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Toxicological and Lactological Monograph: ATC A10AE03 – Insulin (Pork), Long-Acting Preparations

1. ATC Classification and Pharmacological Profile

ATC Code: A10AE03 Active Substance: Insulin (pork), also known as porcine insulin Pharmacotherapeutic Group: Long-acting insulin preparations of animal origin ATC Classification: Alimentary Tract and Metabolism → Drugs Used in Diabetes → Insulins and Analogues → Insulins and Analogues for Injection, Long-Acting → Insulin (Pork) Principal Therapeutic Indications: Diabetes mellitus requiring sustained basal insulin replacement, particularly in patients historically maintained on animal-derived insulin preparations or in exceptional circumstances where porcine insulin remains clinically appropriate.

Insulin (pork), classified under ATC A10AE03, represents a group of prolonged-action insulin preparations derived from porcine pancreatic tissue. These formulations were historically important in the management of insulin-dependent diabetes mellitus before the widespread introduction of recombinant human insulin and modern insulin analogues.

The World Health Organization's Anatomical Therapeutic Chemical classification identifies A10AE03 specifically as long-acting porcine insulin, distinguishing it from fast-acting and intermediate-acting porcine insulin preparations classified elsewhere within the A10A group.

ATC/DDD Index

Porcine insulin is a peptide hormone consisting of 51 amino acids distributed between an A chain containing 21 amino acids and a B chain containing 30 amino acids. The chains are connected by two interchain disulfide bonds, while an additional intrachain disulfide bond stabilises the A chain.

Its primary amino acid sequence differs from human insulin by only one amino acid: alanine replaces threonine at position B30 of the insulin molecule.

This close structural similarity explains the substantial pharmacological equivalence between porcine and human insulin and contributes to the relatively low immunogenicity of highly purified porcine insulin compared with bovine insulin.

Historically, prolonged-action porcine insulin formulations were developed through pharmaceutical modifications designed to delay absorption following subcutaneous injection. These included zinc-containing crystalline preparations and other depot formulations in which the dissolution and absorption of insulin occurred gradually.

The prolonged duration of action therefore results primarily from the physicochemical properties of the formulation rather than from genetic modification of the insulin molecule.

Following subcutaneous administration, insulin is released from the depot into the systemic circulation, where it binds to insulin receptors and activates intracellular signalling pathways involved in carbohydrate, lipid, and protein metabolism.

The principal pharmacodynamic effects include stimulation of glucose uptake in skeletal muscle and adipose tissue, suppression of hepatic glucose production, promotion of glycogen synthesis, inhibition of lipolysis, and regulation of potassium distribution between extracellular and intracellular compartments.

The onset, peak, and duration of activity vary according to the specific preparation, insulin concentration, injection site, administered dose, and individual physiological characteristics. Consequently, a single pharmacokinetic profile cannot be assigned reliably to all historical long-acting porcine insulin formulations.

Unlike contemporary basal insulin analogues designed to produce relatively stable insulin exposure, some traditional prolonged-action porcine insulin formulations exhibit pronounced pharmacodynamic variability and prolonged absorption tails.

The clinical use of porcine insulin has declined substantially in many healthcare systems, although its continued availability and use vary geographically.

From a lactological perspective, the principal characteristics of porcine insulin are its peptide structure, molecular mass of approximately 5.8 kDa, hydrophilicity, and susceptibility to gastrointestinal enzymatic degradation.

These properties strongly influence the expected systemic exposure of breastfed infants and provide the pharmacological foundation for evaluating its compatibility with breastfeeding.

2. Toxicological Profile

The toxicological profile of long-acting porcine insulin is dominated by its physiological insulin activity, particularly the consequences of excessive glucose lowering.

At therapeutic concentrations, porcine insulin generally produces predictable metabolic effects comparable to those of human insulin. However, prolonged systemic exposure, administration errors, altered insulin sensitivity, and immunological responses may produce clinically significant adverse effects.

Hypoglycaemia and Acute Toxicity

Hypoglycaemia represents the principal dose-dependent toxicological risk associated with porcine insulin therapy.

Excessive insulin activity may arise from inappropriate dosing, accidental overdose, reduced carbohydrate intake, increased physical activity, impaired renal function, or changes in insulin requirements.

Clinical manifestations include sweating, tremor, palpitations, hunger, anxiety, dizziness, confusion, behavioural disturbances, seizures, and loss of consciousness.

Severe hypoglycaemia may result in neurological injury, cardiac complications, and, in exceptional circumstances, death.

The prolonged absorption characteristics of certain depot porcine insulin formulations introduce additional toxicological concerns because recurrent hypoglycaemia may persist after initial treatment.

In overdose situations, continued release of insulin from the subcutaneous depot may require prolonged glucose administration and clinical observation.

The risk of nocturnal hypoglycaemia may be particularly relevant when the formulation exhibits a delayed pharmacodynamic peak.

During the postpartum period, insulin requirements frequently decrease because of the rapid reversal of pregnancy-associated insulin resistance. Failure to adjust maternal insulin dosage appropriately may increase susceptibility to hypoglycaemia.

Immunogenicity and Hypersensitivity

Porcine insulin differs from human insulin at a single amino acid position, making it structurally more similar to human insulin than bovine insulin.

Nevertheless, this difference may contribute to immune recognition and anti-insulin antibody formation.

Historically, animal-derived insulin preparations were associated with immunogenic reactions, although their frequency and severity depended substantially on pharmaceutical purity and manufacturing methods.

Highly purified porcine insulin preparations generally demonstrated lower immunogenicity than older, less purified animal-derived products.

Anti-insulin antibodies may alter the pharmacokinetic behaviour of circulating insulin by binding and subsequently releasing biologically active hormone.

In susceptible individuals, these interactions may contribute to unpredictable glycaemic fluctuations, altered insulin requirements, or delayed hypoglycaemic episodes.

Local hypersensitivity reactions may include erythema, swelling, pruritus, and discomfort at the injection site.

Systemic allergic reactions are uncommon but may occasionally occur.

The immunogenic potential of porcine insulin is primarily a maternal treatment consideration. There is no established evidence that maternal anti-insulin antibody formation produces clinically significant adverse effects in breastfed infants through milk exposure.

Metabolic and Electrolyte Disturbances

Porcine insulin promotes intracellular potassium uptake through stimulation of cellular ion transport mechanisms.

Excessive insulin activity may therefore produce hypokalaemia, particularly in individuals with additional electrolyte disturbances or concurrent potassium-lowering treatments.

Severe hypokalaemia may cause muscle weakness, cardiac conduction abnormalities, and arrhythmias.

Other recognised adverse effects of insulin therapy include weight gain, peripheral oedema, sodium retention, and local changes in adipose tissue.

Repeated subcutaneous administration into the same anatomical region may cause lipohypertrophy or, less commonly, lipoatrophy.

These changes may alter insulin absorption and contribute to metabolic instability.

Organ Toxicity and Long-Term Safety

Porcine insulin is not recognised as an intrinsically hepatotoxic, nephrotoxic, genotoxic, or carcinogenic substance at therapeutic doses.

Its biological activity is mediated through physiological insulin receptors, and its metabolic degradation occurs primarily through proteolytic processes involving the liver, kidneys, and peripheral tissues.

Nevertheless, renal or hepatic impairment may alter insulin requirements and increase susceptibility to hypoglycaemia.

The long-term toxicological concerns historically associated with porcine insulin relate mainly to immunogenicity, formulation purity, and variability in insulin absorption rather than direct chemical toxicity.

In lactating women, maternal hypoglycaemia represents the most important indirect safety concern because severe episodes may impair consciousness, judgement, and the ability to provide safe infant care.

3. Lactation Pharmacology and Breast-Milk Exposure

Transfer of Porcine Insulin into Human Breast Milk

Insulin is a naturally occurring component of human breast milk and is involved in the complex hormonal and metabolic environment of mammary secretions.

Endogenous insulin is detectable in milk from women without diabetes, demonstrating that insulin is a normal constituent of human lactational physiology.

Exogenous insulin may also enter breast milk following maternal administration.

Importantly, direct experimental evidence involving porcine insulin is available, although it does not specifically characterise modern or historical long-acting porcine insulin formulations.

A study described in the LactMed database investigated breast-milk insulin concentrations in seven women with diabetes and ten women without diabetes. After experimental elevation of maternal blood glucose, regular porcine insulin was administered intravenously. Milk insulin concentrations increased in the diabetic participants, with peak concentrations occurring approximately 30–50 minutes after injection.

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This observation provides direct evidence that maternally administered porcine insulin can contribute to insulin concentrations in human breast milk.

However, the study involved intravenous regular porcine insulin rather than subcutaneous long-acting porcine insulin.

Consequently, its findings cannot be used to establish the milk concentration–time profile, peak exposure, or infant dose associated with ATC A10AE03 preparations.

The available evidence therefore supports the possibility of mammary transfer but does not permit precise quantification of exposure following therapeutic administration of prolonged-action porcine insulin.

Molecular Characteristics and Mammary Transport

Porcine insulin is a hydrophilic peptide with a molecular mass of approximately 5.8 kDa.

Its molecular size and limited lipid solubility restrict passive diffusion across biological membranes.

Nevertheless, the physiological presence of insulin in breast milk indicates that mammary transfer cannot be explained solely by passive transcellular diffusion.

Regulated transport processes, vesicular mechanisms, or other mammary epithelial pathways may contribute to insulin secretion into milk.

The precise contribution of these mechanisms to exogenous porcine insulin transport remains incompletely characterised.

Because porcine insulin differs from human insulin by only one amino acid, major differences in mammary transfer are not anticipated solely on structural grounds.

However, direct comparative studies are insufficient to establish equivalent transfer kinetics.

Influence of Long-Acting Formulations

The prolonged pharmacological action of A10AE03 preparations is achieved through delayed absorption from subcutaneous depots.

Depending on the historical formulation, insulin may be associated with zinc-containing crystals or other pharmaceutical components that regulate dissolution and absorption.

Following release from the injection depot, the circulating active molecule is porcine insulin.

The intact pharmaceutical depot is not expected to enter breast milk.

Although prolonged systemic absorption may influence the temporal pattern of maternal insulin exposure, the corresponding breast-milk concentration profile has not been adequately investigated.

Therefore, formulation-specific milk-to-plasma ratios, peak milk concentrations, and elimination half-lives cannot be reliably established for long-acting porcine insulin.

Oral Bioavailability and Infant Systemic Exposure

Insulin is susceptible to proteolytic degradation within the gastrointestinal tract.

Following oral ingestion, gastric and intestinal enzymes break down insulin into smaller peptide fragments and amino acids.

Consequently, the systemic bioavailability of orally administered insulin is extremely low under normal physiological conditions.

This property is particularly important when assessing the potential effects of porcine insulin ingested through breast milk.

Even if biologically active porcine insulin is present in milk, the proportion expected to reach the infant's systemic circulation remains very small.

The LactMed database considers maternal insulin treatment compatible with breastfeeding and reports reassuring experience with orally administered recombinant insulin in premature infants.

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Nevertheless, these observations should not be interpreted as direct proof that every porcine insulin formulation has been studied during lactation.

Premature infants may exhibit developmental differences in gastrointestinal enzyme activity and intestinal permeability.

Such differences introduce theoretical uncertainty regarding the absorption of intact peptide hormones, although clinically significant systemic absorption of porcine insulin from human breast milk has not been established.

Relative Infant Dose and Pharmacokinetic Uncertainty

The relative infant dose (RID) is conventionally calculated by comparing the estimated infant dose received through milk with the maternal weight-adjusted dose.

For long-acting porcine insulin, a reliable RID cannot currently be established because sufficiently detailed milk concentration–time data are lacking.

Moreover, conventional RID calculations have important limitations when applied to peptide hormones with negligible oral bioavailability.

The amount of insulin ingested through milk does not directly correspond to the amount reaching the infant's systemic circulation.

Therefore, the lactological risk assessment should distinguish between measurable milk exposure and pharmacologically meaningful systemic infant exposure.

The available evidence supports the expectation of very low systemic exposure, but it does not justify assuming that porcine insulin is completely absent from breast milk.

4. Effects in the Breastfed Infant and on Lactation

Effects on the Breastfed Infant

The principal theoretical concern associated with maternal porcine insulin treatment is infant hypoglycaemia resulting from systemic absorption of biologically active insulin through breast milk.

However, the peptide structure of insulin and its susceptibility to gastrointestinal degradation make this outcome biologically unlikely following normal breastfeeding.

No well-established clinical evidence demonstrates that maternal administration of long-acting porcine insulin causes clinically significant hypoglycaemia in breastfed infants.

Nevertheless, direct studies evaluating infant outcomes specifically following maternal treatment with ATC A10AE03 preparations are limited.

The absence of documented adverse effects should therefore be interpreted as reassuring but not equivalent to comprehensive proof of safety.

Available evidence does not establish a consistent association between maternal porcine insulin treatment and impaired infant growth, neurological abnormalities, gastrointestinal toxicity, or disturbances of glucose homeostasis.

The broader clinical experience with insulin therapy during breastfeeding supports a favourable safety assessment.

LactMed reports that women with diabetes receiving insulin may breastfeed and that published evidence does not identify an established pattern of clinically significant adverse effects attributable to insulin exposure through milk.

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Potential Immunological Effects

Porcine insulin differs from human insulin by one amino acid, creating a potential antigenic distinction.

Theoretically, ingestion of porcine insulin or its peptide fragments could contribute to intestinal immune recognition.

However, the biological consequences of such exposure depend on the amount ingested, the integrity of the peptide, gastrointestinal processing, and the developmental state of the infant immune system.

Research involving dietary insulin and early-life immune development has explored potential relationships between exposure to animal-derived insulin proteins and autoimmune processes.

Nevertheless, dietary exposure through cow's milk or infant formula cannot be considered equivalent to exposure through breast milk following maternal parenteral insulin therapy.

The quantities, molecular forms, and routes of exposure may differ substantially.

There is no established evidence that maternal porcine insulin treatment induces clinically significant immune sensitisation, insulin antibodies, or autoimmune disease in breastfed infants.

Accordingly, potential immunological effects remain theoretical and should not be presented as demonstrated clinical risks.

Physiological Role of Milk Insulin

Insulin present in human milk may contribute to gastrointestinal maturation and local metabolic signalling during early infancy.

Experimental investigations suggest that milk-derived insulin may influence intestinal epithelial differentiation, digestive function, and cellular growth processes.

These potential physiological effects are distinct from systemic glucose-lowering activity.

The clinical significance of exogenous porcine insulin within this physiological environment remains uncertain.

Although endogenous milk insulin may participate in normal infant development, it cannot be assumed that maternally administered porcine insulin produces identical biological effects or additional developmental benefits.

Effects on Lactogenesis and Milk Production

Insulin plays an important role in mammary gland metabolism and supports the biochemical processes necessary for milk synthesis.

Adequate insulin signalling contributes to glucose utilisation, lipid metabolism, and normal mammary secretory function.

Maternal diabetes may be associated with delayed lactogenesis II, particularly when glycaemic control is inadequate or additional obstetric complications are present.

However, this association reflects maternal metabolic dysfunction rather than a direct inhibitory effect of insulin treatment.

Porcine insulin is not recognised as a direct suppressor of prolactin secretion, oxytocin-mediated milk ejection, or mammary milk production.

Appropriate insulin replacement may indirectly support lactation by improving maternal metabolic stability.

LactMed notes that adequate glycaemic control may improve maternal prolactin responses and reduce delays in lactation establishment among women with type 1 diabetes.

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There is no convincing evidence that porcine insulin has a distinct adverse effect on milk production compared with human insulin.

Breastfeeding and Maternal Insulin Requirements

Maternal insulin requirements commonly decrease after delivery because pregnancy-associated insulin resistance declines rapidly.

Breastfeeding may additionally influence glucose utilisation and energy metabolism.

However, the magnitude of these effects varies substantially between individuals.

Clinical investigations have demonstrated that postpartum insulin requirements may remain below prepregnancy levels for varying periods, although breastfeeding itself does not consistently produce significantly lower insulin requirements compared with non-breastfeeding women.

LactMed describes substantial variability in postpartum insulin requirements and emphasises the importance of individualised insulin management.

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For women receiving long-acting porcine insulin, careful monitoring is particularly important because formulation-dependent absorption variability may complicate glycaemic control.

The principal clinical concern during lactation therefore remains maternal metabolic stability rather than direct toxicity to the breastfed infant.

5. Lactological Safety Assessment and Clinical Recommendations

Overall Lactological Safety Classification

Lactological compatibility: Probably compatible with breastfeeding, based on direct evidence of porcine insulin transfer into milk and indirect clinical safety evidence.

Expected systemic infant exposure: Very low.

Risk of clinically significant infant hypoglycaemia: Theoretically very low; not specifically quantified for long-acting porcine insulin.

Effect on milk production: No established direct suppressive effect.

Need for breastfeeding interruption: Not routinely indicated.

The lactological safety assessment of ATC A10AE03 is supported by the physiological presence of insulin in human milk, direct experimental evidence of porcine insulin transfer into milk, its limited expected oral bioavailability, and the broader clinical experience with maternal insulin therapy.

The available evidence does not establish clinically significant systemic toxicity in breastfed infants.

However, the distinction between direct evidence of milk transfer and direct evidence of infant safety is important.

Although porcine insulin has been investigated experimentally in human lactation, detailed studies involving prolonged-action formulations and prospective infant outcomes remain insufficient.

Therefore, the classification of probable compatibility reflects a favourable pharmacological benefit–risk assessment rather than comprehensive formulation-specific clinical validation.

Recommendations for Maternal Therapy

Clinically necessary porcine insulin treatment should generally be continued during breastfeeding.

Abrupt discontinuation or inappropriate dose reduction may result in maternal hyperglycaemia, metabolic instability, and, in insulin-dependent diabetes, diabetic ketoacidosis.

Insulin requirements should be reassessed promptly after delivery because maternal insulin sensitivity may increase substantially.

Subsequent dose adjustments should be guided by blood glucose monitoring, carbohydrate intake, physical activity, and clinical symptoms.

Women receiving long-acting porcine insulin should be evaluated for nocturnal hypoglycaemia, particularly when the formulation exhibits a delayed or variable activity peak.

Adequate nutritional intake and ready access to rapidly absorbable carbohydrates are important components of maternal hypoglycaemia prevention.

Continuous glucose monitoring may be useful in patients with recurrent hypoglycaemia or substantial glycaemic variability.

Where clinically appropriate, recombinant human insulin or modern basal insulin analogues may be preferred because of their wider contemporary availability, standardised pharmaceutical characteristics, and more extensive current clinical experience.

Nevertheless, switching a metabolically stable patient from porcine insulin should not be undertaken solely because of breastfeeding.

Any transition should be individualised and medically supervised because differences in absorption profiles, formulation characteristics, and insulin sensitivity may alter therapeutic requirements.

Recommendations for the Breastfed Infant

Routine interruption of breastfeeding is not indicated solely because the mother receives therapeutic porcine insulin.

Expressing and discarding breast milk after maternal insulin administration is not considered necessary.

Breastfeeding does not need to be synchronised with the timing of maternal insulin injections.

Routine biochemical monitoring of infant blood glucose is not generally required solely because of maternal porcine insulin therapy.

Standard paediatric surveillance should include assessment of feeding effectiveness, hydration, weight gain, and developmental progress.

Additional clinical evaluation may be appropriate in premature infants, medically vulnerable neonates, or infants exhibiting unexplained lethargy, poor feeding, tremor, or other symptoms potentially associated with hypoglycaemia.

Such findings should prompt a comprehensive differential diagnosis rather than automatic attribution to maternal insulin exposure through breast milk.

Special Clinical Considerations

Premature infants: Developmental differences in gastrointestinal digestion and intestinal permeability introduce theoretical uncertainty regarding the handling of orally ingested peptide hormones. Individualised assessment may be appropriate, although clinically significant systemic absorption of porcine insulin through breast milk has not been demonstrated.

Maternal insulin antibodies: Porcine insulin may stimulate antibody formation, particularly with historical or less purified formulations. Antibody-associated changes in insulin pharmacokinetics may complicate maternal glycaemic control, but direct adverse effects in breastfed infants have not been established.

Historical pharmaceutical formulations: Long-acting porcine insulin products may differ in purity, zinc content, preservatives, and absorption characteristics. Product-specific assessment is appropriate when older or exceptionally sourced formulations are used.

Maternal renal or hepatic impairment: Altered insulin clearance may increase susceptibility to hypoglycaemia and necessitate individualised dose adjustment.

Concurrent medications: Additional antidiabetic agents and other systemic medications should be evaluated independently for lactational safety.

Evidence Quality and Research Limitations

The lactological evidence for long-acting porcine insulin is limited by the scarcity of contemporary pharmacokinetic and prospective clinical studies.

Although experimental investigations have demonstrated the presence of porcine insulin in breast milk following maternal administration, these studies do not provide reliable quantitative exposure estimates for prolonged-action preparations.

Milk-to-plasma ratios, relative infant doses, and infant serum concentrations have not been adequately characterised for ATC A10AE03.

Furthermore, prospective investigations assessing long-term infant metabolic, immunological, and developmental outcomes are lacking.

Much of the historical clinical experience with porcine insulin predates contemporary standards for lactation pharmacokinetic research and adverse-event monitoring.

These limitations prevent assignment of a high-certainty, formulation-specific safety classification.

Future investigations could examine the quantitative transfer of porcine insulin into breast milk, the biological activity of milk-derived insulin, and potential immunological interactions within the neonatal gastrointestinal tract.

However, the declining clinical use of animal-derived insulin may limit the feasibility of extensive prospective studies.

In current clinical practice, the lactological assessment should therefore integrate established insulin pharmacology, maternal therapeutic necessity, available milk-transfer evidence, and the absence of a demonstrated clinically significant infant toxicity signal.

6. Conclusion

Long-acting porcine insulin preparations classified under ATC A10AE03 represent historically important forms of basal insulin replacement therapy.

Their toxicological profile is dominated by insulin-mediated hypoglycaemia, electrolyte disturbances, and potential immunogenic reactions rather than intrinsic chemical or organ-specific toxicity.

From a lactological perspective, porcine insulin demonstrates a favourable pharmacological safety profile because of its peptide structure, susceptibility to gastrointestinal proteolysis, and very limited expected systemic absorption following oral ingestion.

Direct experimental evidence confirms that maternally administered porcine insulin can contribute to insulin concentrations in human breast milk. However, quantitative data specifically characterising long-acting porcine insulin formulations remain insufficient.

Available clinical evidence does not establish that maternal porcine insulin treatment causes clinically significant hypoglycaemia, impaired growth, or other consistent adverse effects in breastfed infants.

The potential immunogenicity of porcine insulin warrants scientific consideration but does not constitute evidence of clinically meaningful immune-mediated harm through breastfeeding.

Porcine insulin is not recognised as a direct inhibitor of lactation, and effective maternal insulin replacement may support successful breastfeeding by maintaining metabolic stability.

The principal clinical priority during lactation is appropriate maternal glycaemic management, including individualised postpartum insulin adjustment and prevention of hypoglycaemia.

Although recombinant human insulin and modern insulin analogues may be preferred when clinically suitable because of their broader contemporary evidence base and pharmaceutical availability, breastfeeding interruption is not routinely justified solely because a mother receives porcine insulin.

Overall, long-acting porcine insulin classified under ATC A10AE03 may be regarded as probably compatible with breastfeeding, with very low expected systemic infant exposure and no established clinically significant lactational toxicity. Nevertheless, the limited availability of formulation-specific lactation studies warrants appropriate clinical judgement, individualised maternal treatment, and routine paediatric surveillance.