triglyceride, protein synthesis increase
What is effect of exercise on GLUT4?
Via adrenaline, induces GLUT4 and synergises with insulin
Is GLUT4 present in fat?
Yes - insulin receptors trigger insertion of GLUT4 into membrane and favours glucose uptake
What is effect of insulin on fat?
- Triglyceride storage increased (glucose –> fat by stealing Acetyl CoA)
- Export of FFA and glycerol reduced
- Increased expression of LPL which extracts FFA from VLDL
Do type 2 diabetics produce C peptides?
Yes –> still produce insulin but just faulty receptors
Does injected insulin (for type 1 diabetics) contain C peptides?
No
How does insulin affect potassium?
Insulin also increases the permeability of many cells to potassium. Insulin activates sodium-potassium ATPases in many cells, causing a flux of potassium into cells.
What is hyperkalaemia?
High levels of potassium
What are the ranges of normal potassium?
3.5-5.0 mmol/L
What can hyperkalaemia cause?
Slow heartbeat and weak pulse, may result in heart stopping
How can hyperkalaemia be treated?
Give them glucose and insulin –> will load potassium into cells (decreasing plasma [K])
What can hypokalaemia cause?
Cardiac arrhythmias, cardiac arrest
What must you be careful of when seeing a hypoglycaemic patient?
First thought is to load with glucose (especially if they have lots of insulin)
BUT be careful of [K+] levels as glucose will further decrease [K+] levels –> will have to give them K as well if K+ levels are already low
What is glucagon release antagonised by?
Glucose
What is glucagon release driven by?
Amino acids
What is the glucagon receptor in the liver? What does this receptor active?
GPCR, linked to Gs
Activates adenyl cyclase and activates protein kinase A
PKA then phosphorylates enzymes involved in glycolysis and gluconeogenesis
What is effect of glucagon in the liver?
Glycogen breakdown and increases gluconeogenesis (opposite of insulin)
Liver also breaks down some glucagon
How is glucose exported from the liver?
G6Pase
What are fatty acids used by the liver for?
Energy source and ketone body production
What is effect of high levels of glucagon on adipocytes?
Lipolysis
What is effect of high levels of glucagon in muscle?
Proteolysis (releasing AA for gluconeogenesis)
How is most glucagon largely cleared?
By liver (1st pass metabolism)
Where are very high levels of glucagon normally seen?
Pathologically –> ketoacidosis, sepsis etc
What is the shift in metabolism in fat and muscle largely due to?
Decrease in insulin as glucose levels fall
What is somatostatin?
Peptide hormone
Where is somatostatin released from?
D cells of stomach, duodenum and pancreas
What is somatostatin release stimulated by?
Lumenal [H]+
What is somatostatin release inhibited by?
ACh
What are effects of somatostatin?
- Acts on G cells to inhibit gastrin
- Inhibits CCK and secretin (and sometimes insulin and glucagon)
During exercise, what is effect of adrenaline on liver?
Adrenaline signals via cAMP to enhance:
- Glucose production in liver from gluconeogenesis
- Glycogen breakdown
What is effect of adrenaline on muscle? Where do waste products go?
Glycolysis (to make ATP)
Type 2 muscle –> Pyruvate and lactate go back to liver for gluconeogenesis (Cori cycle)
Type 1 muscle –> uses pyruvate in TCA cycle, takes lactate from type 2 and turns into pyruvate to be used
What is effect of adrenaline on adipocytes?
Triacylglycerol breakdown (fatty acid release)
What are effect of diabetes mellitus?
- Polyuria
- Polydipsia (excessive thirst due to dehydration)
- Weight loss (due to peeing out sugar and energy)
- Blurred vision
- Ketoacidosis (type 1) (due to lack of insulin so livers are fooled into starvation so lots of production of ketone bodies)
What is ketoacidosis?
Ketoacidosis is a metabolic state caused by uncontrolled production of ketone bodies that cause a metabolic acidosis. While ketosis refers to any elevation of blood ketones, ketoacidosis is a specific pathologic condition that results in changes in blood pH and requires medical attention.
What is the primary defect in type 1 diabetes?
Inability to produce enough insulin –> autoimmune disease in which beta cells of pancreas are destroyed
Lots of food around but cells can’t use it
In type 1 diabetes, what can excess glucagon or insulin:glucagon imbalance lead to?
- Lipolysis
- Proteolysis
- Gluconeogenesis and ketogenesis in liver
What is the primary defect in type 2 diabetes?
Can make insulin but impaired cellular response to insulin
- Receptor downregulation
- Reduced signalling
What is type 2 diabetes strongly associated with?
Obesity
Difference in type 1 and 2 diabetes onset time?
1 –> Early onset (10-14 years)
2 –> Late onset (40s-60s)
Describe weight of typical type 1 and 2 diabetes patients?
1 –> Generally lean
2 –> Generally overweight
Describe onset of type 1 and 2 diabetes?
1 –> Rapid onset (days to weeks)
2 –> Gradual onset (years_
Which type of diabetes presents autoantibodies?
Type 1
Which type of diabetes are HLA markers present?
Type 1
Describe the insulin conc in type 1 and 2 diabetes?
1 –> low plasma insulin conc
2 –> insulin resistance (plasma insulin conc may be low, normal or high)
What can trigger type 2 diabetes?
Poor diet / lack of exercise
Describe incidence of ketoacidosis in type 1 and 2 diabetes?
1 –> Ketoacidosis is common
2 –> Ketoacidosis unusual
Which type of diabetes requires exogenous insulin?
Type 1
What drugs are used in type 2 diabetes?
- To enhance insulin secretion
- To enhance insulin sensitivity
- To inhibit gluconeogenesis
Can diet transform type 2 diabetes?
Yes –> healthy eating and exercise
What is effect of insulin on lipolysis and proteolysis?
Reduces
