Insulin human (regular)
soluble insulin, regular insulin, neutral insulin, insulin human rDNA origin, biosynthetic human insulin, insulin human injection
Regular, or soluble, human insulin is the unmodified 51-amino-acid human insulin sequence manufactured by recombinant DNA technology. It is the reference short-acting insulin, the standard preparation for intravenous use in diabetic ketoacidosis and critical illness, and historically the first recombinant DNA medicine ever licensed, approved in 1982. It sits on the WHO Model List of Essential Medicines.
Mechanism
Insulin binds the insulin receptor, a disulfide-linked (alpha-beta)2 receptor tyrosine kinase. Engagement of the asymmetric site 1 and site 2 surfaces across the two alpha subunits produces a large conformational change that brings the intracellular beta-subunit kinase domains together for trans-autophosphorylation. The activated receptor recruits insulin receptor substrate proteins IRS-1 and IRS-2 and the adaptor Shc. The metabolic branch proceeds through phosphoinositide 3-kinase to PIP3, PDK1 and Akt. Akt then inactivates the Rab-GAP AS160 to permit GLUT4 translocation to the plasma membrane in muscle and adipose tissue, inhibits glycogen synthase kinase 3 to activate glycogen synthase, excludes FoxO1 from the nucleus to suppress hepatic gluconeogenic gene transcription, and activates phosphodiesterase 3B to suppress lipolysis. The parallel Ras-MAPK branch mediates the mitogenic and growth-related effects.
Formulation matters as much as receptor pharmacology here. In the vial, insulin is stabilised as zinc-coordinated hexamers. After subcutaneous injection those hexamers must dissociate into dimers and then monomers before absorption into the capillary bed can occur, and that dissociation step is what imposes the roughly 30-minute delay to onset. Rapid-acting analogues such as insulin lispro and insulin aspart were engineered specifically to destabilise the hexamer and remove that delay. Given intravenously, where the dilution is immediate and no hexamer dissociation is required, regular human insulin acts within minutes, and this is why it remains the preparation of choice for infusion protocols.
What the research shows
Keen and colleagues reported the first-in-human study of recombinant human insulin in the Lancet in 1980, establishing that biosynthetic material was as safe and as hypoglycaemically potent as purified porcine insulin in healthy men. That result opened the way to the 1982 licence and, more broadly, to the recombinant biologics industry. Subsequent double-blind crossover trials in established patients confirmed equivalence with animal insulins.
The outcome evidence rests on two landmark trials. DCCT randomised 1,441 people with type 1 diabetes to intensive or conventional insulin therapy for a mean of 6.5 years and found that intensive control reduced the risk of developing retinopathy by 76% and the progression of established retinopathy by 54%, at the cost of a roughly threefold increase in severe hypoglycaemia. UKPDS 33 randomised 3,867 people with newly diagnosed type 2 diabetes to intensive control with a sulfonylurea or insulin, or to conventional management, over a median of ten years, and found a 12% reduction in any diabetes-related endpoint driven almost entirely by a 25% reduction in microvascular complications, with no statistically significant effect on myocardial infarction during the trial itself.
Two results define the limits of regular human insulin. Anderson and colleagues showed in a multicentre randomised crossover trial that insulin lispro reduced postprandial glucose excursions and hypoglycaemic episodes relative to regular human insulin, quantifying the cost of the hexamer dissociation delay and driving the shift towards rapid-acting analogues. NICE-SUGAR, in 6,104 intensive care patients, found that intensive intravenous insulin targeting near-normal glucose increased 90-day mortality compared with conventional targets (27.5% versus 24.9%), a clear negative result that reversed prevailing critical care practice.
Evidence assessment
High-quality evidence
Regular human insulin has held approved labelling in every major jurisdiction since 1982, is on the WHO Model List of Essential Medicines, and is supported by landmark randomised trials including DCCT in type 1 diabetes and UKPDS in type 2 diabetes, alongside first-in-human recombinant safety studies and large intensive-control trials in critical care. All five cited studies were individually verified. The evidence base is among the most extensive for any medicine.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Human insulin produced by recombinant DNA technology: safety and hypoglycaemic potency in healthy men Preclinical only
Recombinant human insulin was as potent and as well tolerated as purified porcine insulin, establishing the safety basis for the first recombinant DNA medicine ever licensed.
The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus Preclinical only
Intensive therapy reduced the development of retinopathy by 76% and progression of established retinopathy by 54%, with parallel reductions in nephropathy and neuropathy, at the cost of an approximately threefold increase in severe hypoglycaemia.
Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) Preclinical only
Intensive control reduced any diabetes-related endpoint by 12%, driven almost entirely by a 25% reduction in microvascular complications. The reduction in myocardial infarction did not reach statistical significance within the trial period.
Reduction of postprandial hyperglycemia and frequency of hypoglycemia in IDDM patients on insulin-analog treatment Preclinical only
The rapid-acting analogue reduced postprandial glucose excursions and lowered the frequency of hypoglycaemic episodes relative to regular human insulin, quantifying the clinical cost of the hexamer dissociation delay.
Intensive versus conventional glucose control in critically ill patients Preclinical only
Intensive glucose control increased 90-day mortality (27.5% versus 24.9%) and severe hypoglycaemia compared with conventional targets.
Safety
Hypoglycaemia is the defining risk and can be fatal; it is more frequent with intensive regimens, and DCCT quantified an approximately threefold increase. Hypokalaemia follows from insulin driving potassium intracellularly, which is therapeutically exploited in the emergency management of hyperkalaemia but is a serious hazard during treatment of diabetic ketoacidosis, where potassium must be monitored and replaced. Weight gain is expected. Lipohypertrophy and, less often, lipoatrophy develop at repeatedly used injection sites and cause erratic absorption. Local and systemic allergy is rare with recombinant human insulin. Beta-blockers can mask the adrenergic warning symptoms of hypoglycaemia. Medication errors involving insulin, particularly confusion between concentrations, between insulin types, and misreading of unit abbreviations, are among the most frequent causes of serious avoidable harm in hospital practice, which is why insulin is subject to dedicated patient-safety alerts in the UK and elsewhere.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Long-standing MHRA marketing authorisation for the treatment of diabetes mellitus in adults and children, including intravenous use in diabetic ketoacidosis and hyperosmolar hyperglycaemic state. Prescription-only medicine; not a controlled drug. It appears on the WHO Model List of Essential Medicines and is widely available on the NHS. Insulin products are subject to specific NHS patient-safety guidance because of the frequency and severity of administration errors. |
| United States | Approved by the FDA in 1982, the first recombinant DNA-derived medicine ever licensed. Since March 2020 insulins have been regulated in the United States as biological products rather than drugs, having transitioned from new drug applications to biologics licence applications under the Biologics Price Competition and Innovation Act, which opened the pathway for interchangeable biosimilar insulins. Regular human insulin is unusual among modern medicines in that it can be purchased without a prescription in many US states, a legacy of its long history. |
| WADA (sport) | PROHIBITED at all times, in and out of competition. Insulins and insulin-mimetics are explicitly named under section S4, Hormone and Metabolic Modulators, of the WADA Prohibited List. Athletes with diabetes require an approved Therapeutic Use Exemption in order to use insulin lawfully in sport. This is the sharpest regulatory contrast within this group of compounds: insulin is banned, whereas glucagon and every GLP-1 receptor agonist listed here are not. |
Questions
It sits on the boundary. At 51 amino acids in two disulfide-linked chains and about 5,808 daltons, it is usually called a protein hormone, but it is small enough that it is also legitimately described as a polypeptide. It is a single gene product, processed from proinsulin by removal of the C-peptide.
Because it is stored as zinc-coordinated hexamers that must dissociate into monomers before they can be absorbed from subcutaneous tissue. Rapid-acting analogues were engineered specifically to destabilise that hexamer. Given intravenously, regular insulin works within minutes, which is why it remains standard for infusions.
Yes, at all times, in and out of competition, under section S4 of the WADA Prohibited List, which names insulins and insulin-mimetics explicitly. Athletes with diabetes must hold an approved Therapeutic Use Exemption. This contrasts with glucagon and the GLP-1 receptor agonists, none of which are prohibited.
Three reasons. It is the preparation of choice for intravenous infusion, where the hexamer delay is irrelevant. It is markedly cheaper, which matters greatly in much of the world. And it remains on the WHO Model List of Essential Medicines precisely because effective diabetes care must not depend on premium-priced analogues.