Regular Insulin

Regular insulin is soluble human insulin, a short-acting insulin given subcutaneously about 30 minutes before meals and the only insulin routinely given by intravenous infusion for diabetic ketoacidosis, hyperosmolar states and hyperkalaemia. It is cheap, widely available in public facilities and the mainstay of insulin supply in many low-resource settings. Dose errors, hypoglycaemia and hypokalaemia are the main risks.

Classification. Short-acting human insulin, produced by recombinant DNA technology. Vials and pens of 100 units/mL (U100); a 500 units/mL concentrate exists for severe insulin resistance. In premixed form with NPH insulin it is a different product.

Mechanism. Binds the insulin receptor, increasing glucose uptake in muscle and fat, suppressing hepatic glucose output and ketogenesis, promoting glycogen, protein and fat synthesis, and driving potassium into cells.

Pharmacodynamics. Subcutaneous onset 30 to 60 minutes, peak 2 to 4 hours, duration 5 to 8 hours. Intravenous effect begins within minutes.

Pharmacokinetics. Cleared by the liver and kidney, with about 50% hepatic first-pass extraction of portal insulin. Intravenous half-life about 5 to 10 minutes; subcutaneous absorption is slower and variable, rising with exercise, heat and injection into the abdomen. Requirements fall as kidney function falls because renal clearance is reduced.

Type 1 diabetes, adults (basal-bolus).

• Total daily insulin about 0.4 to 1 unit/kg, commonly 0.5 unit/kg; about half as basal insulin and half as meal doses.
• Regular insulin is given subcutaneously 30 minutes before each main meal, for example 0.1 unit/kg before each of 3 meals, adjusted to glucose.
• Insulin-to-carbohydrate ratio often 1 unit to 10 to 15 g carbohydrate; correction dose estimated from the rule of 1500 divided by the total daily dose in units, giving the mg/dL fall for 1 unit (for glucose in mmol/L, 83 divided by the total daily dose).
• Titrate meal doses by 1 to 2 units, or 10 to 15%, every 3 days from the next pre-meal or bedtime glucose. No fixed maximum; total needs over 2 units/kg/day suggest insulin resistance or error.

Type 2 diabetes, adults.

• Add prandial insulin to basal insulin when HbA1c stays over target: start 4 units, or 10% of the basal dose, subcutaneously 30 minutes before the largest meal; add further meal doses as needed.
• Titrate by 1 to 2 units, or 10 to 15%, every 3 days. Reduce basal insulin or sulphonylureas if hypoglycaemia occurs.

Children and adolescents with type 1 diabetes.

• Total daily insulin 0.7 to 1 unit/kg before puberty and up to 1.2 unit/kg in puberty, divided as basal and meal doses. Dose steps and targets are directed by a paediatric diabetes team.

Diabetic ketoacidosis, intravenous (adults).

• Start insulin only after fluids have begun and serum potassium is 3.3 mmol/L or more. If potassium is under 3.3 mmol/L, replace potassium first.
• Regular insulin 0.1 unit/kg/hour by fixed-rate intravenous infusion; an initial intravenous bolus of 0.1 unit/kg is optional.
• Aim for a glucose fall of 3 to 4 mmol/L (50 to 75 mg/dL) each hour; if not achieved in 1 hour, double the rate.
• When glucose reaches 14 mmol/L (250 mg/dL), add 5 to 10% dextrose and reduce insulin to 0.02 to 0.05 unit/kg/hour; continue until ketones are under 0.6 mmol/L and pH is over 7.3, then change to subcutaneous insulin and overlap for 1 to 2 hours.
• Replace potassium to keep serum potassium at 4 to 5 mmol/L (20 to 30 mmol in each litre of fluid once potassium is under 5.2 mmol/L and urine is passing).

Hyperosmolar hyperglycaemic state, intravenous (adults).

• Fluids first. Start regular insulin 0.05 unit/kg/hour once glucose has stopped falling with fluids alone; aim for a fall of 3 to 4 mmol/L (50 to 75 mg/dL) each hour. Add dextrose when glucose is about 15 mmol/L (270 mg/dL).

Hyperkalaemia.

• Regular insulin 10 units intravenously with 25 g glucose (50 mL of 50% dextrose) over 15 to 30 minutes. Omit the glucose bolus if glucose is over 14 mmol/L (250 mg/dL). In kidney impairment or low body weight use 5 units to lower the risk of hypoglycaemia.
• Potassium falls by about 0.6 to 1 mmol/L within an hour for 4 to 6 hours. Check glucose hourly for 6 hours.

Perioperative. Variable-rate intravenous regular insulin infusion at 0.5 to 3 units/hour, adjusted to glucose 6 to 10 mmol/L (110 to 180 mg/dL), with dextrose and potassium.

Gestational diabetes and pregnancy. Insulin is the drug of choice when diet is not enough. Needs fall in the first trimester and rise from the second trimester through the third, often doubling by term.

Adjustments.

• Kidney: reduce dose by about 25% when eGFR is 10 to 50 and about 50% when under 10, adjusted to glucose.
• Liver: reduce dose in cirrhosis and acute liver failure.
• Older adults: use less strict targets and lower starting doses.
• Weight: dose by weight in children and for intravenous infusions.
• Pregnancy and breastfeeding: insulin is compatible; needs fall in lactation.

Contraindications. Hypoglycaemia; hypersensitivity to insulin or an excipient (rare).

Hypoglycaemia. The main risk. Treat glucose under 4 mmol/L (70 mg/dL) with 15 to 20 g fast oral glucose and recheck at 15 minutes. For severe hypoglycaemia give intravenous glucose 10% 150 to 200 mL over 15 minutes, or glucagon 1 mg intramuscularly or subcutaneously (0.5 mg for children under 25 kg).

Other serious adverse effects.

• Hypokalaemia with intravenous insulin; fatal arrhythmia if potassium is not replaced.
• Cerebral oedema during rapid glucose fall in children with ketoacidosis.
• Lipohypertrophy at repeated injection sites, erratic absorption; rotate sites.
• Weight gain; fluid retention; rare insulin allergy and injection site reactions.

Common prescribing errors.

• Using a syringe that does not match the vial concentration. Use U100 syringes with U100 vials only; where U40 vials or syringes are still in circulation, mismatch causes a 2.5 fold dosing error.
• Confusing units with millilitres, writing "U" that is misread as a zero, or giving a rapid-acting dose to a patient who is not about to eat.
• Using a tuberculin syringe to draw insulin.
• Omitting potassium or fluids in ketoacidosis, or stopping the infusion without subcutaneous insulin overlap.

Major interactions.

• Increased hypoglycaemia: sulphonylureas, ACE inhibitors, fibrates, fluoxetine, monoamine oxidase inhibitors, salicylates, alcohol.
• Reduced effect: corticosteroids, thiazides, atypical antipsychotics, oestrogen-containing contraceptives, protease inhibitors, thyroid hormones.
• Beta-blockers mask palpitations and tremor of hypoglycaemia.
• Pioglitazone and insulin together: fluid retention and heart failure.
• SGLT2 inhibitors with insulin dose cuts: ketoacidosis.

Special groups.

• Pregnancy: compatible; needs rise from the second trimester; fall sharply after delivery.
• Breastfeeding: compatible; needs fall in lactation.
• Children: 0.7 to 1 unit/kg/day before puberty and up to 1.2 unit/kg/day in puberty, divided as basal and meal doses.
• Older adults: avoid hypoglycaemia; relax targets.
• Kidney impairment: reduce doses; prolonged action.
• Liver impairment: reduced gluconeogenesis; reduce doses.
• East Africa: human regular insulin is usually the affordable insulin in public facilities. Cold chain breaks are a risk: unopened vials keep in a fridge (2 to 8 degrees Celsius), and an in-use vial or pen keeps at room temperature up to 30 degrees Celsius for 28 days; protect from direct sunlight and never freeze. Some patients are fasting during Ramadan; adjust doses with the physician.

Formulation and preparation. Clear, colourless solution; do not use if cloudy or discoloured. Draw up into a U100 syringe or use a pen. Regular insulin may be mixed with NPH insulin in the same syringe, drawing regular first.

Subcutaneous administration. Inject into the abdomen (fastest absorption), thigh or upper arm 30 minutes before the meal; rotate sites. Give meal doses only when the meal is certain.

Intravenous infusion. Add 50 units regular insulin to 50 mL 0.9% sodium chloride (1 unit/mL) by syringe pump; flush 20 to 50 mL through the line before use because insulin binds to the plastic. Infusion rate in units/hour equals mL/hour. Prepare a fresh syringe every 24 hours. Never give other insulin types by intravenous infusion.

Baseline. Capillary and laboratory glucose, serum potassium, bicarbonate, ketones, eGFR, HbA1c.

Monitoring.

• Subcutaneous use: capillary glucose before meals, at bedtime and when unwell; HbA1c every 3 months.
• Intravenous infusion: glucose hourly, potassium and bicarbonate every 2 to 4 hours in ketoacidosis, ketones hourly (or pH, bicarbonate), and fluid balance.
• Hyperkalaemia: glucose hourly for 6 hours.

Dose reduction and stopping. Reduce dose by 10 to 20% after any hypoglycaemia without a clear cause. Stop the infusion when ketoacidosis has resolved and subcutaneous insulin has been given and absorbed.

Referral and escalation. Admit severe hypoglycaemia, ketoacidosis, hyperosmolar state or glucose over 25 mmol/L (450 mg/dL) with illness. Involve critical care for pH under 7.0, serum potassium under 3.3 mmol/L at presentation, reduced consciousness, or shock.