5.2 Diabetes Mellitus Flashcards
What stimulates insulin secretion?
In response to:
Increase glucose
Incretin (GLP-1, GIP)
PS activity (M3)
What is he plasma half life of insulin?
5 minutes
What inhibits insulin release?
Decrease plasma glucose levels
Cortisol
Sympathetic activity at alpha2 receptors
What is the role of insulin?
Inhibition of gluconeogenesis and glycogenolysis
Increasing glycogen stores
Promote uptake of glucose into tissues
Describe the pattern of secretion of insulin
- secreted into the blood even during fasting to prevent receptor downregulation
- biphasic pattern of insulin release due to rate and extent of plasma glucose concentration following a meal
What are common signs and symptoms of T1DM?
Polydipsia Polyuria Weight loss Fatigue/lethargy Blurred vision Hyperglycaemia
What test result are indicative of T1DM?
Fasting glucose of more than 6.9mmol/L
Random plasma glucose greater than 11mmol/L
Plasma or urine ketones in presence of hyperglycaemia.
HbA1c of greater than 48mmol/mol
What does HbA1c represent?
The percentage of RBC with a sugar coated ( glycated haemoglobin). Reflects the average blood sugar over the last 10-12 weeks mmol/mol
What is the biochemical triad of diabetic ketoacidosis?
Hyperglycaemia
Ketonaemia
Acidosis
When should diabetic ketoacidosis be suspected?
Blood glucose of great than 11mmol/L
AND
polydipsia, polyuria, abdominal pain, V+D, lethargy, confusion, visual disturbance, acetonic breath, symptoms of shock
What are the precipitating factors for diabetic ketoacidosis?
Infection, trauma, non-adherence to insulin treatment, DDIs
How is DK treated?
I.V. Infusion of fluids with Potassium and then
I.V. Infusion of soluble insulin.
When might a patient be in DK and euglycaemic?
When T1DM haven’t eaten for a long time
What are the different types of therapeutic insulin’s used?
Porcine
Bovine
Human insulin (recombinant DNA or enzymatic modification of porcine)
Why must insulin be given parenterally?
As insulin is a protein and will be digested in the gut so oral administration not suitable
How is insulin usually administered?
- Subcutaneous injection into adipose
- I.V. Injection used in emergency
What methods are used to reduce the absorption of insulin?
- Protamine and/or zinc complex with natural (bovine/porcine) insulins – used less now
- Soluble (neutral) insulin forms hexamers – delaying absorption from site of injection. [plasma] greatest after 2-3 hr – dosing 15-30 min prior to meals often prescribed
- Insulin analogues – recombinant modifications – a few amino acid changes – changes PK not PD
Why is it important to rotate site of administration of insulin?
Reduce lipodystrophy
What devices are commonly used in insulin administration?
Syringes
Pens
Pumps
Inhalers
What are the adverse effects of insulin?
Hypoglycaemia
Lipodystrophy
What are the contraindications of insulin?
Renal impairment - hypoglycaemia risk
What are the important drug interactions of insulin?
Does of insulin needs increasing with systemic steroids.
Caution with other hypoglycaemic agents
What is basal bolus dosing?
A common dosing schedule for young active T1DM patients. Provides some flexibility. Take 2 insulin medications, 1. Rapid acting bolus 30mins before each meal e.g. aspart 2. Long acting basal once a day e.g. glargine
What is diabulimia?
When a T1DM stops or reduces their insulin to control their weight
Why is insulin administered s.c and not P.o?
As it is a peptide hormone that would be digested in the gut.
What is the difference between [glucose] and HbA1c? What information do they provide?
[glucose] = plasma glucose concentration at that moment in time. Measured in mmol/L HbA1c = glycated haemoglobin, reflects average blood sugar level over last 10-12 weeks mmol/mol
Would you need to increase or decrease insulin dosing in a patient with renal impairment?
In renal impairment the dosing of insulin should be reduced as insulin in excreted through the renal system. Normal dosing could result in hypoglycaemia as the insulin remains for longer
Why does insulin need to be modified or analogues used? How does this change PK properties?
Modified to produce 2 different kinds of insulin analogues. Fast acting bolus (aspart) and slow acting basal (glargine)
Changes the absorption
What is the causation of T2DM?
Insulin into cells reduced due to cellular resistance associated with obesity.
How is T2DM managed?
Education Weight loss - surgery Initially non-insulin therapies. Insulin in poorly managed or later stage disease Treat co-morbidities
Give an example of a biguanide?
Metformin
What is the mechanism of action of metformin?
Decreased hepatic glucose production by inhibiting gluconeogenesis. Some gluconeogenesis remains so risk of hypoglycaemia reduced.
Suppress appetite, limit weight gain.
What are the adverse affects of biguanides?
GI upset - nausea, vomiting, diarrhoea
What are the contraindications of metformin?
Excreted unchanged by kidneys - stop if EGFR is <30mL/min (CKD stage 4/5)
Alcohol intoxication
What are important drug interactions of biguanides?
ACEi, diuretics, NSAIDs - drugs that may impair renal function
Loop and thiazide like diuretics that increase glucose reabsorption so can reduce metformin action
Give an example of sulfonylureas
Gliclazide
How does gliclazide work?
Stimulates pancreatic insulin secretion by blocking ATP-dependant K+ channels
Decreased K+ in the cell causes membrane depolarisation causing calcium influx.
Need residual pancreatic function to work (no use for T1DM)
What are the indications for gliclazide?
Used in combination with other agents (metformin) for the treatment of T2DM
Flirt line option if metformin contraindicated
What are the adverse effects of sulfonylureas?
mild GI upset – nausea, vomiting, diarrhoea, hypoglycaemia (works at low [glucose])
Weight gain through anabolic effects of insulin
What are the contraindications of gliclazide?
Hepatic and renal disease - caution as at risk of hypoglycaemia
What are the important drug interaction of gliclazide?
Other hypoglycaemic agents
Loop diuretics and thiazide like can increase glucose so reduce action of sulfonylureas
Give examples of thiazolidinediones?
Pioglitazones
Rosiglitazone
What is the mechanism of action of glitazones?
Insulin sensitisation in muscle and adipose, ↓hepatic glucose output by activation of PPAR-γ → gene transcription
Why do glitazones take a long time to cause benefit?
As mechanism of decreasing hepatic glucose output is via gene transcription. This takes time and can take 6-8 weeks to show any benefit
What are the side effects of glitazones?
GI upset, fluid retention, fracture risk, bladder cancer, weight gain
What are the warnings and contraindications of glitazones?
Heart failure because of fluid retention
Give examples of SGLT-2 inhibitors
Dapagliflozin
Canagliflozin
What is the mechanism of action of gliflozins?
Competitive reversible binding at the SGLT-2 in the PCT
Decreases glucose reabsorption at the kidneys and increases urinary glucose excretion. Causes modest weight loss and the hypoglycaemic risk is low.
What are the indications of gliflozins?
Adjunct to insulin in TIDM (high BMI)
TIIDM as add on therapy
What are the side effects of gliflozins?
UTI and genital infection
Thirst and polyuria
What a re the contraindications of gliflozins?
DKA in T2DM
Hypotension
What are the drug interactions with gliflozins?
Antihypertensives
Other hypoglycaemic agents
What are the physiological effects of GLP-1?
Pancreas - increase insulin biosynthesis and secretion, decrease glucagon secretion Brain - increased satiety Liver- decreased glucose production Muscle - increased glucose uptake Stomach - decreased gastric emptying
Give examples of Dipeptidyl peptidase -4 inhibitors
Sitagliptin
Saxagliptin
What is the mechanism of action of gliptins?
Prevent incretin (GLP-1) degradation - increases plasma incretin concentrations. Glucose dependant so postprandial action. Do not stimulate insulin secretion at normal blood glucose - lower hypoglycaemic risk. Suppress appetite (weight neutral)
What are the side effects of gliptins ?
GI upset, small pancreatitis risk
What are the contraindications of gliptins?
Pregnancy
History of pancreatitis
What are the important drug interactions of gliptins?
Other hypoglycaemic drugs
Loop and thiazide like diuretics
Give examples of glucagon-like peptide-1 receptor agonists?
Exenatide
Liraglutide
Aka incretin mimetics
Describe the mechanism of action of Exenatide
↑glucose dependant synthesis of insulin secretion from β-cells
activate GLP-1 receptor – resistant to degradation by DPP-4
Why are GLP-1 receptor agonists given subcutaneously?
As they are peptides and would be digested if given orally.
When are GLP-1 receptor agonists indicated?
NICE suggest add-on if triple therapy ineffective
What are the side effects of GLP-1 receptor agonists ?
GI upset, decreased appetite with weight loss
When are GLP-1 receptor agonists contraindicated?
Renal impairment
Wh must extended release metformin tablets be swallowed whole?
As usually it is the capsule coating that is causing the modification and slows the absorption. Breaking the capsule would mean the dose was absorbed quicker than desired.
Metformin can come in combination tablet options. What are the advantages and disadvantages of these options?
Advantages : improved adherence
Disadvantages: difficult to modify doses
Why is there particular caution for metformin in patients with impaired renal function?
As metformin is excreted without being metabolised. If the glomerular filtration rate is impaired then metformin wont be excreted as quickly.
Why do sulfonylureas tend to promote weight gain?
Gliclazide stimulate insulin release by blocking the ATP-dependant K+ channels. As more insulin released, this promotes anabolic reactions and weight gain.
Why do incretin mimetics have a low risk of hypoglycaemia compared to other hypoglycaemic agents?
Incretin mimetics are GLP-1 receptor agonists and increase the synthesis of insulin dependant on levels of glucose.
Why is the duration of action of glitazones such as pioglitazone not related to the T1/2?
As glitazones act via the PPAR-gamma gene causing gene transcription that results in increase insulin sensitisation in muscle and adipose tissue. Gene transcription can take take and benefit from drug can take 6-8 weeks.
For most patients what is the first hypoglycaemic agent that would be prescribed?
Metformin
