Diabetes Flashcards
What are the objectives of treatment in T2DM?
- Glycaemic control
- Reduce complications: Microvascular, macrovascular and side effects
What measure is good in judging the risk of complications (related to glycaemic control)?
HbA1c
What is the HbA1c target?
6.5-7.5% 48mmol/mol - 58mmol/mol. 7%
What is the UKPDS study and its importance?
The UK prospective diabetes study compared standard and intensive Tx in a large trial in people with recently diagnosed T2DM. Gives much of the evidence guiding current Tx recommendations. Intensive Tx was associated in a 25% overall reduction of Microvascular disease end-points, 33% reduction in albuminuria, 30% reduction in the need for laser treatment for retinopathy. These benefits persisted for many years after conclusion of the trial ‘ legacy effect’. Also showed that BP control is needed for the prevention of retinopathy.
What is the pathophysiology of T2DM?
- Insulin resistance
- As insulin resistance develops –> body response is to increase Insulin secretion hence early diabetes often associated with insulin hyper-secretion
3.Loss of the first phase of the normal biphasic insuin secretion
(even though bc of hypersecretion circulating Insulin levels are higher they are still inadequate to restore glucose homeostasis) - At time of diagnosis: AT LEAST 50% of beta cell mass and function have been lost
- In vitro hyperglycaemia and lipid excess are toxic to beta cells –> thought to cause further Beta cell loss and further deterioration of glucose homeostasis
- With time, insulin secretion declines - ‘The starling curve’ of the pancreas - time course varies widely between individuals
Relative insulin lack is associated with:
- Increased glucose production form the liver
- Reduced Insulin mediated glucose uptake into peripheral tissues
What is insulin resistance?
Inability of Insulin to produce its usual biological effect at physiological concentrations. Characterised by an impaired ability of Insulin to:
- Inhibit hepatic glucose output
- Stimulate glucose uptake into skeletal muscle
- Suppress lipolysis in Adipose tissue
What causes Insulin resistance in T2DM?
underlying mechanisms not fully understood but result from Nutrient excess.
- Intracellular trigylceride accumulates in the liver + skeletal muscles –> impedes the phosphorylation of the post-receptor insulin receptors substrate - IRS-1 –> reduce insulin action with regards to Glucose and Lipid Metabolism
- Insulin still able to activate the MAP kinase pathway - regulates a number of intracellular pathways involved in inflammation, cellular proliferation and atherosclerosis.
What is the current Tx/management guideline of T2DM?
Check current NICE guidelines
- Optimal Lifestyle management
- Metformin
Individualised Tx depending on (current lifestlyle, comorbidities, indivisualised HbA1c target, side effects, Tx complexity etc)
If established atherosclerotic CVD:
-GLP1 receptor agonist
SGLT2 inhibitor
If Heart failure or Chronic Kidney Disease:
-SGLT2 inhibitor
Pressing need to minimise weight gain / promote weight loss:
- GLP1 receptor agonist
- SGLT2 inhibitor
Need to avoid hypoglycaemeia
- DPP4 inhibitors
- Thiazolidinediones
Cost is a major issue:
- Sulphonylureas
- Thiazolidinediones
Triple therapy may be required
Beyond triple therapy:
- Insulin is required
- Several fixed dose oral combinations and fixed ratio injectable combinations of Insulin and GLP-1 receptor agonists
What is the first-line Tx in T2DM?
Dietary and lifestyle changes.
- Supported to lose at least 5% of their weight –> can enter remission
- Low glycaemic index foods
- Meditarranean diet (decrease salt intake <6g/day, wholegrans fruit veg, less red and processed meat, less sat fats)
- Limit alcohol intake <14 units/ week
- 150 mins of aerobic excersize + resistance training per week spread over min of 3 days
- Smoking cessation
When is Bariatric surgery indicated in T2DM and how effective is it?
Severe obesity (BMI >35kg/m2). Gastric bypass and sleeve gastrectomy. More effective than medical therapy and can be sustained for more years:
- Mean weight loss of 30%
Diabetes remission in up to 70% of people
-improves QoL
-Reduces risk of CVD and mortality
What pharmacological Tx options are there for T2DM?
- Metformin (first line Tx)
- Sulphonylureas, DPP-4 inhibitors, GLP-1 receptors agonists
- SGLT2 inhibitors
- Insulin
What pharmacological Tx options are there for T2DM?
- Biguinides: Metformin (first line Tx)
- Sulphonylureas
- DPP-4 inhibitors
- GLP-1 receptors agonists
- SGLT2 inhibitors
- Thiazolidinediones
- Alpha-glucosidase inhibitors
- Insulin
What drugs cause increased Insulin secretion?
Sulphonylureas, DPP-4 inhibitors, GLP-1 receptor agonists
What drugs excrete excess glucose load?
SGLT2 inhibitors
How can T2DM be prevented or delayed?
- Intensive diet and excersize programme
- Inc use of Metformin and TZDs (in adults at high risk)
- Difficult to maintain over long term+costly, unwanted side effects of medications
What is Metformin’s mode of action?
May involve: Activation of the enzyme AMP Kinase - which regulates cellular energy metabolism. METFORMIN INCREASES INSULIN SENSITIVITY:
- reduces rate of gluconeogenesis and hence hepatic glucose output
- increases insulin sensitivity
- does not affect insulin secretion
- does not induce hypoglycaemia
- does not predispose to weight gain
- it may also suppress appetite and stabilize weigh
What is the key difference beetween other pharmacological agents and Metformin?
- Least amount / no weight gain
What is the key difference between other pharmacological agents and Metformin?
- Least amount / no weight gain
What does Metformin do and how effective is it?
Increases insulin sensitivity . First line Tx in T2DM
- Lowers fasting plasma glucose by 2-4mmol corresponding to a fall in HbA1c of 11-22mmol/l (1-2%)
- In UKPDS metformin lead to an unexpected reduction in CV events
What are the adverse effects of Metformin and when is it contraindicated?
Adverse effects:
-GI side effects (10-20%) inc anorexia, nausea, abdmonial discomfort, diarrhoea.
( start at low dose and gradually increase. Slow release preparation appears to be better tolerated.)
- reduces GI B12 absorption but only rarely causes anaemia
Contraindications:
- Renal impairment (should not be started it eGFR <45mL/min per 1.73m2, stopped if eGFR falls <30mL/min)
-Cardiac failure
-Hepatic failure
due to risk of Lactic acidosis
- Avoided in people with history of alcohol Misuse
Should be stopped:
- Prior to Intravascular administration of Iodinated contrast agent (risk of renal failure and lactic acidosis)
- Surgery
- Intercurrent illnesses that may affect lactate clearance
When are Sulphonylureas indicated for Tx of T2DM and how effective are they?
- alternative first line agent (where Metformin is contraindicated or not tolerated)
- Can be used in combo with other oral agents or basal insulin (although usually stopped when individual requires short-acting Insulin at mealtimes)
Effectiveness:
- Reduce fasting plasma glucose by 2-4mmol/L corresonding to a 1-2% fall in HbA1c
- More effective than many other oral agents in the SHORT TERM (1-3yrs)
- Sulphonylurea effect wears off as the beta cell mass declines
What is the mode of action of Sulphonylureas?
Act on the beta cell to induce Insulin secretion. bind to the sulphonylurea receptor on the beta cell membrane –> closes the ATP sensitive K+ channels and block K+ efflux –> depolarisation–> promotes Ca++ influx –> stimulates Insulin release
- ineffective in people without a functional beta cell mass hence HAVE NO EFFECT IN T1DM
What are the adverse effects/ contraindications of sulphonylureas?
Adverse effects:
- Weight gain (1-4kg)
- Hypoglycaemia (1/5 of people but severe is uncommon), risk increases w excessive alcohol intake, older age, intercurrent infection
Contraindications: Should be used with care in people with:
- liver disease
- Kidney disease
What are meglitinides ?
Short acting agents that promote insulin secretion in response to meals.
Indicated in:
- Post prandial Hyperglycaemia with normal fasting glucose levels
-Older people when there is an imperative to avoid hypoglycaemia
-ROLE IN DIABETES NOT WELL ESTABLISHED + less effective than other drugs
Adverse effects:
- hypoglycaemia
- weight gain
What are Thiazolidineodiones mode of action?
-Increase insulin sensitivity
Mode of action: Alter cell membrane receptors for the insulin receptors
-Interacts with the PPAR-gamma nuclear receptor that
-Reduce hepatic glucose production
-Enhances peripheral glucose uptake
What is the only available TZD in many countries?
Pioglitazone. Still occasionally given in the UK
- Troglitazone was withdrawn bc of liver toxicity and rsiglitaozone withdrawn bc of concerns of CV safety
When are Thiazolidineodiones indicated?
- Monotherapy
- Combination with other diabetes drugs inc Insulin
- May benefit people with NAFLD
How effective are Thiazolidineodiones?
- Do not cause hypoglycaemia as monotherapy
- May take up to 3months to reach maximal effect
What are the adverse effects / contraindications of Thiazolidineodiones?
- Weight gain (most common) 5-6kg
- Fluid retention –> precipitation Heart failure
- Mild anaemia and osteoporosis resulting in peripheral bone fractures have been reported
What is the incretin effect and what is it mediated by?
The insulin response to oral glucose is greater than the insulin response to IV glucose.
The effect is mediated by 2 hormones released by the GI tract following eating:
- Glucagon like peptide-1 (GLP-1)
- Glucose dependant insulinotrophic polypeptide (GIP)
main action: increase glucose induced beta cell insulin secretion + suppress glucagon secretion. Also
- slow gastric emptying
- Induce satiety
Breakdown:
- Hormones have short half lives
- Broken down by enzyme dipeptidyl peptidase-4 (DPP4)
What happens to the incretin effect in T2DM and what is the consequence?
- Incretin effect impaired hence:
- Glucagon secretion increased (diminished intra-islet insulin) –> increased hepatic glucose output
What are the 2 classes of drug that improve glycaemic control by enhancing the incretin effect?
- GLP-1 analogues (more potent than DPP4 inhibitors)
- DPP4 inhibitors
What is mode of action of DPP4 inhibitors?
- Inhibit the enzyme DPP4 –> prevents the rapid inactivation of GLP-1:
- Increases insulin secretion + reduces glucagon secretion (enhances incetin effect)
When are DPP4 inhibitors indicated?
Current recomendation: 2nd line use in combination with Metformin or a sulphonylurea
- Most effective in early stages of T2DM (when insulin secretion is relatively preserved)
- Included in most T2DM guidelines bc they are well tolerated
How effective are DPP4 inhibitors?
- Most effective in early stages of T2DM (when insulin secretion is relatively preserved)
- Relatively modest effect on glucose lowering compared to others
- DPP4 inhibitors are well tolerated (no weight gain, low risk of hypo, can be used safely in renal impairement)
What are the side effects?
- Nausea
- Occasional reports of acute pancreatitis
- Saxagliptin may increase risk of Heart failure
What do SGLT-2 inhibitors do + their mode of action?
Lower the renal threshold for glucose –> increasing urinary glucose excretion:
- Block the SLG2 protein in the PCT involved in 90% of the glucose reabsorption
When are SGLT-2 inhibitors indicated?
- Used more often in combination with all other antidiabetes drugs in T2DM
- Can be monotherapy in T2DM
-Adjunctive therapy to insulin in T1DM (higher risk of DKA and fungal infections)
When are SGLT-2 inhibitors indicated?
- Used more often in combination with all other antidiabetes drugs in T2DM
- Can be monotherapy in T2DM
- Used in people with reduce eGFR
-Adjunctive therapy to insulin in T1DM (higher risk of DKA and fungal infections)
What are the adverse effects / contraindications of SGLT-2 inhibitors?
Most common:
- Genital candidasis
- Dehydration
Rare:
- DKA
- Fournier’s gangrene and lower limb amputation
What are alpha-glucoside inhibitors and why are they not widely used?
Designer drug that reduce carb absorption after a meal.
- Prevent alpha glucosade from breaking down disaccharides to monosaccharides –> lowers post-prandial glucose
- Not widely used bc of limited efficacy and GI side effects
- GI effects: flatulance, abdominal distension and diarrhoea
How do GLP-1 analogues / receptor agonists work?
Injection that Enhances incretin effect by:
- Activate the GLP-1 RECEPTOR –> increase insulin secretion and reduce glucagon secretion
- Act on hypothalamus –> reduce appetite and food intake –> weight loss
- Short acting agonists also slow gastric emptying
- Protect heart against ischaemic damage
What are the different types of GLP-1 receptor agonists ?
2 main groups:
- ) Exendin based GLP-1 receptor agonists
- )Human GLP-1 analogues
Pharmacokinetics have been modified –> prolong duration of action (as usually physiological GLP-1 has short half life).
When are GLP-1 receptor agonists indicated?
- Widely used in combo with other antidiabets agents as 2nd or 3rd line therapies
- Should not be combined with DPP4 inhibitors
- Particularly suitable in patients with obesity
What are the side effects of GLP-1 receptor agonists and when are they contraindicated?
Most common:
- GI: Nausea, vomiting, bloating, diarrhoeae
- Diminish with time
- Occur less frequently with longer acting agonists
Rarer
- Risk of hypo
- May occur if combined with insulin or sulphonylureas
Contraindications:
-Should not be used in patients with History of pancreatitis (bc of risk of acute pancreatitis)
How effective are GLP-1 receptor agonists?
- Reduce HbA1c (0.8-1.8% reduction)
- Reduce weight (0.6-4.4kg)
What is the aim of bariatric surgery?
-Reduce weight by achieving malabsorption
When is Insulin required for T2DM?
NICE 2016
- Blood glucose levels are inadequately controlled despite dual therapy with metformin plus another oral antidiabetic drug (if the person is markedly hyperglycaemic and prefers to start insulin rather than adding another drug).
- Oral antidiabetic drugs are contraindicated or not tolerated.
What are the 2 broad groups of Insulins?
Long acting insulins
Short acting insulins
What are the different Insulin reigmes / approaches?
- Basal-bolus therapy
- Twice daily mixed insulin regime
- Once daily basal Insulin / basal only and basal-plus
What Insulin regimes are suitable for T1DM?
- Basal-bolus
- Twice daily mixed Insulin
What Insulin regimes are suitable for T2DM?
- Twice daily mixed Insulin
- Once daily basal insulin
- Basal-bolus (sometimes used)
What is a basal bolus insulin regime? When is it suitable? What are the advantages and disadvantages?
- Long acting Insulin is injected 1-2 times a day –> provides the background (basal) Insulin - keeps the glucose concentration consistent during periods of fasting
- Short acting insulin is given shortly before eating as a bolus (to control glucose conc following a meal)
Advantages:
- Regimen that most closely resembles normal Insulin Physiology
- More flexible than other regimens as injection can be adjusted individually
- Reduce risk of hypoglycaemia particularly at night
Disadvantages:
-number of injections
Suitable for:
- Treatment of choice for T1DM
- increasingly used in younger people with T2DM
- Good for people who have busy jobs , travel lots, work shifts
What is twice daily insulin mix?When is it suitable? What are the advantages and disadvantages?
A mixture of short and long-acting insulin is injected before breakfast and the evening meal. Number of preparations with premixed insulin (also can self-mix)
Suitable for:
- More common in T2DM
- T1DM patients if not possible to inject 4 times a day
Disadvantages:
- Lack of a lunch-time bolus
- Higher basal levels between meals –> increase risk of hypoglycaemia at night
- Less controlled HbA1c
What is a once-daily Basal insulin and basal-plus regimen?When is it suitable? What are the advantages and disadvantages?
Less intensive Insulin regimen. Basal long acting insulin at night (together with other non-insulin Tx during the day) for those with T2DM
Suitable for:
-T2DM only
Advantages:
- Initially as effective as multidose insulin regimens
- Less likely to promote weight gain
Disadvantages:
-Postpandrial hyperglycemia - additional insulin may be necessary to control this
What Insulins are available?
Basal Insulin
- NPH insulin
- Insulin glargin
- Insulin detemir
- Insulin degludec
Prandial (rapid acting analogues)
- Insulin lispro
- Insulin glulisine
- EDTA/citrate human insulin
- Faster-acting insulin aspart
What are short acting Insulins?
What are the properties of soluble human Insulin?
Absorbed slowly - reaches peak at 60-90 mins after subcutaneous injection. Action tends to persist after meals -> predisposing to hypoglycaemia.
Absorption is delayed bc soluble insulin forms Hexamers (6 Insulin molecules around a zinc core) which need to dissociate to monomers or dimers before it can enter the circulation.
-Delay is inconveniant bc Insulin should be injected 20-30 mins before meal –> often not feasible
What has been developed to to overcome the problems of soluble Human Insulin
Short acting insulin analogues
-enter and dissapear from circulation much more rapidly
What are the advantages of short acting Insulin analogues over soluble human insulin?
T1DM:
- Reduce total and nocturnal hypoglycaemia episodes
- Improves glycaemic control judged by postpandrial glucose concentrations and HbA1c
T2DM: More modest benefits
-Better control of HbA1c and pospandrial glucose conc
What is the aim of modern Insulin therapy?
Give insulin to try and mimick the natural body physiology: what the body does when not eating particularly:
- Separation of basal from bolus insulin to mimic physiology – background insulin, same dose if not eating
- Quick acting insulin before meal – calculate amount that matches carb load
What is the aim of Basal Insulin?
To control blood glucose in between meals and particularly during the night
What are longer-acting Insulins? Aims of treatment? Why were they developed?
Zinc or Protamine added to human insulin to prolong action. Also long-acting analogues available. NPH insulin, Insulin glargine, Insulin detemir, Insulin degludec
NPH insulin:
- Human insulin with zinc or protamine added
- Use hampered by variability from one injection to the other, the need to resuspend the insulin prior ti injection and a peak action which tends to occur in the middle of the night.
Insulin glargine:
- long-acting analogue of human insulin
- Longer duration of action (new ones with longer and flatter)
Insulin detemir + Insulin degludec:
-Fatty acid tail binds to serum albumin –> slow dissociation, prolonged duration of action
What is the advantage of Long acting insulin analogues? When are they indicated?
Reduce risk of hypoglycaemia particularly at night in both T1DM and T2DM
-Bc analogues are more expensive than NPH insulin NICE recommends that they are reserved for people who do not respond well to NPH
What is the classification of Hypoglycaemia?
3 diff types:
- Level 1: plasma glucose <3.9mmol/L and no symptoms (don’t depend on symptoms)
- Level 2: Plasma glucose <3.0mmol/L
- Level 3: severe: not dependant on glucose level, patient has impaired congnitive function and needs to require on external help
At what level of hypoglycaemia does the brain begin to dysfunction?
Level 2: <3mmol/L
neurones cant get enough glucose from bloodstream. Confusion , reaction time, cardiac arrhythmias, shift in bodys defences
Is hypoglycaemia more likely in T1DM or T2DM?
T1DM, more likely to have a severe episode/
What are the 2 main types of symptoms of Hypoglycaemia?
1-Autonomic (bc of the activation of the adrenergic and cholinergic parts of the autonomic NS)
2-Neuroglycopenic (bc of inadequate supply of glucose to the brain)
What are the symptoms of hypoglycaemia (be specific)?
Autonomic:
- Trembling
- Palpitations
- Sweating
- Anxiety
- Hunger
Neuroglycopenic:
- Difficulty concentrating
- Confusion
- Weakness
- Drowsiness, dizziness
- Vision changes
- Difficulty speaking
Non-specific:
- Nausea
- Headache
What type of symptoms tend to develop first in hypoglycaemia?
The autonomic symptoms –> alert the individual to hypo and prompt them to take action
What is the normal physiological response when blood glucose levels fall? Compare this to the pathophysiological response to hypoglycaemia in patients with T1DM?
Normal response:
Fall in glucose level –> suppression of endogenous Insulin secretion and stimulation of secretion of counter regulatory hormones: glucagon + epinephrine –> act rapidly to stimulate endogenous glucose production, limit peripheral glucose utilisation –> increase glucose delivery to brain and raise blood sugar
In T1DM:
- Reduced and inadequate glucagon response to hypoglycemia. (glucagon main regulator is a fall of intra-islet insulin)
- Reduced autonomic response (adrenaline) which acts to increase hepatic glucose production and decrease peripheral glucose uptake . Especially in long standing diabetes
How can hypoglycaemia in patients with T1DM increase the risk of future hypoglycaemia?
Repeated episodes of hypoglycaemia –> defected autonomic NS response:
-Body resets Adrenaline level to a lower level of glucose needed to provoke an autonomic response –> (glucose levels below the threshold for neuroglycopenic symptoms) –>Hypoglycaemia awareness becomes impaired and the risk of severe hypoglycaemia increases?
Why is the risk of hypoglycaemia increased ,in patients withlong term diabetes / repeated hypoglycaemia ?
Longstanding diabates/ Repeated episodes of hypoglycaemia –> defected autonomic NS response:
-Body resets Adrenaline defence to a lower level of glucose needed to provoke an autonomic response –> (glucose levels below the threshold for neuroglycopenic symptoms) –>Hypoglycaemia awareness becomes impaired and the risk of severe hypoglycaemia increases?
What predisposes an individual to hypoglycaemia?
- T1DM
- Long-standing diabetes
- previous episodes of hypo
- young children
- Those trying to achieve tight glycaemic control
- Low HbA1c: high pretreatment HbA1c in T2DM
- Impaired awareness of hypoglycaemia
- Daily insulin dosage >0.85 U/Kg/Day
- Physically active (athlete)
- Impaired renal function
What is the Tx of Hypoglycaemia?
- Recognise symptoms
- Confirm the ned for treatment if possible (bg<3.9mmol/L is alert value)
- Treat with 15-20g of oral glucose to relieve symptoms
- Retest in 15mins to ensure blood glucose >4mmol/L. Re-treat if necessary
- Eat a long acting carb to prevent recurrence of symptoms
What is the Tx of severe hypoglycaenia resulting in confusion and coma?
Diagnosis: clinical + bedside blood test
- IM glucagon or IV glucose injection
- Does not work when liver glycogen stores are low (e.g after a prolonged fast)
- Eat long acting carb after revived
How do you prevent hypoglycaemia in diabetic patients?
- Discuss hypo risk factors and treatment
- Educate patients and caregivers on how to recognise and treat
- Instruct patients to report hypo episodes to their doctor/ educator
- Consider enrolling patients with frequent hypo in a blood glucose awareness training programme
When does permanent brain damage from hypoglycaemia occur?
2-3 hrs of v low glucose, not very reliable, not reliable for suicide via severe insulin overdose
