DIABETES Flashcards
Insulin synthesis
Insulin is protein synthesized by ribosomes on the surface of the RER.
- RER - The protein is folded and disulphide bonds are created.
- Golgi body - Cleavage
Secondary diabetes
Diabetes that is caused due to an underlying disease. This includes…
* Liver disease
* Pancreatic disease
* Endocrine disease
* Drug-induced diabetes - Thiazide duiretics, Corticosteroids
Gestational diabetes
Diabetes that occurs during pregnancy (2nd or 3rd trimester) due to insulin resistance.
Managed: Diet, Insulin
Risk: Large bith weight baby
Metabolic syndrome
A combination of medical conditions that together greatly increase the risk of CVD and Type II diabetes .These are…
* High blood presure
* High Blood glucose
* High cholesterol
- Central abdominal obesity
Diabetes symptoms
Also known as the 4Ts…
* Tired [FATIGUE]
* Thirst [POLYDIPSIA]
* Toilet [POLYURIA]
* Thinner [WEIGHT LOSS]
also blurred vision
What is Diabetes ketoacidosis and its symptoms ?
A condition in which the body severely lacks insulin and sugar is no longer used for energy. Instead, fat is broken down and used as energy.
Symptoms:
* Excessive thirst
* Polyurea
* Nausea
* Vomiting
* Hyperventilation
* Ketone breath
* Dehydration
DKA pathophysiology
- Blood glucose increase {HYPERGLYCEMIA} = osmotic diuresis; dehydration, hypotension
- Ketone body increase ; metabolic acidosis -> hyperventilation
- Hypokalemia
- Muscle catabolism
Type I diagnosis
- Symptoms: Random VPG > 11.1mmol/l + Fasting VPG >7 mmol/l
- No symptoms: {Random VPG + Fasting VPG}x2
VPG = Venous plasma glucose
Type II diagnosis
HbA1c > 48 mmol/ml + symptoms
Insulin treatment problems
Local treatment
* Bruising/scarring
* Allergic reaction (rare)
* Lipohypertrophy
Weight gain
Hyperglycaemia
Hypoglycaemia symptoms
- Confussion
- Weakness
- Mood changes (agressive)
- Impaired speech
- Unconciousness
How would you treat hypoglycaemia if the person can swallow
1.5-2 tubes of GlycoGel 40%
OR
Fresh juice
OR
Sweets
IM = Intramuscular
AIM: BG > 4mmol/l
How do you treat hypoglycaemia if a person can’t swallow
IM Glucagon 1mg
OR
IV Glucose (150ml of 10% over 15 minutes)
AIM: BG > 4mmol/l
Microvascular complications
- Diabetic eye disease
- Diabetic nephron disease
- Diabetic nerve disease
What are the complications of diabetic eye disease ?
- Diplopia (double vision)
- Cataracts
- Glaucoma (High fluid pressure in the eye)
- Retinopathy
Prevention/treatment of Retinopathy
- Good blood glucose control
- Good hypertension management
- No smoking
- Laser treatment (to seal of the leaking blood vessels)
Why are the microvascular complications so?
The nephron, nerves and eyes are especially vulnerable to due to difference in epithelial cells.
The cells DO NOT REQUIRE insulin for the diffusion of glucose through the cell membrane into the cell. Ergo, they are most vulnerable during hyperglycaemic conditions.
Screening for nephropathy
- Use of specialist dipstick
- Detecting the presence and quantity of microalbuminauria
- Calculate the ACR
ACR >3 mg/mmol requires treatment.
ACR = Albumin to creatine ratio
Treatment of nephropathy (blood glucose)
Aim for HbA1c < 48mmol/mol
OR
<53mmol/mol if type 2 diabetic
TYPE 1 diabetes
Nephropathy treatment targets (BP)
- ACR < 70mg/mmol: <140/90mmHg
- ACR >70mg/mmol: <130/80mmHg
- Over 80 years old: <150/90mmHg
TYPE 2
Nephropathy treatment targets (BP)
- ACR is not considered
- BP target: <140/90mmHg
- Over 80 years old: <150/90mmHg
High BP-nephropathy treatment
- Initially: ARB/ACEi
- Second step: ARB/ACEi + CCB
ARB: Losartan, ACEi: Lisinopril, CCB: Amlodipine
What are the contra-indications of Pioglitazone ?
- Ketoacidosis
- Heart failure (history of or otherwise
- Bladder cancer
First-line treatment for type II diabetes with no CVD risk
- Metformin (Metformin MR if GI disturbance)
- SGLT-2 inhibitor (IF established CVD or risk)
- Add one of Pioglitazone, Sulfonylurea, DPP4-inhibitors to the metformin treatment for dual therapy.
- Triple therapy for Metformin, SGLT2 inhibitor and one of the other 3 classes of drugs.
- Replace all but SGLT-2 with inter insulin regime
3,4, or 5 can be used in place of metformin if contraindicated
What are all insulin increasing drugs contraindicated by ?
Diabetic ketoacidosis
How often should the HbA1c of a type II DM patient be measured ?
Every 6 months.
What is lipohypertrophy and what are its complications ?
It is a lump of fatty tissue under your skin caused by the repetitive injections of insulin at the same area.
Complications include…
* Decreases insulin absorption
* Poor blood glucose control
* Pain
What are the effects of somatostatin ?
- Inhibits insulin
- Supresses gastric absorption
Give an example of RAPID insulin
Novorapid, Humanlog
Give an example of SHORT acting insulin
Actarapid, Humulin S
Give an example of LONG acting insulin
Lantus (glargine)
Summarise the 3 insulin regimes
1) Basal-bolus (Type I): Long acting ON+ rapid/short with each meal
2) Twice daily (Type II): Intermediate+short Insulin taken OM + ON
3) Inter (stage 3 type II): Intermediate OR long ON
What is metformin and how does it work?
A biguanide drug that essentially inhibits mitochondrion complex 1 which results in an increase in the AMP:ATP ratio thereby causing stimulation of AMPK.
How does glucose uptake cause insulin secretion
1) Glucose enters cell via GLUT2
2) Glycolysis of glucose = ATP
3) ATP inhibits K+ channels
4) Depolarisation = activation of voltage-gated Ca2+ channel
5) Influx of Ca2+causes exocytosis of insulin-filled vesicles.
Summarise MOA of sulfonylureas
High-affinity for binding to K-ATP channel. They…
* Bind to SUR1 subunits at K channel
* Block the transporter
* Depolarization of the membrane
* Activation of the voltage-gated Ca2+ channel = Insulin released by vesicle exocytosis
Can cause hypoglycaemia -insulin is secreted even in the absence of gluc
What is a GLP-1 agonist and what do they do?
Glucagon-like peptide that binds to GPCRs therefore causing an increase in cAMP thereby stimulating various pathways; CHOP, Epac2, PI3K, EGFR. It…
* Increase insulin secretion (glucose-dependent pathway)
- Stimulates proliferation of β-cells = Increase in insuling secretion
- Decrease gastric emptying and stops absorption of glucose in stomach
- Decreases glucagon secretion
They are rapidly cleaved by DPP4 enzymes (Half-life: 1-2 mins)
What are DPP4 inhibitors and what do they do ?
They inhibit DPP4 enzymes resulting in longer half-lives of GLP-1. This…
* Supresses gastric emptying and absorption
* Increases insulin secretion - cAMP pathway
Examples: Alogliptin, Linagliptin, Sitagliptin
Summarise PPAR agonist MOA
PPAR agonists…
1) Bind to PPAR (transcription factor)
2) Translocate to the nucleus
3) Form heterodimers with retinoid X receptor
4) The dimer binds to PPAR response element and activate the transcription of adjacent genes.
This increases transcription of genes involves in insulin signalling = Enhances effectiveness of insulin
Give an example of an inrreversible inhibitor of DPP4
- Saxogliptin
- Vildagliptin
What is Liraglutide ?
A modified GLP-1 with a lipophilic fatty acid chain at C16. This drug binds to the albumin proteins and effectively ‘hides’ from the DPP4. It has a half-life of 11-15 hrs therefore it is suitable for one daily administrations.
What is Albiglutide ?
It is a GLP-1 agonist drug. It is two GLP-1 compounds conjugated together thereby increasing resistance to DPP4. The suitable administration for this drug is once weekly by subcutaneous injection.
What does the activation of AMPK lead to ?
Increases…
* Glucose uptake by cells
* Fat oxidation
* Improves insulin sensetivity which increases insulin receptor function
Reduces…
* Lipid synthesis and carbohydrate absorption from the GIT.
- ATP synthesis = Inhibition of glucagon
- Transcription of genes for gluconeogenesis = Inhibition
Give an example of DPP4 inhibitors and their starting dose
- Linagliptin 5mg OD
- Alogliptin 25mg OD
- Sitagliptin 100mg OD
What antidiabetic medication can cause hypoglycaemia ?
- Sulfonylureas
- GLP-1 agonists
- DPP4 inhibitors
Give examples of Sulfonylureas and their starting doses
- Glicazide 40-80mg OD
- Glimepiridine 1mg OD
- Glipizide 2.5 mg OD
Give examples of SGLT2 inhibitors
- Dapagliflozin 10mg OD
- Empagliflozin 10mg OD -> 25mg OD (if needed)
- Canagliflozin 100mg OD -> 300mg OD (if needed)
What are SGLT2 inhibitors and what do they do ?
They are selective SGLT2 (transporter) inhibitors. They block/inhibit the transporter from reabsorbing glucose.
* Decreases blood glucose
* Does not affect insulin
* Results in glucosuria
SGLT2 would otherwise reabsorb ~90% of filtered glucose (BAD)
What is the first-line treatment for type 1 DM ?
BASAL-BOLUS
1) Basal:
* Offer twice daily long acting (Detemir)
* If twice not acceptable then offer OD detemir or glargine
2) Bolus:
* Offer rapid-acting analogues for BEFORE each meal.
DO NOT OFFER NON-BASAL-BOLUS REGIMES TO NEWLY DIAGNOSED TYPE 1 DM
Detemir = Levemir, Glargine = Lantus
Describe the Twice-daily regime ?
Consists of the administration, of either Novomix 30 or Humulin M3, before breakfast and before dinner. These contain a mix of short acting and intermidiate acting insulins.
This regime is rarely used.
What are the sick day rules for type 1 diabetics
Advice:
* DO NOT stop taking your insulin
* Test blood glucose more often (4x daily)
* Test for ketones using a kit
* Drink plenty of fluids
* REPLACE meals with carbohydrate containing drinks IF NECESSARY.
Give examples of PPAR agonists and their starting dose
Pioglitazone 15-30mg OD -> 45mg OD (if needed)
15mg for elderly
What are the target glucose level for diabetics
Before meals and waking: 4-7
90mins after meals: 5-9mmol/L
What can treat the symptoms of hypoglycaemia
Beta-blockers: Propanolol, bisoprolol
What is the lifestyle advice you would give to a type I diabetic ?
x /4
Diet
* Low salt, carbs, fat foods
* Atleast 5 portions of veg/fruit per day
* Monitor glucose intake
Alcohol
* Don’t drink more than 14 units a week
* Don’t drink alcohol on an empty stomach
Exercise
* Atleast 150 minutes of moderate intensity activity (walking/cycling) per week
* Advise them that their blood glucose levels.
Smoking
* Explain that smoking is a risk factor for cardiovascular disease
What lifestyle advice would you give to a type II diabetic ?
- Regular meals based on starchy, high fibre foods [eg bread, pasta, rice, cereals, potatoes]
- Reduce intake of saturated fat
- Five portions of fruit and veg
- Low salt intake
- Exercise 30mins per day for atleast 5 days of each week
- No more than 14 units of alcohol per week
What renoprotective medicine would you offer to a diabetic patient
Ramipril 1.25-2.5mg OD or Candersartan 8mg OD
(ACEi or ARB)
What antihypertensive medicine can cause a dry cough and what steps would you take going forward
ACE inhibitors like Ramipril and lisinopril. Replace them with an ARB such as candersartan 8mg
What are the recommendations for initial drug treatment for a type 2 diabetic
1) Start on Metformin 500mg OD with breakfast for 1 week
2) Change to BD with breakfast and evening meal for atleast 1 week
3) Change to TD with breakfast, lunch and dinner
4) Assess for CVD risk - If Qrisk > 10% then add an SGLT2 inhibitor - Dapagliflozin 10mg OD (with counselling)
Why is the risk of hypoglycaemia
less with metformin
Because metformin works by decreasing the output of glucose from the liver and does not increase the secretion of insulin thereby inducing less of a hypoglycaemia risk.
Give examples of GLP-1 agonists and their starting doses
- Exenatide 5 mcg TD
- Liraglutide 0.6mg OD -> 1.2 mg OD (after 1 week)
- Semaglutide 0.25mg qw for 4 weeks -> 0.5mg qw for 4 weeks
qw = Once weekly
What is the only recommended statin for CVD protection
Atorvastatin 20 mg ON
