Endocrine (Diabetes) Flashcards
T1DM pathophysiology
Autoimmune condition characterised by prolonged hyperglycaemia caused by destruction of Beta cells i the islets of Langerhans in the pancreas
- Beta cells produce insulin, therefore if they are destroyed blood glucose levels rise
RF for T1DM
- Family history
- Some environmental factors are thought to play a role (e.g. some viral infections)
presentation of T1DM
symptoms tend to start more acutely than type 2
- Polyuria – excessive thirst
- Polyuria – excessive passage of urine
- Weight loss
- Fatigue – often seen in children/young people
key acute complication of T1DM
DKA
Diabetic ketoacidosis (DKA) presentation
- Abdominal pain
- Vomiting
- Clinical features of dehydration
- Tachypnoea
- Altered consciousness or coma
T1DM investigations
- urine dipstic e.g. glucose, ketones
- blood tests suggesting raised blood glucose
- coeliac screening
Specific
- C-pepide levels
- Autoantibodies e.g. anti-GAD
blood glucose tests for T1DM
A helpful way to remember the thresholds for fasting and random blood glucose in diabetes is ‘7-11 fr (For Real)’ for Fasting blood glucose and Random respectively
Fasting blood glucose:
- ≥7.0 mmol/L
Random blood glucose:
- ≥11.1 mmol/ L – see Diagnosis section on diagnosing T1DM
HbA1c:
- ≥48 mmol/mol
- Not as useful as it reflects hyperglycaemia over the last 3 months and does not show quick fluctuations in blood glucose
fasting blood glucose
> 7.00 mmol/L
random blood glucose
> 11.1 mmol/L
HbA1C
> 48 mmol/mol
C-peptide in someone with T1DM
Low or undetectable
Pro-insulin is cleaved to form insulin and C-peptide.
main autoantibody for T1DM
Glutamic acid decarboxylase antibodies (anti-GAD): may be positive
World Health Organisation (WHO) criteria for T1DM
T1DM is diagnosed if:
SYMPTOMATIC +
one of the following on one occasion:
- Raised fasting glucose (≥7.0 mmol/L)
- Raised random glucose (≥11.1 mmol/L)
ASYMPTOMATIC but one of the above criteria has been demonstrated on two separate occasions.
T1DM monitoring
- HbA1c measured every 3-6 months - aim to be kept below 48mmol/mol
- Blood glucose should be self-monitored at least x4 a day including before each meal and before bed
Optimal blood glucose targets
- 5-7 mmol/L on waking
- 4-7 mmol/L before meals at other times of the day
Screening
- Screen for eye disease annually from 12 years of age
- Screen for diabetic nephropathy annually from 12 years of age
- Screen blood pressure annually from 12 years of age
Insulins can broadly be categorised based on their time-action profiles:
-
Rapid- and short-acting insulins: quick onset and short duration of action
* This is to mimic an ‘insulin spike’ that normally occurs in response to glucose absorbed from a meal or sugary drink -
Intermediate- and long-acting insulins: slow onset and long duration of action
* This is to mimic the effect of endogenous basal insulin (insulin that is released continuously throughout the day)
basal bolus regimes
One of the main advantages of a basal-bolus regimen is that it allows you to fairly closely match how your own body would release insulin if it was able to.
Basal
- Background insulin- keeps blood glucose levels at a consistent levels whilst fasting
- Given once a day - long acting or intermediate insulin
Bolus
- dose taken at meal times
- short acting or rapid acting insulin
Examples of long-acting basal insulin for people with diabetes include:
- glargine (Basaglar or Toujeo, which is ultra long-acting)
- detemir (Levemir)
- degludec (Tresiba}
Rapid-acting insulins include:
- aspart (Novolog)
- lispro (Humalog)
- glulisine (Apidra)
microvascular complications of T1DM
- Diabetic retinopathy – due to damage to small blood vessels in the kidney
- Diabetic retinopathy – due to damage to small blood vessels in the retina
- Diabetic neuropathy – due to direct damage due to hyperglycaemia and decreased blood flow due to damage to small blood vessels supplying the nerves.
diabetic neuropathy can lead to
- Painful diabetic neuropathy
- Diabetic foot disease
- Autonomic neuropathy – late-stage complication where there is autonomic nervous system dysfunction. This can lead to reduced hypoglycaemia awareness.
Macrovascular complications
Atherosclerosis and increased risk of cardiovascular diseases such as
* myocardial infarction
* stroke
* heart failure
* peripheral arterial disease
DKA is a characterised by a triad of
- Hyperglycaemia (i.e. blood glucose > 11 mmol/l)
- Ketosis (i.e. blood ketones > 3 mmol/l)
- Acidosis (i.e. pH < 7.3)- low bicarbonate
ketoacidosis is caused by
The lack of insulin in the body leads to the release of fatty acids from adipose tissue which are then metabolised into ketones, leading to ketosis.
- Ketones ordinarily act as a source of energy in states of energy deficiency (e.g. starvation), however, in DKA, they can lead to acidosis.
- The body initially resists the change in pH using the bicarbonate buffering system but becomes overwhelmed, leading to other compensatory mechanisms to combat the acidosis (e.g. hyperventilation to lower the blood CO2 levels, known as Kussmaul respiration if severe).
potasium imbalance in DKA
Insulin normally causes cells to take up potassium. Without insulin, potassium remains in the blood, leading to high serum potassium, but low total body potassium as none is stored in the cells. This is important because treatment with insulin can lead to hypokalaemia which carries complications such as arrhythmia.
Dehydration and DKA
Hyperglycaemia can lead to glucose being filtered out in the urine, taking water along with it via osmotic diuresis. This leads to polyuria, polydipsia, and dehydration.
Factors that may precipitate a DKA
often physical stresses:
- Infection
- Discontinuation of insulin
- Inadequate insulin treatment
- Stroke
- Myocardial infarction
features of DKA
Features may be:
- Abdominal pain – may be the presenting complaint
- Nausea and/or vomiting
- Altered consciousness
- Hyperventilation (Kussmal breathing- deep sighing breaths at a slow rate)
- Polyuria
- Polydipsia
- Dehydration
- Acetone-like breath smell:
- Similar in smell to pear drops or nail varnish remover
- Features of a precipitant (e.g. infection or discontinuation of insulin)
DD for DKA
Hyperosmolar hyperglycaemic state (HHS)
- Patients are generally older and have a history of type 2 diabetes
- The onset of symptoms is usually over days to weeks
- Focal neurological signs may be seen
- Ketones are normal, urinary ketones are normal/slightly raised
- On an arterial blood gas, the pH is usually >7.30
investigations for DKA
Capillary blood glucose:
- Hyperglycaemia >11.1
Venous or arterial blood gas:
- Shows metabolic acidosis with a raised anion gap
Blood ketones:
- Ketones are raised >3
FBC:
- May show leukocytosis which can suggest infection
U&Es:
- May show hyponatraemia
- May show hyperkalaemia or hypokalaemia in severe DKA
- Hypokalaemia can occur due to excessive urination excreting potassium
- May show hypomagnesaemia and hypophosphataemia
Urinalysis:
- Shows ketonuria
- May show glycosuria
ECG:
- To check for arrhythmias due to hypo-/hyper-kalaemia and to be used as monitoring during treatment
management of DKA
1. Correct dehydration evenly over 48 hours. This will correct the dehydration and dilute the hyperglycaemia and the ketones. Correcting it faster increases the risk of cerebral oedema.
- 0.9% NaCl 500ml bolus
2.Give a fixed rate insulin infusion This allows cells to start using glucose again. This in turn switches off the production of ketones
- 0.1 units/kg/hour
- remember insulin drives potassium into cells so can cause hypokalaemia
Other important principles:
- Avoid fluid boluses to minimise the risk of cerebral oedema, unless required for resuscitation.
- Treat underlying triggers, for example with antibiotics for septic patients.
- Prevent hypoglycaemia with IV dextrose once blood glucose falls below 14mmol/l.
- Add potassium to IV fluids and monitor serum potassium closely.
- Monitor for signs of cerebral oedema.
- Monitor glucose, ketones and pH to assess their progress and determine when to switch to subcutaneous insulin.
cerebral oedema
Children and young adults (generally <25 years of age) are susceptible to cerebral oedema. Dehydration and hyperglycaemia cause water to move from the brain cells into the extracellular space, causing them to shrink. Correcting the dehydration and hyperglycaemia too quickly leads to water moving from the extracellular space back into the brain cells leading to swelling and oedema, which can lead to death.
Features of cerebral oedema usually arise within 24 hours of treatment. Changes in consciousness or behaviour, headaches, or bradycardia are suggestive of cerebral oedema.
cerebral oedema treatment
- Seek immediate senior care and critical care support
- IV mannitol or hypertonic saline may be used to reduce the swelling
- Consider ordering a CT head
after initial treatment for DKA
They should be managed in a high-dependency unit type of setting. In general:
- U&Es and venous blood gases are checked every 1-2 hours initially
- Fluid balance and capillary blood glucose are measured hourly
- When plasma glucose is <12 mmol/L, then normal saline is replaced with 5% dextrose to avoid over-correcting the blood glucose concentration and causing hypoglycaemia.
complications of DKA
- Cerebral oedema
- Pulmonary oedema
- Iatrogenic hypokalaemia
- Iatrogenic hypoglycaemia
- Cardiac arrhythmia
- Venous thromboembolism
- Myocardial infarction
- Acute respiratory distress syndrome
- Pulmonary oedema
T2DM pathophysiology
Diabetes mellitus is characterised by prolonged hyperglycaemia. Type 2 diabetes mellitus (T2DM) occurs due to insulin resistance and the inability of the beta cells to release sufficient amounts of insulin.
Maturity-Onset Diabetes of the Young (MODY)
MODY describes the development of T2DM in adolescence or early adulthood (usually <25 years) that is inherited in an autosomal dominant manner. There are many different monogenic mutations associated with MODY.
T2DM rf
- Obesity
- Inactivity
- Increased age
- Family history
- People of Asian, African, or Afro-Caribbean ethnicity
- Hypertension
- Dyslipidaemia
- Cardiovascular disease
- Previous gestational diabetes
- Some drugs (e.g. corticosteroids)
- Polycystic ovary syndrome
T2DM presentation
The presentation of T2DM tends to be milder and more subacute. T2DM is often incidentally picked up on routine tests. Features may be:
- Asymptomatic
- Polyuria
- Polydipsia
- Recurrent urinary tract infections
- Recurrent skin infections
- Candida infections
- Fatigue
- Acanthosis nigricans – a sign of insulin resistance: Velvety dark skin usually on the neck, underarms, or groin
T1DM vs T2DM
- Patients are generally younger and the onset is quicker over hours – days
- Weight loss is common
- C-peptide levels are low/undetectable
- Autoantibodies are present
- Ketonuria is common
investigations for T2DM
Fasting blood glucose
- >7.0 mmol/L
Random plasma glucose
- >11.1 mmol/l
HbA1c (not useful in haemaglobinopathies)
- 48 mmol/mol
Oral glucose tolerance test (OGTT)
- >11.1 mmol/L
Others
Albumin:creatinine ratio (ACR):
- Proteinuria can indicate diabetic nephropathy
- Measured yearly
- ≥3 mg/mmol indicates proteinuria
U&Es:
* May show renal insufficiency in diabetic retinopathy
LFTs:
* May be deranged in non-alcoholic fatty liver disease (NAFLD)
T2DM is diagnosed if:
The patient is symptomatic and has one of the following on one occasion:
- Raised fasting glucose (≥7.0 mmol/L)
- Raised random glucose (≥11.1 mmol/L)
- OGTT (≥11.1 mmol/L)
The patient is asymptomatic but one of the above criteria has been demonstrated on two separate occasions.
Prediabetes and impaired glucose regulation
A patient has impaired fasting glucose if their fasting glucose is between 6.1 – 7.0 mmol/L. they have impaired glucose tolerance if their OGTT result is between 7.8 – 11.1 mmol/L.
T2DM Treatment targets
Treatment targets are set according to one’s HbA1c levels. They can vary depending on what stage of management a patient is on:
- Lifestyle changes: 48 mmol/mol
- Lifestyle changes + drug that does not cause hypoglycaemia (metformin): 48 mmol/mol
- Lifestyle changes + drug that does cause hypoglycaemia (sulfonylurea): 53 mmol/mol
- If already taking 1 drug but HbA1c is ≥58 mmol/mol: 53 mmol/mol
contraindication for metformin
renal problems e.g. eGFR below 30
management of T2DM in patients where Metformin is not contraindicated
First line
Metformin + check cardiovascular disease (CVD) status:
- If they have heart failure, established CVD, or are at high risk for CVD (QRISK >10%): add an SGLT-2 inhibitorafter the metformin has been established and titrated up
- If metformin is not tolerated, switch to a modified-release form
- If the patient develops heart failure, or CVD, or becomes at high risk for CVD at any point: add an SGLT-2 inhibitor regardless of HbA1c
Second line
Dual therapy – if the HbA1c has risen to 58 mmol/mol, then another drug is indicated, which may be one of the following:
- Metformin + DPP-4 inhibitor
- Metformin + pioglitazone
- Metformin + sulfonylurea
- Metformin + SGLT-2 inhibitor if a sulfonylurea is contraindicated/not tolerated, or the person is at risk of hypoglycaemia or its consequences
Third line:
Triple therapy – one of the following:
- Metformin + DPP-4 inhibitor + sulfonylurea
- Metformin + pioglitazone + sulfonylurea
- Metformin + pioglitazone or sulfonylurea + canagliflozin or empagliflozin (specific SGLT-2 inhibitors)
- Metformin + DPP-4 inhibitor + ertugliflozin (SGLT-2 inhibitor) if sulfonylurea or pioglitazone is inappropriate
- Start insulin-based treatment
management of T2DM in patients where metformin is contraindicated
Metformin contraindicated
First line:
Check CVD status:
- If they have heart failure, established CVD, or are at high-risk for CVD: SGLT-2 inhibitor monotherapy
- If no heart failure, established CVD, or are not at high-risk for CVD then consider:
- Pioglitazone, sulfonylurea, or a DPP-4 inhibitor
- Offer an SGLT-2 inhibitor if none of the above is appropriate
Second line
Dual therapy – one of the following:
- DPP-4 inhibitor + pioglitazone
- DPP-4 inhibitor + sulfonylurea
- Pioglitazone + sulfonylurea
Third line insulin-based treatment
which hypoglycaemic agents can cause hypoglycaemia
- Sulphonylures such as glicazide -> increased panceeatic insulin secretion
- Glitazones such as pioglitazone -> enhances insulin sensitivity and glucose utilisation
sulphonylureas
e.g. Glicazide
- hypoglycaemia risk
- increased weight
- PO
MOA stimualtes pancreatic insulin secretion
Biguanides
Metformin
- no hypoglycaemia risk
- suppresses appetides
- oral
MOA: reduces hepatic glucose output
glitazones
e.g. Pioglitazone
- hypoglycaemia risk
- increases appetite
- oral
MOA: enhances insulin sensitivity and glucose utilisation
Dipeptidyl peptidase -4 (DPP-4) inhibitors (gliptins)
e.g. Saxagliptin and sitagliptin
- no hypoglycaemia risk
- reduces appetite
- oral
MOA: Incretins promote insulin secretion and supress glucagon release - prevent incretin degradation
Sodium glucose co-transporter SGLT-2 hinhibitors (gliflozins)
e.g. Canagliflozin
- no hypoglycaemia risk
- decreases weight
- oral
MOA: reduces glucose reabsorption
Glucagon-like peptide-1 (GLP-1) receptor agonists (incretin mimetics)
e.g. Exenatide, Liraglutide
- no hypoglycaemia risk
- increases satiety
- subcut
MOA: increased glucose dependent synthesis of insulin
further treaments for diabetics
- Antihypertensives e.g. ACEi or ARB
- Atorvastatin
- Annual influenza vaccination
- One off pneumococcal vaccination
complications of T2DM
Acute: HSS
Chronic
- microvascular complications
- macrovascular complications
Hyperosmolar hyperglycaemic state (HHS)
is a potentially life-threatening endocrine emergency usually seen in patients with type 2 diabetes mellitus (T2DM).
HHS must be differentiated from diabetic ketoacidosis (DKA), as their management steps vary significantly, and giving a patient with HHS insulin can lead to adverse outcomes.
HSS pathophysiology
HHS is usually precipitated by an acute illness (e.g. infection, myocardial infarction etc.). The stress leads to the release of hormones such as cortisol and glucagon, leading to increased blood glucose concentrations. Since there is a relative insulin deficiency (as patients with T2DM have insulin resistance), blood glucose concentrations cannot be effectively controlled, leading to incredibly high glucose concentrations (often over 40 mmol/L).
The increased blood glucose concentration leads to an osmotic shift of water into the blood vessels, away from cells, leading to intracellular dehydration. Ketosis does not occur as insulin is still released in T2DM, preventing adipose breakdown which leads to the production of ketones.
-
HSS Risk Factors
- Acute illness (e.g. infection, stroke, myocardial infarction)
- Hyper-/hypothermia
- Burns
- Cushing’s syndrome
- Substance misuse (e.g. alcohol, cocaine etc.)
- Dehydration
HHS presentation
- Acute cognitive changes (e.g. drowsiness, confusion etc.)
- Polyuria – onset is usually over days-weeks
- Polydipsia – onset is usually over days-weeks
- Fatigue
- Lethargy
- Weakness
- Headaches
- Nausea and vomiting
- Tachycardia – due to hypovolaemia
- Hypotension – due to hypovolaemia
- Focal neurological deficits
- Seizures
HHS investigations
Blood glucose:
* High, usually ≥30 mmol/L
* Blood ketones – used to distinguish HHS from DKA
* Negative or low, unlike in DKA
Venous or arterial blood gas:
* Acidosis is not present, but may show mild acidosis (pH >7.30 and bicarbonate >15 mmol/L)
* May show lactic acidosis (e.g. if due to sepsis)
Serum osmolality:
* Elevated (≥320 mOsm/kg) due to hypovolaemia
FBC:
* May show leukocytosis, which is common in HHS
* Higher levels (usually >25 x 109/L) suggest an infection
U&Es:
* May show renal impairment
* May show hypernatraemia:
* Hypernatraemia is seen due to severe dehydration
* May show hypo/hyperkalaemia:
* Hypokalaemia is common
* Hyperkalaemia may occur if an acute kidney injury is present
* May show hypophosphataemia
* May show hypomagnesaemia
ECG:
To look for triggers of HHS (e.g. myocardial infarction), or complications of HHS (e.g. hypo/hyperkalaemia)
management of HHS
1. IV fluids to correct osmolality – monitor the serum osmolality:
* Serum osmolality can be estimated via the formula: (2 x Na+) + glucose + urea
* Rapid changes in serum osmolality can lead to central pontine myelinolysis (CPM) and cardiovascular collapse (e.g. fluid overload)
1. Replace fluid and manage electrolyte imbalances
2. Gradually normalise blood glucose concentration:
* Fluid replacement alone with normal saline can gradually reduce blood glucose and osmolality
* Using insulin before adequate fluid replacement can lead to a rapid decline in glucose and hence, serum osmolality which can precipitate CPM and cardiovascular collapse.
* Insulin should be considered if fluid replacement alone is ineffective. If significant ketonaemia is present, this can suggest a mixed DKA/HHS picture and insulin may be given at a rate of 0.05 units/kg/hr. If there is no ketonaemia present, do not start insulin.
osmolality calculation
Serum osmolality can be estimated via the formula: (2 x Na+) + glucose + urea
Hypoglycaemia
is defined as a blood glucose concentration <3.5 mmol/L and most commonly occurs due to excess insulin or oral hypoglycaemic agents combined with reduced glucose intake or increased activity.
which triad used to diagnose hypoglycaemia
Whipple’s triad:
- Plasma hypoglycaemia
- Symptoms that correlate with hypoglycaemia
- Resolution of symptoms after correcting hypoglycaemia
RF for hypoglycaemia
- Alcohol consumption
- Insulinoma
- Excess insulin or hypoglycaemic agent (e.g. sulfonylurea) use
- Starvation
- Self-induced hypoglycaemia (factitious hypoglycaemia)
- Adrenal insufficiency
presentation of hypoglycaemia
Sympathoadrenal (responses to hypoglycaemia from the sympathetic nervous system and adrenal glands, usually seen at glucose concentrations <3.3 mmol/L):
* Sweating
* Anxiety
* Palpitations
* Tremor
* Nausea
* Hunger
* Tingling
Neuroglycopenic (brain malfunction secondary to hypoglycaemia, usually seen at glucose concentrations <2.8 mmol/L):
* Confusion
* Drowsiness
* Irritability
* Vision blurring
management of hypoglycaemia
Any patient that has hypoglycaemia secondary to an oral antidiabetic drug must be admitted to the hospital, as their hypoglycaemic effects can linger for 12-24 hours.
First line oral glucose via liquid, gel, or tablet form
Second line
- If the patient is unconscious or unable to swallow, consider SC or IM glucagon
- If there is IV access through a large vein, consider IV 20% glucose solution
Treat underlying cause
complications of hypoglycaemia
- Seizure
- Coma
- Permanent neurological complications
insulinoma
Insulinomas are the most common pancreatic endocrine tumours that arise from beta cells in the Islets of Langerhans and are associated with multiple endocrine neoplasia 1 (MEN-1). They can release excess amounts of insulin in response to glucose, leading to hypoglycaemia.
presentation of insulinoma
Features of hypoglycaemia
Unexplained weight gain, particularly rapid weight gain
investigations for insulinoma
Insulin:
* Elevated
Proinsulin:insulin ratio:
* Elevated
C-peptide:
* Elevated
Supervised 72-hour fast:
- Hypoglycaemia should suppress insulin release. Insulin is not properly suppressed
CT pancreas:
May show insulinoma
management of insulinoma
- 1st-line: surgical removal
- If unsuitable for surgery: diazoxide + somatostatin
