9. Diabetes mellitus Flashcards
What increases secretion of insulin?
- ↑glucose
- incretins (GLP-1, GIP)
- glucagon
- parasympathetic activity (M3)
What decreases secretion of insulin?
- ↓glucose
- cortisol
- sympathetic activity (α2)
What is the role of insulin?
- ↓hepatic glucose output via inhibition of gluconeogenesis
- Inhibits glycogenolysis
- Promotes uptake of fats
describe insulin regulation
- Secreted into blood even during fasting – prevents receptor downregulation
- Rate and extent of [glucose] change leads to biphasic pattern of insulin release
what are the symptoms of diabetes?
- polyuria – waking in the night is common
- polydipsia
- weight loss
- fatigue/lethargy
- generalised weakness
- blurred vision
How is diagnosis of diabetes made?
- Hyperglycaemia – fasting glucose ≥ 6.9 mmol/L or random plasma glucose ≥ 11 mmol/L
- Plasma or urine ketones in presence of hyperglycaemia
- HbA1c ≥ 48 mmol/mol (≥6.5%)
- Single raised plasma glucose without symptoms not sufficient for diagnosis
Glucose vs HbA1c
• Glucose – immediate measure of glucose levels in blood mmol/L (mg/dL – USA)
• HbA1c – haemoglobin A1c – glycated haemoglobin - percentage of red blood cells with “sugar
coating” – reflects average blood sugar over last 10-12 weeks – mmol/mol or %
What are the risk factors for type 2 diabetes?
- Obesity - 80-85% of risk
- Family history
- Ethnicity
- Diet
- Drugs - thiazides/thiazide-like, glucocorticoids and β-blocker
- Low birth weight?
WHat is the triad with DKA?
Hyperglycaemia, Acidosis, Ketonaemia
When might you suspect DKA?
*blood glucose >11 mmol/L AND…..
polydypsia, polyuria, abdominal pain, V+D, lethargy, confusion, visual disturbance, acetonic breadth, symptoms of shock
*Hyperglycaemia may not always be present
what are precipitating factors of DKA?
infection, trauma, non adherence to insulin treatment, DDIs
what should be tested for in DKA?
Test for ketones – urine and or blood
What is the priority when treating DKA?
i.v.i. fluids (with K+) and then i.v.i. soluble insulin
initial SBP and [K+] dictate precise treatment regimen
How must insulin be given and why?
Must be given parenterally to avoid digestion in the gut - as it is a protein
where is insulin usually obtained from?
- Historically bovine and porcine
* now Human insulin - recombinant DNA (bacteria/yeast) or enzymatic modification of porcine
How is insulin usually formulated?
Usually formulated in 100 units/mL
obesity and insulin resistance
300 and 500 units/mL available to reduce volume
How is insulin usually administered?
- Routine delivery by s.c. injection upper arms, thighs, buttocks, abdomen
- i.v.i. for emergency treatment
What is the half life of insulin and where is it metabolised and eliminated?
t1/2 - ~ 5 minutes in plasma - renal and hepatic metabolism and elimination
what are ways in which insulin preparations can be made to slow absorption?
- 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?
Avoid lipodystrophy
Give an example of rapid acting insulin.
Insulin aspart
Give examples of short acting insulin.
Soluble insulin - Humulin S, Actrapid
Give an example of intermediate acting insulin.
Isophane insulin (NPH)
Give an example of long acting insulin.
Insulin glargine
What is basal-bolus dosing?
Using rapid acting and long acting insulin to mimic normal levels of insulin
e.g. glargine BID (basal), aspart before meals (bolus)
what are ways in which insulin can be administered?
Syringes, pens, pumps, (inhalers?)
what are adverse effects of insulin?
hypoglycaemia, lipodystrophy – lipohypertrophy or lipoatrophy
what are warnings, contraindications of insulin?
Renal impairment - hypoglycaemia risk
what are important drug interactions of insulin?
dose needs increasing with systemic steroids caution with other hypoglycaemic agents
what are Emerging therapeutics for diabetes?
- Immunotherapy – monoclonal antibodies for high risk groups – delay progression
- Islet transplantation?
- Islet cell regeneration?
- Inhaled insulin – pharmaceutical challenge but for fast acting pre meal, doing challenges and problems for asthma and COPD patients
- SGLT-2 inhibitors – TI and TII DM and other possibly cardiovascular diseases
what happens in type 2 diabetes?
• Insulin into cells reduced due to cellular resistance associated with obesity
• Insulin resistance initially overcome by increased pancreatic insulin secretion but…
↓insulin receptors – ↓GLP-1 secretion in response to oral glucose and response reduced at β- cells and eventually insulin production reduced
How is the blood sugar rise different in type 1 and 2 diabetes?
• Blood sugar rise typically slower than TIDM so variable symptoms – often diagnosed through midlife “MOT”
what are non pharmacological treatments for type 2 diabetes?
• Lifestyle!!!, education Weight loss (surgery in more and more instances)
is insulin given to patients with type 2 diabetes?
- Initially non-insulin therapies
- Insulin may form part of treatment plan in poorly managed or later stage disease
- Treat comorbidities – part of overall reduction in cardiovascular risk
What are the different drugs used in treatment of type 2 diabetes? (6)
- biguanides (e.g. metformin)
- sulfonylureas (e.g. gliclazide)
- thiazolidinedione(glitazones)
- SGLT-2 inhibitors
- DPP4 inhibitors
- GLP1 agonists
How do Biguanides work?
- ↓hepatic glucose production by inhibiting gluconeogenesis
* Supress appetite so limit weight gain
does biguanides have a risk of hypoglycaemia?
ome gluconegenic activity remains so hypoglycaemia risk reduced
adverse effects of biguanides?
GI upset – nausea, vomiting, diarrhoea
warnings, contraindications of biguanides?
excreted unchanged by kidneys – stop if eGFR < 30 mL/min, alcohol intoxication
important drug reactions of biguanides?
ACEi, diuretics, NSAIDs – drugs that may impair renal function
loop and thiazide like diuretics ↑glucose so can reduce metformin action
Give an example of Biguanides.
Metformin
which drug is offered first to type 2 diabetic patients?
Metformin
can be taken concomitantly with other hypoglycaemic agents
How do sulfonylureas work?
- Stimulate β-cell pancreatic insulin secretion by blocking ATP-dependant K+ channels
- Need residual pancreatic function
- Weight gain through anabolic effects of insulin
how are sulfonylureas typically prescribed?
Typically in combination with other agents or a first line option if metformin contraindicated
adverse effects of sulfonylureas
mild GI upset – nausea, vomiting, diarrhoea, hypoglycaemia (works at low [glucose])
warnings, contraindications of sulfonylureas
hepatic and renal disease – caution, those at risk of hypoglycaemia
important drug reactions of sulfonylureas
Other hypoglycaemic agents,
loop and thiazide like diuretics ↑glucose so can reduce SU action
Give an example of sulfonylureas?
gliclazide
How do thiazolidinediones/glitazones work?
• Insulin sensitisation in muscle and adipose, ↓hepatic glucose output
- activation of PPAR-γ nuclear receptor → gene transcription which leads to increased adipogenesis
- t1/2 not related to duration of action - 6-8weeks
- Weight gain - fat cell differentiation
Are Thiazolidinediones/glitazones frequently prescribed?
Used much less frequently and other agents
adverse effects of thiazolidinediones/glitazones
GI upset, fluid retention, fracture risk, bladder cancer
warnings, contraindications of thiazolidinediones/glitazones
heart failure because of fluid retention
important drug reactions of thiazolidinediones/glitazones
other hypoglycaemic agents
Give 2 examples of thiazolidinediones.
pioglitazone, rosiglitazone
how do Sodium-glucose co-transporter (SGLT-2) inhibitors (gliflozins) work?
- ↓↓glucose absorption from tubular filtrate, ↑urinary glucose excretion
- competitive reversible inhibition of SGLT-2 in PCT
- Modest weight loss, hypoglycaemic risk is low
Give 2 examples of Sodium-glucose co-transporter (SGLT-2) inhibitors (gliflozins).
dapagliflozin, canagliflozin
how are glifozins prescribed?
Adjunct to insulin in TIDM (high BMI)
TIIDM as add on therapy
adverse effects of gliflozins
UTI and genital infection, thirst and polyuria
warnings, contraindications of gliflozins
risk of DKA in TIDM, possible hypotension
important drug reactions of gliflozins
antihypertensive and other hypoglycaemic agents
WHat are the physiological effects of GLP-1?
- pancreas: ↑Insulin secretion ↓Glucagon secretion ↑Insulin biosynthesis
- stomach: ↓Gastric emptying
- brain: ↓Food intake through increased satiety
- liver: ↓Glucose production
- muscle: ↑Glucose uptake
What is the function of Dipeptidyl peptidase-4 (DPP-4) in glucose metabolism?
Incretin (e.g. GLP1) degradation
how do Dipeptidyl peptidase-4 (DPP-4) inhibitors
(gliptins) work?
- Prevent incretin degradation - ↑[plasma] incretin levels Glucose dependant so postprandial action
- Supress appetite ~ weight neutral
is there risk of hypoglycaemia with gliptins?
do not stimulate insulin secretion at normal blood glucose – lower hypoglycaemic risk
adverse effects of gliptins?
GI upset, small pancreatitis risk (up to 1%)
warnings, contraindications of gliptins?
avoid in pregnancy, history of pancreatitis
important drug reactions of gliptins?
other hypoglycaemic agents, drugs ↑glucose can oppose gliptin action – thiazide like and loop diuretics
Give examples of DPP-4 inhibitors?
sitagliptin, saxagliptin
how do Glucagon-like peptide-1 (GLP-1) receptor agonists (incretin mimetics) work?
- ↑glucose dependant synthesis of insulin secretion from β-cells by activating GLP-1 receptor – resistant to degradation by DPP-4
- Promote satiety – possible weight loss?
How are GLP-1 agonists administered?
Subcutaneous injection
how are GLP-1 agonists prescribed?
NICE suggest add-on if triple therapy ineffective
adverse effects of GLP-1 agonists
GI upset, decreased appetite with weight loss
warnings, contraindications of GLP-1 agonists
Renal impairment
important drug reactions of GLP-1 agonists
other hypoglycaemic agents
Give examples of GLP-1 agonists?
exenatide, liraglutide
what is the advantage of Modified/extended release (metformin, incretin mimetics) ?
overcome GI upset, less frequent dosing, slower release changes PK properties
Why swallow extended release tablet whole?
they are encapsulated to slow absorption, chewing or drinking with water will disrupt modified release so absorb too much
what is the disadvantage of combined drugs?
fixed dose of drug 1 + fixed dose of drug 2 – presents a challenge if you want to change the dose of drug 2
of the 6 diabetic drugs, which ones cause hypoglycaemia when prescribed alone and which do not?
- biguanides - no
- sulfonylureas - yes
- thiazolidinedione - yes
- SGLT-2 inhibitors - no
- DPP4 inhibitors - no
- GLP1 agonists -no
of the 6 diabetic drugs, what are their effects of weight?
- biguanides - suppress appetite
- sulfonylureas - increased
- thiazolidinedione - increased
- SGLT-2 inhibitors - help to decrease
- DPP4 inhibitors - reduce appetite
- GLP1 agonists -increased satiety
of the 6 diabetic drugs, what are their routes of administration?
all oral except GLP1 agonists which is subcutaneous
what are the primary mechanisms of the 6 diabetic drugs?
- biguanides - Reducing hepatic glucose output
- sulfonylureas - Stimulating pancreatic insulin secretion
- thiazolidinedione - Enhanced insulin sensitivity and glucose utilisation
- SGLT-2 inhibitors - Reduce glucose reabsorption
- DPP4 inhibitors - Incretins promote insulin secretion and supress glucagon release - Prevent incretin degradation
- GLP1 agonists -Increased glucose- dependant synthesis of insulin
