Drug-induced IAS during colorectal cancer therapy

Recurrent hypoglycemia in adults without diabetes receiving colorectal cancer therapy is unusual and prompts careful clinical reasoning. In the case at hand, the pattern and timing of symptoms, the biochemical profile, and the presence of insulin autoantibodies converged on a diagnosis of insulin autoimmune syndrome (IAS). IAS, sometimes termed Hirata disease, is characterized by spontaneous episodes of hypoglycemia accompanied by inappropriate insulin levels and circulating antibodies that bind insulin. Many cases are drug-induced, classically by compounds with sulfhydryl groups that can modify insulin antigenicity, but oncologic contexts raise additional considerations related to polypharmacy, immune perturbation, and the need to maintain anticancer efficacy.

The clinical narrative followed a familiar arc for IAS: initial symptomatic hypoglycemia occurring after meals or at variable times during treatment cycles, inconsistent correlates with calorie intake, and lab results that at first glance could be mistaken for assay error. The turning point was the targeted measurement of insulin autoantibodies, which reframed the puzzle from a tumor-secreting or exogenous insulin problem to an autoimmune binding-release phenomenon. From there, the multidisciplinary team coordinated medication adjustments and metabolic supports that brought the episodes under control while keeping cancer therapy on track.

Presentation and diagnostic path

IAS often declares itself with neuroglycopenic symptoms: confusion, diaphoresis, palpitations, tremor, and, in more severe events, transient loss of consciousness. In oncology infusion and outpatient settings, these manifestations can be mistakenly ascribed to dehydration, drug-induced nausea, or vasovagal reactions. A decisive clue is the recurrence of low capillary glucose readings unaccompanied by exogenous hypoglycemic agents.

Biochemically, the hallmark triad is: (1) symptomatic hypoglycemia with verified low plasma glucose, (2) inappropriately elevated or fluctuating total insulin levels, and (3) positive insulin autoantibodies. C-peptide is often normal or high rather than suppressed, signaling endogenous insulin secretion. However, interpretation is nuanced because high-titer autoantibodies can confound immunoassays, occasionally yielding paradoxical insulin concentrations depending on whether the assay measures free versus total insulin. When available, methods such as polyethylene glycol precipitation to assess free insulin, or alternative assay platforms, help reconcile discordant results.

In the reported scenario, the temporal association with colorectal cancer pharmacotherapy, the absence of diabetes medications, and the confirmation of insulin autoantibodies clinched the diagnosis. The broader workup that is typical for hypoglycemia was either completed or carefully deemphasized once the autoimmune mechanism became clear. This approach helped avoid unnecessary abdominal imaging for insulinoma, invasive localization studies, or empiric endocrine therapies not tailored to IAS.

Clinical triggers of IAS can include certain medications encountered in supportive or adjunctive oncology care, such as supplements or drugs with sulfhydryl-containing moieties, as well as the immunologic milieu created by antineoplastic regimens. The mechanistic throughline is that altered antigen presentation or chemical modification of insulin can break tolerance, leading to immunoglobulins that bind circulating insulin with variable affinity. Postprandial insulin surges are then sequestered by antibodies and released unpredictably, producing late hypoglycemia. This binding-release kinetics explains the patient experience of delayed crashes hours after meals or infusions.

Because many cancer regimens are multi-agent and interspersed with premedications and supportive prescriptions, a thorough medication history is fundamental. That history should include over-the-counter supplements and complementary therapies, as alpha-lipoic acid and other compounds have been linked to IAS. In this case trajectory, the timing of hypoglycemia relative to treatment blocks and ancillary agents informed decisions on which medications to discontinue, substitute, or re-challenge under observation.

Differential and assay considerations

The differential diagnosis of spontaneous hypoglycemia with high insulin and preserved C-peptide includes insulinoma, noninsulinoma pancreatogenous hypoglycemia (nesidioblastosis), and IAS. Factitious hypoglycemia from exogenous insulin characteristically shows high insulin with suppressed C-peptide, whereas sulfonylurea exposure shows high insulin and high C-peptide but is identified by a positive urine or plasma sulfonylurea screen. In people receiving cancer care, there may also be intermittent fasting, reduced appetite, and intercurrent illness that complicate interpretation. The key is to anchor the analysis on objective data and pattern recognition.

Insulin autoantibodies provide the most direct evidence for IAS. Yet one must also respect the limitations of routine immunoassays. High-titer autoantibodies can trap insulin, influencing measured concentrations in ways that depend on the assay architecture. Some platforms preferentially detect free insulin; others report total insulin (free plus antibody-bound). When results are incongruent with the clinical picture, laboratories can employ dilution studies, heterophile-blocking reagents, or alternative assays to clarify. Communication with the lab is often decisive. A practical step for clinicians is to request both insulin and C-peptide at the time of symptomatic hypoglycemia and to confirm autoantibodies when suspicion arises.

Imaging for insulinoma can be deferred when autoantibodies are positive and the clinical context strongly indicates IAS. This is especially prudent in patients already undergoing serial imaging for cancer staging or response assessment, where additional scans add expense and radiation without changing management. If uncertainty persists despite serology, a supervised fast with serial glucose, insulin, and C-peptide can be informative, bearing in mind that IAS often produces variable results due to antibody dynamics rather than the steady hyperinsulinemia typical of insulinoma.

Finally, it is worth considering whether immune-modulating cancer therapies could accentuate autoantibody production in susceptible individuals. Even if the precise oncologic agent is not directly responsible, the milieu of antigen release, cytokine shifts, and adjuvant medications could tilt the balance toward autoimmunity. This frame supports a strategy that couples withdrawal of the most likely culprit with immunologic calming measures while preserving the core anticancer intent whenever feasible.

Management, oncology coordination, and outcome

Management of IAS has two parallel goals: suppress clinically significant hypoglycemia and remove or mitigate the trigger. The first interventions are supportive: patient education on symptom recognition, provision of rapid-acting carbohydrates, and advice to distribute carbohydrate intake across smaller, frequent meals to smooth insulin peaks. For some, adding protein and fat to meals can dampen postprandial excursions. During active episodes, supervised correction with oral glucose or intravenous dextrose can be administered as needed.

Acarbose is a rational pharmacologic adjunct in IAS because it slows carbohydrate absorption and blunts postprandial insulin surges, thereby reducing the magnitude of antibody binding and subsequent delayed release. In more severe cases or when rapid control is needed, glucocorticoids can decrease antibody production and lower immune activation, often providing symptomatic relief within days. Immunosuppressants such as rituximab have been used in refractory IAS, especially when high-titer autoantibodies persist and hypoglycemia is dangerous or frequent. Plasmapheresis, though rarely required, can rapidly reduce circulating antibodies in critical situations.

Equally important is withdrawing the offending medication. In oncology, this can be delicate. If a supportive agent with a plausible mechanistic link to IAS is identified, it can often be stopped or substituted without jeopardizing cancer control. When a core antineoplastic is suspected, the team must weigh risks and benefits, considering alternative regimens, dose modifications, or empiric re-challenge under close metabolic monitoring if no equivalent alternatives exist. The case illustrates that early identification of IAS allows such decisions to be made proactively rather than reactively after severe hypoglycemia.

Close coordination between oncology, endocrinology, pharmacy, and nursing is essential. Practical steps that facilitated stabilization included:

• Mapping the timing of hypoglycemic episodes against infusion schedules, premedications, and home therapies to pinpoint likely triggers.
• Creating a structured monitoring plan: fasting and postprandial glucose checks during high-risk windows and symptom-contingent testing outside those windows.
• Preparing a rescue protocol at the infusion center and at home so the patient and caregivers knew when and how to treat emerging symptoms.
• Implementing dietary adjustments with dietitian support to reduce postprandial insulin spikes.
• Documenting baseline and follow-up autoantibody titers where available to track immunologic response to therapy.

In this narrative, glycemic stability improved after the suspected trigger was removed and metabolic supports were initiated. The ability to continue colorectal cancer therapy, whether unchanged or with adjustment, hinged on early recognition and cross-disciplinary planning. The clinical course underscores a pragmatic point: IAS is often self-limited when the trigger is withdrawn, but proactive management shortens the symptomatic period and reduces risk.

For survivorship and long-term care, patients benefit from counseling about medication and supplement exposures that could rekindle IAS. Clear documentation in the medical record about the episode and suspected triggers can prevent re-exposure as care transitions between oncology, primary care, and other specialties. If oncologic therapy resumes with a related class agent, a cautious reintroduction with glucose monitoring can be considered, ideally after autoantibody titers have declined.

Clinical teaching points

The case provides several practical lessons for clinicians who encounter unexplained hypoglycemia in oncology settings:

• Think autoimmune early: Unexplained hypoglycemia with high insulin and preserved C-peptide warrants testing for insulin autoantibodies. A positive result shifts management away from tumor localization and toward immune modulation and medication review.
• Anchor on patterns, not single values: Antibody binding can produce erratic insulin measurements. Consider free versus total insulin and correlate with timing of meals, infusions, and symptoms.
• Mine the medication list: Look beyond antineoplastic agents to premedications, supportive therapies, and supplements. Withdrawal or substitution of the most plausible trigger is often decisive.
• Use acarbose and diet to smooth curves: Postprandial dampening reduces the amplitude of insulin peaks that feed the antibody binding-release cycle.
• Escalate when needed: Short courses of glucocorticoids can be effective for significant or persistent episodes. Reserve advanced immunosuppression or plasmapheresis for refractory or severe cases.
• Protect the cancer plan: Early diagnosis allows continuation or thoughtful modification of colorectal cancer therapy, avoiding unnecessary delays while safeguarding patient safety.
• Document and educate: Clear records of suspected triggers and explicit patient instructions reduce recurrence risk during future care.

Stepping back, the pathophysiology of IAS offers a unifying explanation for clinically puzzling features: the dissonance between insulin levels and symptoms, the delayed timing of hypoglycemia relative to meals, and the occasional disappearance of hypoglycemia after discontinuing a nononcologic co-medication. Recognizing this pattern is especially valuable in cancer care, where multiple variables can obscure causal links.

Finally, the report reinforces a compassionate, patient-centered rhythm: listen for hypoglycemia narratives that do not fit common patterns, validate them with targeted testing, and mobilize a team to restore safety without derailing cancer treatment. In that balance lies the art of practicing alongside science in complex, multimodal care.