Physiology
Endocrine
Question 4 of 180
A 21 year old women, with known diabetes mellitus, is brought to ED with diabetic ketoacidosis (DKA). An insulin infusion would be expected to cause an increase in which of the following:
Answer:
Before the injection of insulin, the woman would typically have had hyperglycemia, glycosuria, hyperkalemia, and metabolic acidosis with compensatory hyperventilation. The injection of insulin would be expected to decrease her blood glucose (by increasing the uptake of glucose into the cells), decrease her urinary glucose (secondary to decreasing her blood glucose), decrease her blood K+ (by shifting K+ into the cells), and correct her metabolic acidosis (by decreasing the production of ketoacids). The correction of the metabolic acidosis will lead to an increase in her blood pH and will reduce her compensatory hyperventilation.Diabetes Mellitus
Physiology / Endocrine / Pancreatic Function
Last Updated: 21st April 2019
Diabetes mellitus is a metabolic disorder characterised by persistent hyperglycaemia which is a result of defects in insulin secretion, insulin action or both.
Classification
Diabetes mellitus is broadly classified as type 1 or type 2 (although rarer causes of diabetes exist):
- Type 1 (5 - 10%)
- Autoimmune destruction of beta-cells of the pancreas results in absolute insulin deficiency with patients requiring insulin to survive
- In absence of insulin action in muscle and adipose tissue, glucose is not transported into cells by the GLUT4 transporter
- Type 2 (90 - 95%)
- Caused by both insulin resistance and a defect in insulin secretion as a result of beta-cell dysfunction
- Insulin resistance occurs in skeletal muscle, adipose tissue and liver, resulting in reduced glucose uptake in skeletal muscle, impaired inhibition of hepatic glucose output and increased fatty acid production in adipose tissue, which stimulates gluconeogenesis and triglyceride synthesis
- Risk factors include obesity, lack of physical activity, increasing age, dyslipidaemia, hypertension, certain ethnic groups, genetic predisposition
Clinical Features
T1DM:
- Osmotic symptoms
- Thirst, polydipsia, polyuria
- Dehydration, hypovolaemia, drowsiness
- Blurred vision
- Cutaneous Candida infections
- Catabolic symptoms
- Muscle wasting, fatigue and weight loss
- Diabetic ketoacidosis (approx 25% of children with T1DM present in DKA)
- Aetiology
- Impairment of glucose utilisation in the peripheral tissues leads to increased gluconeogenesis and glycogenolysis in the liver with consequent worsened hyperglycaemia.
- Simultaneous counter-regulatory hormone hypersecretion (including cortisol, glucagon and catecholamines) in tandem with insulin deficiency causes release of free fatty acids into the circulation as a result of lipolysis in adipose tissue.
- Free fatty acids undergo oxidation in the liver to produce ketone bodies and subsequent ketonaemia. As ketone bodies are weakly acidic, this causes increased plasma hydrogen ion concentrations and metabolic acidosis.
- Characterised by the biochemical triad:
- Hyperglycaemia (> 11 mmol/L)
- Ketonaemia (> 3 mmol/L)
- Acidosis (pH < 7.3 +/- HCO3 < 15 mmol/L)
- Clinical features
- Symptoms
- Polyuria, polydipsia, thirst, lethargy, weight loss, nausea, vomiting, anorexia, abdominal pain, dehydration, headache, altered mental state
- Signs
- Dry mucous membranes, ketotic breath, tachycardia, hypotension, Kussmaul breathing, focal signs of precipitant e.g. infection
- Symptoms
- Management
- Fluid replacement
- Insulin (+ glucose)
- Monitoring of [K+] (+/- replacement)
- Treat underlying cause
- Aetiology
T2DM:
- One-third of cases are detected incidentally
- Diagnosis is often delayed for many years and the patient can therefore present with complications from prolonged hyperglycaemia
- Only about half of patients present with the classic symptoms of thirst, polydipsia, polyuria and tiredness secondary to hyperglycaemia, although these symptoms are less marked than in T1DM
- Hyperglycaemic hyperosmolar state (up to 25% of patients with T2DM present as HHS)
- Aetiology
- Prolonged hyperglycaemia from insulin resistance or insulin deficiency results in an osmotic diuresis with renal sodium and potassium loss.
- This results in extracellular volume depletion and dehydration, with a raised serum osmolality.
- Ketosis/ketonaemia does not typically occur in HHS, because some insulin is still present and hyperosmolality can inhibit lipolysis.
- Characterised by triad:
- Hypovolaemia
- Marked hyperglycaemia (> 30 mmol/L) without significant hyperketonaemia or acidosis
- Osmolality > 320 mosmol/kg
- Clinical features
- Polydipsia, polyuria, impaired cognitive function, tachycardia, hypotension, seizures
- Management
- Treat underlying cause
- Fluid replacement (+/- insulin)
- Correct electrolyte imbalance
- Treat with prophylactic anticoagulation
- Aetiology
Diagnosis
- Glucose concentration criteria:
- In symptomatic individuals (e.g. thirst, polyuria, polydipsia and unexplained weight loss):
- A random venous plasma glucose concentration ≥ 11.1 mmol/L OR
- A fasting plasma glucose concentration ≥ 7.0 mmol/L OR
- Two-hour plasma glucose concentration ≥ 11.1 mmol/L after 75g anhydrous glucose in an oral glucose tolerance test (OGTT)
- In asymptomatic individual:
- At least one of the above criteria fulfilled on two separate occasions
- In symptomatic individuals (e.g. thirst, polyuria, polydipsia and unexplained weight loss):
- HbA1c criteria:
- HbA1c ≥ 48 mmol/mol (6.5%) confirmed with second sample unless individual is symptomatic with plasma glucose ≥ 11.1 mmol/L when confirmation is not needed
- N.B. Not to use in children and young people, type 1 DM, symptom onset within 2 months, pregnancy, drugs causing hyperglycaemia (e.g. steroids) or blood conditions affecting Hb (e.g. haemolytic anaemia)
Complications
- Macrovascular
- Ischaemic heart disease
- Angina, ACS
- Cerebrovascular ischaemia
- TIA, stroke
- Peripheral vascular disease
- Intermittent claudication, acute ischaemic limb, foot ulcer
- Ischaemic heart disease
- Microvascular
- Autonomic neuropathy
- Resting tachycardia, postural hypotension, cardiac ischaemia, sudden cardiac death
- Gastroparesis, constipation/diarrhoea, oesophageal dysmotility
- Erectile dysfunction, neuropathic bladder
- Mononeuropathies
- Often cranial nerves III and VI, median, ulnar and radial nerves
- Diabetic peripheral neuropathy
- Glove and stocking distribution, foot ulceration
- Diabetic nephropathy
- CKD
- Diabetic retinopathy
- Blindness
- Autonomic neuropathy
Hypoglycaemia
Hypoglycaemia occurs when plasma glucose falls below 4 mmol/L. It commonly occurs as a result of insulin therapy; it can also occur with certain oral hypoglycaemic agents.
In individuals without diabetes, the normal response to hypoglycaemia comprises reduced insulin secretion from the pancreas and increased glucagon release. A number of counter-regulatory hormones, including noradrenaline, cortisol and growth hormone, are also released. In patients with diabetes, these responses are reduced, especially with recurrent hypoglycaemia and with increased duration of disease - this can result in hypoglycaemic unawareness.
Clinical features of hypoglycaemia:
- Autonomic symptoms
- Sweating, feeling hot, anxiety/agitation, palpitations, shaking, paraesthesia, dizziness
- Neuroglycopaenic symptoms
- Weakness, blurred vision, difficulty speaking, poor concentration, poor coordination, drowsiness, confusion, seizures, coma
- Other symptoms
- Nausea, fatigue, hunger
Any suspected hypoglycaemia should be managed as an emergency, and treated immediately to return blood glucose to the normal range.
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- Biochemistry
- Blood Gases
- Haematology
| Biochemistry | Normal Value |
|---|---|
| Sodium | 135 – 145 mmol/l |
| Potassium | 3.0 – 4.5 mmol/l |
| Urea | 2.5 – 7.5 mmol/l |
| Glucose | 3.5 – 5.0 mmol/l |
| Creatinine | 35 – 135 μmol/l |
| Alanine Aminotransferase (ALT) | 5 – 35 U/l |
| Gamma-glutamyl Transferase (GGT) | < 65 U/l |
| Alkaline Phosphatase (ALP) | 30 – 135 U/l |
| Aspartate Aminotransferase (AST) | < 40 U/l |
| Total Protein | 60 – 80 g/l |
| Albumin | 35 – 50 g/l |
| Globulin | 2.4 – 3.5 g/dl |
| Amylase | < 70 U/l |
| Total Bilirubin | 3 – 17 μmol/l |
| Calcium | 2.1 – 2.5 mmol/l |
| Chloride | 95 – 105 mmol/l |
| Phosphate | 0.8 – 1.4 mmol/l |
| Haematology | Normal Value |
|---|---|
| Haemoglobin | 11.5 – 16.6 g/dl |
| White Blood Cells | 4.0 – 11.0 x 109/l |
| Platelets | 150 – 450 x 109/l |
| MCV | 80 – 96 fl |
| MCHC | 32 – 36 g/dl |
| Neutrophils | 2.0 – 7.5 x 109/l |
| Lymphocytes | 1.5 – 4.0 x 109/l |
| Monocytes | 0.3 – 1.0 x 109/l |
| Eosinophils | 0.1 – 0.5 x 109/l |
| Basophils | < 0.2 x 109/l |
| Reticulocytes | < 2% |
| Haematocrit | 0.35 – 0.49 |
| Red Cell Distribution Width | 11 – 15% |
| Blood Gases | Normal Value |
|---|---|
| pH | 7.35 – 7.45 |
| pO2 | 11 – 14 kPa |
| pCO2 | 4.5 – 6.0 kPa |
| Base Excess | -2 – +2 mmol/l |
| Bicarbonate | 24 – 30 mmol/l |
| Lactate | < 2 mmol/l |
