Insulin Preparations

Insulin preparations are recombinant human insulin and structurally modified analogues, given by subcutaneous injection (soluble forms also intravenously) to replace or supplement endogenous insulin in type 1 diabetes, insulin-deficient type 2 diabetes, diabetes in pregnancy, acute hyperglycaemic emergencies and hyperkalaemia. They are effective at any degree of beta cell failure and have no ceiling dose.

Mechanism. Insulin binds the alpha subunit of the insulin receptor and activates the beta subunit tyrosine kinase. This drives GLUT4 translocation in muscle and fat, glycogen and protein synthesis, and suppression of hepatic glucose output, lipolysis and ketogenesis. It also shifts potassium into cells.

Pharmacokinetics. Free insulin has a plasma half-life of minutes, so the clinical profile is set by absorption from the subcutaneous depot. Absorption is fastest from the abdomen and slowest from the thigh, is quickened by heat, massage and exercise, and is delayed and erratic through lipohypertrophy. Clearance is renal and hepatic, so kidney impairment prolongs action.

Classification. Rapid acting analogues, short acting soluble human insulin, intermediate acting isophane (NPH), long acting analogues, ultra long acting analogues and premixed preparations. Most products are U100 (100 units/mL). U200, U300 and U500 products exist and are used only with their matched pen or device.

Human insulin versus analogues. Analogues give a more predictable profile with less late hypoglycaemia and less nocturnal hypoglycaemia in type 1 diabetes. Glycaemic control (HbA1c) is similar. Human insulin is cheaper and often the only option available.

Biosimilars. Biosimilar glargine, lispro and aspart are interchangeable at unit-for-unit doses in most settings, with closer glucose checks for the first 1 to 2 weeks after a switch.

• Type 1 diabetes: basal bolus regimen, total daily dose 0.5 to 0.8 units/kg, roughly 40 to 50% as basal. Carbohydrate ratio in g/unit is approximately 500 divided by the total daily dose. Correction factor in mmol/L is approximately 100 divided by the total daily dose (1800 divided by the dose gives mg/dL). These are starting estimates only.
• Type 2 diabetes: add basal insulin when HbA1c stays over target on oral agents. Start 10 units daily or 0.1 to 0.2 units/kg. Increase by 2 units every 3 days to a fasting glucose of 4.4 to 7.2 mmol/L (80 to 130 mg/dL), or by 4 units if fasting glucose is over 10 mmol/L (180 mg/dL). Reduce the dose by 10 to 20% after any hypoglycaemia.
• Overbasalisation: a basal dose over 0.5 units/kg, a bedtime to morning glucose fall of 3.3 mmol/L (50 mg/dL) or more, or recurrent hypoglycaemia means mealtime insulin or a GLP-1 receptor agonist should be added rather than basal increased.
• Diabetic ketoacidosis: soluble insulin 0.1 units/kg/h intravenously once potassium is confirmed over 3.3 mmol/L.
• Hyperkalaemia: soluble insulin 10 units intravenously with 25 g glucose (50 mL of 50% dextrose); use 5 units in renal failure or low weight, omit the glucose if glucose is over 13.9 mmol/L (250 mg/dL), and check glucose hourly for at least 6 hours.

Special groups. Pregnancy: human insulin, lispro, aspart, detemir and glargine are used. Requirements fall in the first trimester, rise progressively from about 16 to 20 weeks, often by 50 to 100% by late pregnancy, and fall abruptly after delivery. Targets: fasting under 5.3 mmol/L, 1 hour under 7.8 mmol/L, 2 hours under 6.7 mmol/L. Breastfeeding: compatible; reduce doses, as hypoglycaemia is more likely.

Kidney impairment: reduce total dose by about 25% at eGFR 10 to 50 mL/min and by about 50% under 10 mL/min. Liver impairment: reduced gluconeogenesis, higher hypoglycaemia risk. Older adults: relax targets (HbA1c 7.5 to 8.5%) in frailty.

Regional: unopened insulin is kept at 2 to 8 degrees C; in-use vials and pens keep for 28 days below 30 degrees C. Where U40 syringes remain in circulation, using one with U100 insulin delivers 2.5 times the intended dose.

Adverse effects. Hypoglycaemia (glucose under 3.9 mmol/L, or 3.0 mmol/L as clinically significant; severe if help is needed), weight gain, lipohypertrophy, injection site reaction, hypokalaemia with intravenous use, transient oedema after starting therapy, and rarely antibody-mediated resistance or systemic allergy.

Common prescribing errors. Writing "U" for units (misread as 0), confusing concentrations, omitting basal insulin in type 1 diabetes when a patient is fasting or acutely ill, using sliding scale doses alone in hospital, and stopping intravenous insulin without subcutaneous cover.

Interactions. Beta blockers blunt adrenergic warning symptoms. Corticosteroids, thiazides and antipsychotics raise requirements. Sulphonylureas, alcohol and salicylates add to hypoglycaemia. Pioglitazone with insulin increases oedema and heart failure risk.

Monitoring. Capillary or sensor glucose before meals and at bedtime; HbA1c every 3 months; injection sites at every review; potassium during infusion; renal function at least annually.

Referral and escalation. Recurrent severe hypoglycaemia, hypoglycaemia unawareness, ketoacidosis, unexplained insulin requirements over 1.5 units/kg, or pregnancy.