Week 4 - Diabetes & Lipid Disorders Flashcards
What are the effects of insulin on the Liver?
o Promotes Glycogen synthesis and storage
o Promotes synthesis of protein, triglycerides, VLDL
o Promotes glycolysis
o Inhibits gluconeogenesis, glycogenolysis, ketogenesis, lipolysis
What are the effects of insulin on muscle?
o Promotes protein synthesis – amino acid transport, ribosomal protein synthesis
o Promotes Glycogen synthesis – stimulates Glycogen synthetase and inhibits phosphorylase
o Increased Glucose entry into muscle cells
What are the effects of insulin on addipose tissue?
o Triglyceride storage – increased Lipoprotein Lipase (LPL) activity to hydrolyse triglycerides from lipoproteins
o Increased glucose entry – increased availability of glycerol phosphate as substrate for esterification of free fatty acids (FFA) into triglycerides
o Inhibits intracellular lipoprotein lipase
What is the pathogenesis of type 1 DM?
Genetic susceptibility & environmental factors
Autoimmune destruction of pancreatic beta-cells»_space;> Insulin deficiency
• Hyperglycaemia
• Ketonaemia - acidic
What is the general management of type 1 DM?
Insulin replacement
What is the mechanism of disease in type II DM?
Insulin resistance at muscle, liver and in adipose tissue
What is the rough management in type II DM?
- Lifestyle changes
- Glucose-lowering agents
- Dietary control - (Reduce calorie load which will Reduce obesity & Reduce insulin resistance)
- Increase physical exercise
What is the first line drug treatment in Type II DM?
Metformin - Biguanide
What type of drug is metformin?
Biguanide
What is the mechanism of action of metformin (biguanide)?
Inhibits hepatic gluconeogenesis
What are the advantages of metformin (biguanide)?
Weight neutral/Weight loss
Low cost & Long track record
What are the disadvantages of metformin (biguanide)?
GI adverse effects
• Nausea, Loose stool & Flatulence
Lactic acidosis
• Mainly in patients with → Renal impairment, Heart failure or Liver disease
Name 2 sulponylureas…
Gliclazide, Glimepiride, Tolbutamide
What is the mechanism of action of sulponylureas?
Increase insulin secretion
• Bind to SU receptor on beta cell
• Open K+ channel & depolarize cell membrane
• Increase insulin release
What are the advantages of sulponylureas?
o Works quickly, is Low cost & long track record
What are the disadvantages of sulponylureas?
o Hypoglycaemia (tell DVLA) & Weight gain
Name a thiazolidinedione (TZDs)….
Pioglitazone
What is the mechanism of action of (TZDs)?
o Enhance lipogenesis
o Decrease lipolysis
o Decrease plasma FFAs → PPAR g agonists
What are the advantages of (TZDs)?
‘Insulin sensitisers’
What are the disadvantages of (TZDs)?
o Fluid retention
o Weight gain
o Increased peripheral fracture rate
o Bladder cancer?
Name a SGLT2 (sodium glucose transporter 2 inhibitor)…
Empagliflozin, Dapagliflozin, Canagliflozin
What is the mechanism of action of SGLT2?
Prevent renal glucose reabsorption (piss out calories and glucose)
• Inhibit SGLT2 in proximal tubule
What are the advantages of SGLT2?
Weight loss
What are the disadvantages of SGLT2?
o Increases chances of urinary tract infections and thrush
o Uncertain long term effects
o High cost
What are incretins and where are they made?
Hormones secreted by intestinal endocrine cells in response to nutrient intake
• Glucagon-like peptide I (GLP-1) → 30 amino-acid peptide
• Gastric inhibitory peptide (GIP)
• Source → L cells of the gut
What is the action of incretins?
- Glucose homeostasis
* Multiple levels
What is GLP-1 - how does it work around the body?
include all targets - Brain, beta cells, alpha cells, stomach and liver
o Brain → Promotes satiety & reduces appetite
o Beta Cells → Enhances glucose-dependent insulin secretion
o Alpha Cells → Suppresses them to reduce glucagon production
o Stomach → Slows rate of gastric emptying
o Liver → reduces hepatic glucose output
What are the limitations of GLP-1 as a therapeutic agent?
DPP-IV (Dipeptidyl peptidase IV) cleaves GLP-I at c-terminus
Therefore GLP-I has a short half life ~ 1-2 mins
o Therefore it would require a continuous infusion unless we blocked DPP-IV (the enzyme that is breaking it down)
What is the mechanism of action of DPP-IV inhibitors?
Inhibit DPP-IV and therefore prolong half-life of GLP-I
What are the advantages of DPP-IV inhibitors?
o Oral
o No hypoglycaemia
o Well tolerated
o Some licensed at low GFR (in patients with renal impairment)
What are the disadvantages of DPP-IV inhibitors?
Long term effects uncertain and it is expensive
GLP-1 Mimics
What is the mechanism of action of GLP-1 mimics?
Resistant to DPP-IV therefore has a half life of hours not minutes
o Enhanced incretin effects
What are the advantages of GLP-1 mimics?
No hypoglycaemia
Weight loss
What are the disadvantages of GLP-1 mimics?
o Sc. Injection – similar to an insulin pen
o Adverse effects → nausea & vomiting
o Long term effects unknown
o Expensive
What are the three main categories of insulin?
Mealtime insulins
Basal insulins
Insulin mixes
What is the optimal insulin regimen?
Basal - Bolus therapy
Give an example of a rapid-acting and a long-acting insulin analogues…
Rapid-acting → Novorapid or Humalog
Long-acting → Glargine or Detemir
What are the advantages of Insulin analogues?
o reduced nocturnal hypo
o reduced fasting glucose (pre-breakfast)
What are the disadvantages of Insulin analogues?
o ‘active’ self-management
o high cost
What is the principle of Continuous Subcutaneous Insulin Infusion (CSII) – “Insulin pump”?
Constant infusion rapid-acting analogue
• Smaller sc. volume
• More predictable absorption
Basal rate + meal-time boluses
What are the advantages of Continuous Subcutaneous Insulin Infusion (CSII) – “Insulin pump”?
o Less hypoglycaemia
o Less glucose variability
o HbA1c reduction
o Flexibility for the patient
What are the disadvantages of Continuous Subcutaneous Insulin Infusion (CSII) – “Insulin pump”?
o DKA risk
o High cost – few thousand/pump
What is the stepwise approach to treating a type 2 diabetic?
- Step 1 → lifestyle measures only
- Monotherapy → add metformin
- Dual therapy →add sulphonylurea
- Triple therapy →add on agent (PPARg, GLP-I enhancer or SGLT2 inhibitor)
- Insulin (if not already used)
What is the direct mechanism of action of Statins?
Decreasing cholesterol biosynthesis
• By inhibiting…. HMG-CoA Reductase
Increasing uptake of cholesterol from the circulation into the liver
What is the possible indirect mechanism of action of Statins?
- Improved endothelial function
- Reduced inflammation
- Plaque stabilisation
- Inhibition of thrombus formation
What are the most potent statins?
Atorvastatin and Rosuvastatin
What are the side effects of statins?
Hepatic – deranged LFTs, Liver injury
Myalgia and Myositis – elevated CK (Creatine Kinase) levels
• “Minor” side effects: skin rash, GI upset, sleep disturbance, aches and pains
• Very small increased risk of diabetes in non-diabetic population
• Peripheral Neuropathy
What are possible drug interactions of statins?
Statins metabolised by Hepatic Cytochrome P450 (CYP3A4)
CYP3A4 inhibitors include…
• Ciclosporin, Clarithromycin, Erythromycin, Diltiazem, Verapamil, Amlodipine, Amiodarone, Ketoconazole, HIV protease inhibitors, Grapefruit juice!
Risk of increased plasma concentrations of statins causing myopathy and/or rhabdomyolysis
Name 3 other classes of lipid lowering drugs
Fibric Acid Derivatives – “Fibrates”
Ezetimibe
PCSK9 inhibitors
Which enzyme do statins inhibit?
HMG-CoA Reductase
How do you calculate anion gap?
Anion gap= Unmeasured cations – Unmeasured anions
Na + K - (HCO3 - + Cl-)
What is the mneumonic for metabolic acidosis (high anion gap?
MUDPILES
What are the causes of metabolic acidosis + mneumonic?
- M: methanol, metformin
- U: uremia
- D: DKA
- P: paraldehyde, paracetamol,phenformin
- I : Iron, Isoniazid
- L: lactic acidosis
- E: ethanol, ethylene glycol
- S: salicylate
What are the parameters for a diagnosis of DKA?
Ketonaemia ≥3 mmol/L or Significant ketonuria (>2+ on urine dipstick)
Blood glucose >11 mmol/L or Known diabetes mellitus
Bicarbonate (HCO3-) < 15 mmol/L and/or venous pH < 7.3
Why do you need to monitor potassium?
Hypokalaemia and hyperkalaemia are life-threatening conditions and are common in DKA.
Serum potassium is often high on admission (although total body potassium is low) but falls precipitously upon treatment with insulin.
Regular monitoring is mandatory
May need to replace with potassium infusion
How should you prescribe insulin in DKA?
Insulin IV infusion (6 units/hour)
What cautions do you need to take when replacing a patients IV insulin back to their usual regime?
Very very short half life of IV insulin and normal insulin takes a while to kick in.
Give fast-acting insulin s/c with a meal and discontinue insulin infusion 30 minutes later
o Then start on Basal-bolus
What signs would point towards a severe DKA?
The presence of one or more of the following may indicate severe DKA
o Blood ketones > 6 mmol/L
o Bicarbonate level < 5 mmol/L
o Venous/arterial pH < 7.1
o Hypokalaemia on admission (< 3.5 mmol/L)
o GCS < 12 or abnormal AVPU scale
o Oxygen saturation < 92% on air (assuming normal baseline respiratory function)
o Systolic BP < 90 mmHg
o Pulse >100 or <60 bpm
o Anion gap > 16 [Anion Gap = (Na+ + K+) –(Cl- + HCO3-) ]
What do you need to monitor in a DKA patient?
- Hourly capillary blood glucose
- Hourly capillary ketone measurement if available
- Venous bicarbonate and potassium at 60 minutes, 2 hours and 2 hourly thereafter
- 4 hourly plasma electrolytes
What are your treatment aims in the first 6 hours in a DKA patient?
o Clear the blood of ketones and suppress ketogenesis
o Achieve a rate of fall of ketones of at least 0.5 mmol/L/hr
o In the absence of ketone measurement, bicarbonate should rise by 3 mmol/L/hr and blood glucose should fall by 3 mmol/L/hr
o Maintain serum potassium in normal range
o Avoid hypoglycaemia
What parameter defines a resolution in DKA?
Resolution is defined as blood ketones < 0.3 mmol/L, venous pH > 7.3
How do you avoid making a patient hypoglycaemic whilst treating DKA?
Replace 0.9% saline with glucose-insulin infusion
What action is appropriate if a patient is having a severe hypoglycaemic attack?
Dextrose infusion or glucagon
- Glucagon 1 mg IM
- Recheck BM in 10 minutes
- If BM<4.0, Repeat glucose bolus
- If BM>4.0, give long-acting oral CHO when patient recovered.
If diabetic patients are trying to get pregnant what advise should you give?
Folic acid supplementation – HIGH DOSE
5 mg pre-conception until 12 weeks post-conception
What advice do you give during pregnancy?
Monitor BMs pre-meal (target 4 -5.9) and 1-hour post-meal (target < 7.8) and at night. Monitor ketones in urine or blood Counsel about hypoglycaemia o Reduced hypoglycaemia awareness o Increased CHO requirements Provide partner with glucagon
What is the appropriate treatment During Labour or Caesarean Section?
- GKI (glucose-potassium-insulin) infusion to maintain glucose 4 -7
- Monitor BM every 30min - 1hour.
What is the appropriate action post partum?
- Following pIacental delivery,maternal insulin sensitivity improves.
- Monitor BMs
- May need to reduce insulin infusion rate by up to 50% post partum.
- When converting back to s/c insulin, most need roughly pre-pregnancy dose of insulin
If a patient is on a statin and gets community acquired pneumonia what treatment should you use for the pneumonia?
What other considerations should you take?
Treat with amoxicillin and clarithromycin (same as all patients)
Stop statin - P450 interaction
What enzyme do statins inhibit?
HMG-CoA Reductase
