Diabetes mellitus Flashcards
Microvascular complications of diabetes mellitus? (specific to diabetes)
Retinopathy, nephropathy, neuropathy (foot)
Macrovascular complications of diabetes mellitus?
Cerebrovascular, ischaemic heart disease, peripheral vascular disease (foot)
Difference between type 1 a and b?
1a is destruction of beta cells due to an AI response
1b is idiopathic
Hallmark of type 1?
Absence of C-peptide
MODY 1-7 =
Monogenic diabetes
Genetic defects in insulin action:
Type a insulin resistance
Leprechaunism
Rabson-Meldenhall syndrome
Diabetes can develop secondary to which conditions?
Other endocrine conditions e.g. Cushing’s or acromegaly
Endocrine causes of diabetes?
Glucocorticoids and thyroxine
Infectious causes of diabetes?
Congenital rubella
CMV
Stiff man =
Antibodies to the insulin receptor
Osmotic symptoms of diabetes?
Thirst, polyuria and polydipsia
Associated genetic syndromes:
Down’s
Huntington’s
Proteolysis and lipolysis in marked/complete insulin insufficiency leads to…
Weight loss
Ketogenesis and ketosis leading to acidosis resulting in vasodilation and causing (along with dehydration) hypotension
Mononeuritis in diabetes?
Diplopia
Neuropathies:
Peripheral - numbness/pain/tingling in hands and feet
Autonomic - sweating, gastroparesis, postural dizziness, erectile dysfunction, diarrhoea and incontinence
Radiculopathy - pain and wasting
Mononeuritis - diplopia
Compression - carpal tunnel, ulnar nerve, lateral popliteal nerve
Diagnosis of diabetes mellitus (symptomatic):
Diabetes symptoms (e.g. polyuria or weight loss in type 1) and any one of:
1) Random venous plasma glucose > 11.1mmol/L
2) Fasting plasma glucose concentration > 7mmol/L, whole blood > 6.1mmol/L
3) Two hour plasma glucose > 11.1mmol/L after 75g glucose in an oral glucose tolerance test
Diagnosis of diabetes mellitus (asymptomatic):
Absence of any symptoms with raised venous plasma glucose with a raised fasting plasma glucose or OGTT on a seperate day
Diagnosis with HbA1c:
Pre-diabetes = 6.1-6.4% (43-47 mmol/L)
Diabetes = 6.5% (48 mmol/L)
A value of less than 6.5% does not exclude diagnosis of diabetes with glucose tests
When is HbA1c not an appropriate diagnostic tool?
All children and young people Suspected type 1 Diabetes symptoms < 2 months High risk acutely ill patients Patients taking any medications that can cause rapid glucose rise e.g. antipsychotics or steroids Acute pancreatic damage Pregnancy Other influencing factors on HbA1c
Features of the oral glucose tolerance test (OGTT):
180gm CHO for 3 days before Overnight fast Sedentary during test Fasting venous plasma glucose 75g anhydrous glucose over 5 minutes 2 hour venous plasma glucose
Clinical features of type 1:
Insulin deficient Ketosis prone HLA markers Autoimmune (other AI conditions) Peak of onset in adolescence Weight loss
Clinical features type 2:
Insulin resistant and deficient Not ketosis prone Polygenic South Asians > Africans and Carribeans > Europeans Increases with ageing Associated with central obesity
Genetic markers of type 1 diabetes:
HLA-DR3 HLA-DR4 DQalpha and beta IDDM2 IDDM12
Can a patient with a HbA1c under 6.5% be diagnosed with diabetes?
Yes
What are the hyperglycaemic diabetic emergencies?
Diabetic ketoacidosis
Hyperosmolar hyperglycaemic state
Triad of DKA:
Hyperglycaemia, hyperketonaemia, metabolic acidosis
Diagnosis of DKA:
Blood glucose > 11mmol/L or known diabetes
Blood ketones > 3mmol/L or ketonuria > 2+
Bicarbonate < 15mmol/L and/or venous pH < 7.3
Which hormones can cause DKA?
Stress hormones - catecholamines, cortisol
Why can DKA cause disordered potassium?
Insulin causes K to move into cells
Insulin deficiency means that K moves into the blood (hyperkalaemia) and is lost in the urine - whole body loss
Acidosis causes similar effect as H and K compete
Problem with treating DKA?
K moves from the blood to the intracellular compartment too quickly and can cause arrhythmias
What can cause DKA?
Infection
Poor compliance
Newly diagnosed/failure of care
Complications of DKA:
Cerebral oedema (fluid shift) Adult respiratory distress syndrome/acute lung injury PE (dehydration) Arrhythmias Multi-organ failure (acidosis) Co-morbid state
Symptoms of DKA:
Blurred vision not due to retinopathy but due to fluid-shifts
Leg cramps
Weakness
Osmotic symptoms
Signs of DKA:
Kussmaul respiration (laboured and deep, hyperpnoea) Ketotic fetor (sweet smell on breath) Dehydration Tachycardia Hypotension Mild hypothermia Confusion, drowsiness, coma
Step 1 of treating DKA:
Fluid replacement
IV 0.9% saline
Perfuse the kidneys to normalise the acid-base balance
Step 2 of treating DKA:
Insulin replacement
Fixed rate IV 0.1 units/kg/hour
Step 3 of treating DKA:
Potassium replacement
Replace the K as soon as in normal range as serum K falls very rapidly post fluid and insulin correction
Step 4 of treating DKA:
Address cause of the DKA
Step 5 of treating DKA:
VTE prophylaxis - LMWH
Step 6 of treating DKA:
Monitor - HDU
Type 2 diabetic emergency?
Hyperosmolar hyperglycaemic state (HHS)
HHS osmolality and glucose =
Hyperosmolality > 320 mosmol/kg
Hyperglycaemia > 30 mmol/L
HHS pathology:
Severe dehydration and hypovolaemia
Without ketonaemia
Without acidosis
HHS complications:
Cerebral oedema Osmotic demyelination syndrome Seizures Arterial thrombosis - MI, CVA, strokes VTE, PE Multiorgan failure Foot ulceration Co-morbid condition
Clinical features of HHS:
Osmotic symptoms Blurred vision Weakness Dehydration Tachycardia Hypotension Confusion, drowsiness and coma
What is the potentially life-threatening complication of not gradually normalising HHS?
Cerebral oedema
How is HHS treated?
The exact same protocol as for DKA except a lower fixed rate of insulin at 0.05 units/kg/hour
(Still have to give LMWH for VTE risk)
When do you give an extra short-acting insulin bolus?
sick day rules
If CBG > 13mmol/L
If blood ketones >1.5mmol/L
Why are sick day rules necessary?
When ill, glucose levels and insulin requirements go up causing ketones to rise as well
Sick day rules:
Never stop background long-acting insulin
Check cap BG every 2-4 hours
100ml/hour fluid
Bolus for carbohydrate
Med help if start vomiting, CBG/ketones not improving, hypos
Definition of a hypo:
<3.5mmol/L (<4 in hospital)
Main effect of sever hypo:
Confusion, seizure, coma and death (neuro)
Drug induced hypo:
Side effect of insulin or sulphonylureas
Symptoms of hypos:
Autonomic: sweaty and palpitations
Neuro: confusion, visual disturbances, circumoral paraesthesia
Hunger
Treatment for hypo with conscious patient who can walk?
Fast-acting carbohydrate oral 15-20g
Check in 10 mins, if still hypo then repeat and then check again in 5 minutes
Treatment for severe hypo with unconscious patient?
IV glucose 20% 75-100ml or 1mg SC/IM
Re-check and repeat if need be
If they can swallow and it is severe but two glycogen tablets in the inner cheek
Treatment after initial management of the hypo?
Eat 15-20g long acting carbohydrate like one slice of bread or two biscuits, do not omit insulin injection and address the cause
Effect of somatostatin?
Blocks both insulin and glucagon release
Example of a biguanide:
Metformin
Effect of Metformin?
Decreases hepatic gluconeogenesis (+gene expression)
Also activates AMPK which increases GLUT4 expression in muscle cells
Stimulates glycolysis in tissues
Decreases carbohydrate reabsorption in the gut
Stimulates lactate production
Lowers LDL and VLDL
Reduces microvascular complications
Benefits of Metformin?
Does not stimulate appetite
Does not cause hypos
Does not cause weight gain
Side-effects of Metformin?
Metallic taste
Diarrhoea, nausea
Decreased B12 and folate absorption
Rare: lactate acidosis
Features of Metformin:
Not bound to plasma protein
t(1/2) = 3hours
Absorbed in the small intestine
Sulphonylureas:
-mide/-zide
e.g. Glibendamide, Glipizide
(Old: carbutamide, tolbutamide, chlorpropramide)
Effect of Sulphonylureas?
Bind to KATP channels causing depolarisation of Beta cells and release of insulin
Decrease hepatic clearance of insulin
Features of Sulphonylureas?
Plasma protein bound so displace other plasma bound drugs and increase their plasma concentration e.g. NSAIDs, MAO inhibitors and Abx
Excreted in urine with enhanced effect in elderly/renal impairment
Main side-effect of sulphonylureas?
Hypos
May need IV glucose, glucagon or adrenaline
Meglitinides:
Rapaglinide and Nateglinide
t(1/2) = 1 hour
Effect on meglitinides?
Close KATP channels selective in beta cells
Guidelines for meglitinides:
Can be used as monotherapy
Take just before meal
Comparison between sulphonylureas and meglitinides?
Meglinitides are less potent but more rapid and are less prone to causing hypos
Glutaziones:
Pioglitazone (risk of bladder cancer)
Effect of glutaziones:
Nuclear receptor (PPARgamma and RXR) agonists
Decrease insulin resistance in peripheral tissues
Reduces hepatic gluconeogenesis
Increases uptake and potentiates action of insulin
Side-effects of glutaziones:
Increased food intake in the brain
Decrease in bone density
Increase in sodium and water retention in the kidney
Increased growth and lipid storage in the heart
Increases adipocyte no. and lipogenesis so weight
Directions for glutaziones:
The t(1/2) = 7 hours, 24 hours for the active metabolite
Give with metformin or other hypo drugs
6-12 weeks of therapy for the maximum effect
Incretins:
Glucagon-like peptide-1 (GLP-1) agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors
Effect of incretins?
Incretins are gut derived peptides that stimulate insulin release, decrease glucagon release
In the brain they reduce appetite so help lose weight
They slow glucose absorption in the gut by slowing gastric emptying
Stimulate an increase in beta cells
Guidance for incretins:
Must be given IV as an injection
No effect on weight or hypos however Loraglutide has been given at a high dose as a weight loss drug (daily injections)
Possible increase in cancer
DPP-4 breaks down GLP-1 so glistens inhibit this
Reduce risk of microvascular and renal outcomes
alpha-glucosidase inhibitors:
Acarbose - inhibits alpha-glucosidase at the intestinal brush border
Effect of alpha-glucosidase inhibitors?
Decrease in carbohydrate breakdown and postprandial absorption
Features of alpha-glucosidase inhibitors:
Does not cause hypos
Used in both T1DM and T2DM
May cause flatulence and diarrhoea
SGLT2 inhibitors:
Dapagliflozin + empagliflozin are both SGLT2 inhibitors
Cangliflozin is an SGLT1 and an SGLT2 inhibitor
Xigduo = metformin + dapagliflozin
Vokanamet = metformin + canagliflozin
Effect of SGLT2 inhibitors?
SGLT2 is responsible for 80-95% of the glucose reabsorption in the proximal tubule
Inhibits glucose re-uptake in the kidney
Causes around 10% excretion of calorie intake
Decreases CVD secondary to diabetes
Effect of amylin analogues:
Inhibits glucagon release
Decreases gastric emptying
Promotes satiety
Features of amylin analogues:
Can cause amyloid aggregates - Alzheimer’s
Pramlintide is an analogue that doesn’t cause aggregates
Adjunct for both T1DM and T2DM
Which drugs increase insulin secretion?
Sulphonylureas
Meglitinides
Incretins
Which drugs decrease glucagon secretion?
Incretins
Amylin analogues
Which drugs decrease appetite?
Incretins
Amylin analogues
Which drugs decrease glucose reabsorption?
SGLT2 inhibitors
Which drugs increase cellular glucose uptake and utilisation?
Glutaziones (thiazolidinediones)
Metformin
Which drugs decrease hepatic gluconeogenesis?
Glutaziones (thiazolidinediones)
Metformin
Obesity treatment:
Serotonin uptake agonists help appetite control
What does U100 mean?
100 units of insulin per ml
Basal dose of insulin?
Long acting for whole day
One per day = glargine (acid solution in vial that precipitates at body pH)
Twice per day = detemir (attached to fatty acid as bigger molecules = longer action)
Prandial dose of insulin?
Fast acting dose before meal (e.g. monomers Lispro and Aspart)
What does insulin pump therapy provide (CSII)?
Basal and prandial spikes
Insulin for type 2 diabetes?
Long dose e.g. glargine once a day or mixed before breakfast and before dinner
CKD in diabetes type 2:
GFR can drop by 1ml a year (if 10 or over in a year then biopsy)
GFR can drop without proteinuria
SGLT2 inhibitor empagliflozin and incretin loraglutide improves renal outcomes
Side-effects of insulin?
Hypos increase risk of cardiac arrhythmias
Neuroglycopaenia
Higher risk of hypo if patient taking insulin has poor renal function
Weight reduction therapies:
Orlistat = weight reduction 5%, improves HbA1c
Bariatric surgery = weight reduction 15-25%, diabetes remission
Reducing cholesterol:
Statins
PSK9 inhibitors - Evolcumab
BP targets?
< 140/80
< 130/80 if there are complications
Step 1 of drug BP control:
ACE inhibitor
+ CCB/diuretic if African/Carribean
Step 2 of drug BP control:
+ CCB/diuretic
Step 3 of drug BP control:
+ diuretic/CCB
Step 4 of drug BP control:
+ alpha-blocker/beta-blocker/K-sparing diuretic
Step 5 of drug BP control:
+ alpha-blocker/beta-blocker/K-sparing diuretic/refer to a specialist
When can reducing BP too much increase mortality risk?
Elderly patients >65 y/o
Patients with reduced kidney function
Contraindication of glutaziones?
Heart failure (they caused oedema and heart failure)
