Session 5: Diabetes Flashcards
What stimulates insulin secretion?
Increase in glucose
Incretins like GLP-1 and GIP
Glucagon
Parasympathetic activity via M3
What is insulin inhibited by?
Decrease in glucose
Cortisol
Sympathetic activity (alpha 2)
Role of insulin
Reduce hepatic glucose output via inhibition of gluconeogenesis
Inhibits glycogenolysis
Promotes uptake of fats
Diagnostic criteria of diabetes.
Hyperglycaemia with a random plasma glucose >11 mmol/l
Some symptoms such as polyuria, polydipsia, weight loss, fatigue/lethargy.
Single raised plasma glucose without symptoms is not sufficient.
Risk factors of type 2 diabetes.
Obesity
FH
Ethnicity
Diet
Drugs like thiazides, glucocorticoids and b-blockers
Low birth weight
Ways to investigate diabetes.
Glucose levels in blood
HbA1c levels (glycated haemoglobin) which reflects the average blood sugar over last 10-12 weeks.
What is insulin made from?
Human insulin via recombinant DNA and reproduced via bacteria or yeast.
Or
Enzymatic modification of porcine insulin.
How is insulin given and why?
Parenterally to avoid digestion in the gut.
This is because it is a protein.
Routine administration of insulin.
Subcutaneous injection in upper arms, thighs, buttocks or/and abdomen.
IV is only given for emergencies.
Pharmacokinetics of insulin.
Half-life of 5 minutes in plasma and both renal and hepatic metabolism as well as elimination.
When should insulin be given?
15-30 min prior to a meal.
Why might protamine and/or zinc be given in the same dose as insulin?
To modify absorption.
What are insulin analogues and why might they be given?
A lab-grown modification of insulin to make it for example more rapidly acting.
Why is it important to rotate the site of administration of insulin?
Because given in the same spot can lead to lipodystrophy.
What are insulin aspart and insulin glargine?
Insulin analogues
What is Ispophane/NPH insulin?
Insulin mixed with protamine and zinc.
This gives a slower acting insulin
Are combinations of insulin prescribed?
Yes.
Short and long acting mixtures of insulin can be prescribed and they may be taken separately.
How might insulin be administered? (what equipment)
By syringes, pens, pumps or inhalers
ADRs of insulin
Hypoglycaemia
Lipohypertrophy
Lipoatrophy
Also renal impairment leads to a higher risk of hypoglycaemia.
When should you not take/be careful insulin?
When with steroids
Other hypoglycaemic agents
Give an example of a bolus dosing insulin.
Insulin Aspart which is rapid acting
Give an example of a basal dosing insulin.
A long acting such as Insulin glargine
What is diabetic ketoacidosis?
Hyperglycaemia
Acidosis
Ketonaemia
When should you suspect DKA?
When blood glucose is above 11 mmol/l and there is:
an infection
Stress or trauma
Poor insulin adherence
ADRs
ketosis
Hyperglycaemi may not always be present and it can also present with low blood ketones.
Treatment of DKA
Prioritise fluids due to huge diuresis and then you give insulin.
You may also give glucose and K+ in order to not make them go hypoglycaemic or hypokalaemic.
How is the insulin resistance usually overcome in T2DM?
By increased pancreatic insulin secretion.
What will the increase in pancreatic insulin secretion lead to?
Decrease in expression of insulin receptors and therefore less GLP-1 secretion in response to oral glucose as well.
How does beta-cell dysfunction happen in T2DM?
Glucotoxicity from fatty acids and ROS will cause beta-cell dysfunction.
What are the initial treatments of T2DM?
Lifestyle modifications
Education
Surgery
Why might adherence be low when been given insulin?
Due to perceived hypoglycaemia and perceived weight gain.
First line treatment of T2DM if HbA1c rises to 6.5% on lifestyle modifications.
Standard-release metformin
What is given if standard-release metformin is not tolerated?
Modified release metformin
If HbA1c still rises to 7.5% what is the next line of treatment?
Dual therapy with metformin and…:
DPP-4 inhibitors
Pioglitazone
An SU (gliclazide)
SGLT-2 inhibitor
If dual therapy isn’t effective what is considered?
Tripe therapy of metformin, SU and…
DPP-4i
Pioglitazone
Give an example of a biguanide.
Metformin
Explain the mechanism of metformin.
Inhibition of gluconeogenesis and glycogenolysis
Also an increase in the glucose utilisation in skeletal muscle.
It also supress appetite
Why might metformin have a better adherence than insulin?
Because it limits weight gain due to the suppression of appetite.
It is also taken in tablet form.
ADRs of metformin.
Nausea
Vomiting
Diarrhoea
Lactic acidosis
When should you be wary or not take metformin?
When eGFR is <30 ml/min
ACEi
Diuretics
NSAIDs
Any drugs really that can impair renal function.
Thiazide like diuretics
Why might metformin not work well with thiazide like diuretics?
Because thiazide like diuretics can lead to increase in blood glucose and reduce metformin action.
Mechanism of sulfonylureas.
Stimulate beta-cell pancreatic insulin secretion by blocking the ATP-dependant K+ channels. This leads to decrease in K+ conductance and membrane depolarisation.
The membrane depolarisation leads to an influx of Ca2+ and the Ca2+ binds to the insulin vesicle and insulin is released.
What are sulfonylureas dependant on to work?
Residual pancreatic function.
If the beta-cells are destroyed then there is no insulin to be secreted.
Why might adherence be worse with sulfonylureas than metformin?
Because of weight gain due to the anabolic effects of insulin
When are sulfonylureas given?
In combination with other agents like dual or triple therapy or as a first line option if metformin is contraindicated.
Give an example of a sulfonyurea.
Gliclazide
ADRs of gliclazide.
Mild GI upset
Nausea, vomiting and diarrhoea
Hypoglycaemia
Some rare hypersensitivity reactions
When should you not take gliclazide or be careful with it?
When taking other hypoglycaemic agents
Hepatic impairment
Renal impairment
Thiazide like diuretics leading to increased glucose.
Explain the mechanism of Thiazolidinediones (glitazones)
Activation of PPAR-gamma. This leads increase insulin sensitivity where glucose is taken up by muscle and adipose tissue and that leads to reduced hepatic glucose output and lowered blood glucose.
Why might adherence be worse with glitazones than with metformin?
Because glucose is turned into TAGs causing fat cell differentiation and weight gain.
ADRs of glitazones.
GI upset
Fluid retention
Fracture risk
CVD concerns
Bladder cancer
When should you be careful or wary of prescribing glitazones?
When the patient is on other hypoglycaemic agents
Give examples of glitazones.
Pioglitazone
Rosiglitazone
Explain mechanism of SGLT-2 inhibitors.
Less glucose absorption from tubular filtrate leading to increased urinary glucose excretion.
They are competitive reversible inhibitors of SGLT-2 in PCT.
SGLT-2 inhibitors and weight.
Modest weight loss and a low risk of hypoglycaemia.
When are SGLT-2is given?
Used in type 1 diabetes but with a risk of DKA.
Used for type 2 as add on therapy.
ADRs of SGLT-2i
UTI
Genital infection
Thirst
Polyuria
Contraindications of SGLT-2i
Antihypertensives
Hypoglycaemic
Examples of SGLT-2i
Dapagliflozin
Canagliflozin
Physiological effects of GLP-1 (an incretin)
Glucagon-like peptide
Explain mechanism of DPP-4is
Prevent incretin degradation leading to increased plasma incretin levels.
The incretins glucose dependant so postprandial action.
Why is the risk of hypoglycaemia low with DPP-4is?
Do not stimulate insulin secretion at normal blood glucose.
Incretins are dependant on glucose to stimulate the insulin secretion.
DPP-4 inhibitors and weight.
Supress appetite meaning weight neutral.
When are DPP-4is given?
Combination with other agents or a first line option if metformin is contraindicated.
ADRs of DPP4i.
GI upset
Small pancreatitis risk
Avoid in pregnancy
Contraindications of DPP-4i
Hypoglycaemic agents
Drugs that increase glucose blood can oppose the action such as thiazide like diuretics and loop diuretics.
Give examples of DPP4-is.
Sitagliptin
Saxagliptin
Explain mechanism of GLP-1 receptor agonists.
Glucose dependant synthesis of insulin secretion from Beta-cells activate GLP-1 receptor and are not degraded by DPP-4.
They are incretin mimetics.
How are GLP-1 receptor agonists administered?
Subcutaneous injection
GLP-1 receptor agonists and weight.
Promote satiety
When is GLP-1 receptor agonist prescribed?
Add-on if triple therapy ineffective.
ADRs of GLP-1 receptor agonists.
GI upset
GORD
Contraindications of GLP-1 receptor agonists.
Stop if eGFR <30 ml/min
Other hypoglycaemic agents
Why is modified release commonly used in diabetes treatment?
Less GI upset, less frequent dosing and a slower release.
Why are tablets swallowed whole?
So it isn’t released and absorbed to quickly
What is diabulimia?
Diabetes eating disorder
Why caution of metformin in impaired renal function?
Can lead to lactic acidosis because of build up of lactate due to inhibition of gluconeogenesis and therefore the cori cycle.
Normally the kidneys can deal with this but if impaired it can lead to build up and lactic acidosis.
Why do sulfonylureas tend to promote weight gain?
Stimulate secretion of insulin and weight gain through the anabolic effects of insulin.
How is insuline release controlled at site of injection?
It’s in soluble form. This means that it forms hexamers in order to not get absorbed all at once.
