Week 1 Flashcards
How can insulin resistance cause hypertension
Insulin resistance increases sodium retention hence water = increase in blood volume
Activates the sympathetic nervous system = increased vasoconstriction
How can insulin resistance cause atherosclerosis
Insulin resistance decreases lipoprotein lipase activity so clearance of VLDL decreases
Increase in VLDL = increase in LDL
How can insulin resistance cause steatosis -> steatohepatitis -> cirrhosis
Insulin inhibits lipolysis which breaks down fatty acids
= increased fatty acid level in blood
= more fatty acids to liver (steatosis)
fatty liver triggers inflammation -> steatohepatitis
Fibrosis due to chronic inflammation -> cirrhosis
Describe the likely insulin level and blood sugar level in early type 2 diabetic patients
High insulin
High blood glucose level
Why is there high insulin level and high blood sugar level initially in type 2 diabetic patients
Insulin resistance; cells in the body does not respond to insulin but beta cells are still producing insulin. This causes beta cells to produce more insulin to try decrease blood glucose level
Which hormone stimulates lipolysis
Glucagon
Which cluster of cells in the pancreas regulate blood sugar level
Islet of Langerhans
Which cell in the pancreas secretes insulin
Beta cells of islets of Langerhans
Which cell in the pancreas secretes glucagon
Alpha cells of islets of Langerhans
Effect of insulin
Inhibit hepatic glucose production
Inhibit lipolysis
Stimulate glucose uptake in cells
Stimulate storage of glucose as glycogen in cells
= lowers blood sugar level back to normal
Effects of glucagon
Stimulate hepatic glucose production
Stimulate Lipolysis
= increases blood sugar level back to normal
In mM, what is the fasting blood sugar level considered as diabetes
above 7mM
In mM what is the fasting blood sugar level considered as pre-diabetes
6-7mM
Why is it important to recognize pre-diabetics
Because they have very high risk of developing into diabetes hence we should start prevention treatment asap
What is the likely insulin level and blood sugar level in type 1 diabetics
low insulin and high glucose level
When can insulin become poisonous
When injected to a normal healthy person.
It can cause hypoglycaemic coma
What are the cells of islets of Langerhans
Beta cells
Alpha cells
Delta cells
PP cells
What is the function of delta and PP cells
Regulatory cells; they regulate beta and alpha cells
What blood glucose level is considered as hypoglycaemia and what is at risk
<4mM
Hypoglycaemia coma
What hormone does delta cells produce and what is its function
Somatostatin
Inhibit release of pancreatic enzymes, hormones (insulin, glucagon)
Inhibit release of gastrin and secretin (when acted on the gut)
Decrease motility of the gut
How is insulin formed in beta cells
Synthesized in RER as larger chain of polypeptide preprohormone -> cleaved -> proinsulin -> cleaved -> insulin
Which chain is cleaved in proinsulin to form active insulin
C chain
What peptide chains are in proinsulin
A, B, C chains
What peptide chain is used to measure insulin secretion
C peptide chain
In relation to the peptide chains of insulin, what data would suggest that the insulin was injected
Cannot detect C peptide chain but can detect insulin
Endogenous insulin came from cleavage of C chain from proinsulin hence C chain must be present if the insulin was made by the body
Example of an ultra fast acting synthetic insulin
Lispro
Mechanism of lispro
Swaps lysine and proline amino acids in B chain of active insulin to make it faster acting
Short action of Lispro means that
Lispro cannot be administered on its own. Needs to be administered with another longer acting insulin
Example of a ultra long acting synthetic insulin
Glargine
Mechanism of Glargine
Adds 2 argine amino acids at the end of B chain to cause prolonged action
When is Lispro usually injected
Within 15 minutes of beginning a meal
When is Glargine usually injected
Single bedtime dose
Which intracellular enzyme phosphorylates glucose
Glucokinase
Which transporter allows glucose to move into beta cell
GLUT2
What happens once the glucose enters the beta cell
1) Glucose enters cell through GLUT2
2) Glucose phosphorylated into glucose 6 phosphate by glucokinase
3) glucose 6 phosphate used to produce ATP
How is insulin secreted
1) Because presence of ATP closes ATP sensitive K+ channels which stops K+ from leaving the cell
2) Causes cell to become hyperpolarised
3) Activates voltage gated Ca2+ channels
4) Ca2+ move into cell
5) Presence of Ca2+ stimulate release of insulin
What happens to beta cells in type 1 diabetes compared to type 2
In type 1, most beta cells are lost
In type 2, beta cells are present but lose their ability to sense changes in blood glucose level
How do beta cells lose their sensitivity to blood glucose level in type 2 diabetics
Hyperglycaemia causes blood glucose level to be outside the Km of glucokinase
Outside Km, change in glucose level only leads to small change in activity of glucokinase
= reduced sensitivity
What does a definitive diagnosis of Type 1 diabetes require
Presence of specific autoantibodies
Declining C peptide production (=less insulin produced)
What happens to beta cells in type 2 diabetics over a period of time
Beta cell mass decreases
Reduction in insulin secretion (secretory failure)
Why do beta cells lose their function at late stages of diabetes
Mitochondrial exhaustion
Run out of insulin stores
What is gestational diabetes
Diabetes diagnosed for the first time during pregnancy (24-28 weeks)
Why is the diagnostic criteria for gestational diabetes lower than other forms of diabetes
Because gestational diabetes comes with significant risk of increased weight of offspring at birth = can be dangerous for the mother and baby during delivery
What is the criteria for gestational diabetes
Fasting blood sugar level >5.6
2 hour glucose > 7.8
What is the fasting blood glucose criteria for diabetes
Fasting blood sugar level >7
What is the 2hr oral glucose tolerance test criteria for diabetes
> 11.1
What is overt diabetes
Pregnant woman diagnosed with diabetes for the first time at the first antenatal visit (early pregnancy
What is the criteria does overt diabetes
Same as other forms of diabetes (not gestational).
>7 FBG
>11.1 2hr OGTT
What is the threshold of diabetes based on
The risk of developing retinopathy
What is type 1 diabetes
Autoimmune destruction of beta cells resulting in beta cell deficiency
What is type 2 diabetes
Insulin resistance + relative insulin deficiency progressing to insulin secretory defect + insulin resistance
Risk factors of type 2 diabetes
Obesity
Poor dietary habits
PCOS
Family history
History of gestational / overt diabetes
What occurs in skeletal muscle when insulin binds
1) Insulin binds to INSR (insulin’s receptor)
2) Stimulates downstream phosphorylation
3) GLUT4 then moves from the cytoplasm up to the cell membrane
4) Enables glucose uptake
5) Glucose phosphorylated by glucokinase into glucose 6 phosphate
6) glucose 6 phosphate can then be used to generate ATP / stored as glycogen
What occurs in skeletal muscles in insulin resistance
1) Decreased activity of INSR hence decreased downstream phosphorylation
2) Less GLTU4 transported to cell membrane
3) decreased glucose uptake
Mechanism of obesity induced inflammation
1) Obesity triggers JNK and NF alpha B inflammatory cytokines
2) JNK triggers phosphorylation of Ser IRS1
3) this inhibits phosphorylation of Tyr IRS1 which is used to signal insulin
4) JNK and NF alpha B also initiates gene expression of pro inflammatory cytokines
5) pro inflammatory cytokines travel by blood to cause systemic effects
What are the sub units of ATP induced K+ channels in beta cells
Kir6
SUR1 (sulphonylurea receptor)
Function of ATP sensitive K+ channels
K+ channels are closed to hyperpolarise the beta cell in order to activate the voltage gated Ca2+ channels -> release insulin
What conditions are caused by mutations in ATP sensitive K+ channels
Neonatal diabetes
Congenital hyperinsulinism
Which drug can allow neonatal diabetics to recover euglycaemia quickly and why
Sulphonylurea because the SUR1 subunit still responds to binding of Sulphonylurea
Which drug can inhibit insulin secretion in congenital hyperinsulinism
diazoxide
Diabetic ketoacidosis is most commonly seen in which type of diabetes
Type 1
How does diabetic ketoacidosis occur
1) Not enough insulin so not enough glucose being transported into cells
2) causes hypergylcaemia
3) Causes the body to use fatty acid oxidation for fuel which produces ketones
4) level of ketones build up and cause acidosis
5) Hyperglycaemia causes osmotic diuresis (increased urination) and hypovolaemia
6) hypovolamia exacerbates acidosis
7) causing severe electrolyte derangement, coma, possibly death
Risk factors for diabetic ketoacidosis
Type 1 diabetes
Non-compliance to drugs
Infection
Inappropriate drug dose
Symptoms of diabetic ketoacidosis
Polydipsia (extreme thirst)
Polyuria
Hypotension
Ketotic breath (acidic)
Vomiting
Confusion
Kussmaul breathing
Management for diabetic ketoacidosis
Fluid resuscitation
Insulin
Symptoms of diabetes
Blurred vision
Polyuria
Polydipsia
Fatigue
Weight loss