A complex maze representing the diagnostic challenges of endogenous hyperinsulinism, with insulin molecules as pathways.

Unlocking the Mystery of Endogenous Hyperinsulinism: Two Diagnostic Puzzles

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Mira Elwood in Health & Wellness August 2026 • 4 min read.

"Navigating the complexities of hypoglycemia: A closer look at two unusual cases of endogenous hyperinsulinism and their diagnostic challenges."


Hypoglycemia in otherwise healthy adults is an uncommon finding in clinical practice, often necessitating a thorough and exhaustive investigation to determine the underlying cause. When low plasma glucose levels are detected alongside inappropriately normal or elevated insulin and C-peptide concentrations, it's critical to rule out rare conditions such as pancreatic beta-cell disorders and autoimmune hypoglycemia.

Endogenous hyperinsulinism presents a complex diagnostic challenge, requiring clinicians to differentiate between various potential causes. This condition, characterized by the body's own overproduction of insulin, can stem from a variety of factors, some of which are quite rare and difficult to identify. Diagnostic delays can have significant consequences for patients, underscoring the importance of vigilance and a systematic approach to evaluation.

In this article, we delve into two intriguing cases of hypoglycemia associated with endogenous hyperinsulinism, each stemming from causes not typically encountered in everyday clinical settings. By examining these cases, we aim to highlight essential aspects of the diagnosis and management of hypoglycemia within the context of endogenous hyperinsulinism.

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What Causes Endogenous Hyperinsulinism?

Endogenous hyperinsulinism is an abnormal clinical condition involving excessive insulin secretion. Insulinoma is the most common cause, accounting for approximately 55% of cases. Other recognised causes include islet cell hyperplasia, nesidioblastosis, and antibodies directed against insulin or the insulin receptor. This range of underlying aetiologies makes accurate diagnosis a persistent clinical challenge.

Diagnosing Endogenous Hyperinsulinism: Methods and Shortfalls

The standard approach to suspected endogenous hyperinsulinism begins with identifying hypoglycaemia and then confirming endogenous insulin excess, followed by testing for insulin antibodies to rule out insulin autoimmune hypoglycaemia. However, the condition remains diagnostically difficult to confirm in practice. In one study, endogenous hyperinsulinism was diagnosed in only 10 of the enrolled participants, and the authors noted that such low case counts can lead to statistical overfitting and reduce the power to detect meaningful differences. These limitations underscore the need for larger, more robust study designs.

CHOP's Role in Advancing Hyperinsulinism Care

Children's Hospital of Philadelphia (CHOP) has been at the forefront of treating children with hyperinsulinism for decades. Ben Raskin-Gross's story illustrates the consequences of a delayed diagnosis of hyperinsulinism, which had a lifelong impact on both him and his family. Early and accurate intervention at CHOP ultimately made a significant difference in his outcome. These foundational efforts in paediatric hyperinsulinism care have shaped current diagnostic and treatment paradigms.

Case Studies: Diagnostic Journeys

A complex maze representing the diagnostic challenges of endogenous hyperinsulinism, with insulin molecules as pathways.

The following case studies exemplify the diagnostic challenges and the importance of considering unusual etiologies in patients presenting with hypoglycemia and evidence of endogenous hyperinsulinism.

Case 1: Proinsulin-Producing Adenoma. A 64-year-old woman was admitted to the hospital for the investigation of recurrent hypoglycemic episodes. The patient had been asymptomatic until six months prior to admission, when she began experiencing recurrent episodes of disorientation and headache, typically occurring upon waking and resolving with food intake. The increasing frequency of these episodes prompted multiple visits to the emergency department. On one occasion, a blood glucose level of 32 mg/dL was recorded during a symptomatic period, which resolved following the administration of hypertonic glucose. A subsequent prolonged fasting test confirmed hypoglycemia (30 mg/dL) after 14 hours, accompanied by an inappropriately elevated insulin level of 7.7 mmol/L and a non-suppressed C-peptide level.

  • Further testing revealed elevated proinsulin concentrations.
  • Imaging studies, including ultrasound, CT, and MRI, were initially unremarkable.
  • Endoscopic ultrasound ultimately identified a 12 x 8 mm nodule in the pancreas.
  • Histopathological analysis of the resected tumor confirmed a well-differentiated adenoma with immunoreactivity for insulin, consistent with a proinsulin-producing adenoma.
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A 24-Case Review of Endogenous Hyperinsulinism

A published review studied 24 patients who presented with hypoglycaemia attributable to endogenous hyperinsulinism. The authors sought to describe the diagnostic and treatment aspects observed across these cases. The study provides clinical detail on how endogenous hyperinsulinism manifests and responds to therapy in a real-world cohort. Such case-series reviews remain valuable for refining diagnostic criteria and management strategies for a relatively uncommon condition.

Diagnostic and Therapeutic Difficulties Persist

Despite advances in understanding, endogenous hyperinsulinism continues to pose significant diagnostic and therapeutic difficulties. The heterogeneity of causes — from insulinoma to islet cell hyperplasia, nesidioblastosis, and receptor-level antibody disorders — means no single test or pathway reliably resolves every case. The condition is described as abnormal precisely because its clinical presentation can mimic other causes of hypoglycaemia, complicating timely and correct identification. These persistent challenges highlight that current diagnostic frameworks, while useful, are not infallible.

Differential Diagnosis of Endogenous Hyperinsulinism

In apparently healthy individuals presenting with hypoglycaemia, the differential diagnosis for endogenous hyperinsulinism includes insulinoma, functional β-cell disorders, and insulin autoimmune conditions. It is also important to exclude accidental, surreptitious, or factitious causes of hypoglycaemia before attributing symptoms to an endogenous source. Clinicians are advised that investigations should be guided by the specific clinical scenario rather than a one-size-fits-all protocol. This comparative framing is essential for distinguishing true endogenous hyperinsulinism from conditions that closely mimic it.

Case 2: Insulin Autoimmune Syndrome. A 52-year-old male engineer was admitted for evaluation of hypoglycemia. The patient reported experiencing episodes of tremor and diaphoresis, typically in the late afternoon, which improved with food intake. He had two episodes of loss of consciousness, with a recorded glucose level of 23 mg/dL on one occasion. He recovered after receiving intravenous glucose at a local hospital. He denied experiencing hypoglycemic symptoms during fasting. A prolonged fasting test revealed markedly elevated insulin concentrations. The patient remained asymptomatic, and glucose levels remained above 40 mg/dL. C-peptide levels were low but detectable. Further workup revealed a monoclonal spike in the beta region on serum protein electrophoresis, identified as IgG Kappa by immunoelectrophoresis, indicative of multiple myeloma. It was hypothesized that the elevated insulin levels were due to the presence of an insulin-binding antibody produced by the myeloma cells.

Conclusions: Navigating the Diagnostic Maze

Endogenous hyperinsulinism poses significant diagnostic challenges. Accurate diagnosis relies on a high degree of clinical suspicion, a systematic approach to investigation, and awareness of unusual etiologies, such as proinsulin-producing adenomas and insulin autoimmune syndrome. In cases of suspected hyperinsulinism, proinsulin levels should be specifically measured to avoid diagnostic delays. While rare, insulin autoimmune syndrome should be considered in the differential diagnosis to prevent unnecessary surgical interventions.

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The 72-Hour Fast and Non-Diabetic Hypoglycaemia

The 72-hour supervised fast remains a cornerstone investigative tool when evaluating non-diabetic patients for hypoglycaemia caused by endogenous hyperinsulinism. This method allows clinicians to provoke and document low blood glucose under controlled conditions, facilitating biochemical confirmation of inappropriate insulin secretion. Case studies of endogenous hyperinsulinism consistently emphasise the importance of this test in establishing the diagnosis. Its role as a diagnostic anchor continues to be affirmed in the clinical literature.

Evolving Diagnosis and Management Strategies

The diagnostic and therapeutic landscape of endogenous hyperinsulinism continues to evolve. Research into congenital forms of the condition has examined both diagnosis and management, with a focus on improving outcomes for affected patients. Recent work has also explored two specific diagnostic challenges that complicate identification of the condition in clinical practice. As understanding deepens, more refined approaches to both diagnosis and treatment are anticipated.

Addressing Gaps in Recognition and Care

Endogenous hyperinsulinism, while uncommon, reflects broader systemic challenges in diagnosing rare endocrine conditions. Limited clinician familiarity, the overlap of symptoms with more common disorders, and the rarity of individual aetiologies all contribute to delayed or missed diagnoses. Improving awareness and access to specialised investigative pathways is likely essential for better patient outcomes. Without deliberate efforts to address these systemic gaps, diagnostic delays will likely persist.

When Endogenous Hyperinsulinism Mimics Psychiatric Illness

Insulinoma, the most common cause of endogenous hyperinsulinism, is typically benign and solitary, yet its presentation can be profoundly alarming. In one case report, a 36-year-old woman was admitted with confusion, aggressive behaviour, and visual hallucinations — symptoms that initially suggested a psychiatric rather than metabolic cause. This illustrates how the neurological and behavioural consequences of hypoglycaemia can obscure the underlying endocrine diagnosis. Timely recognition of endogenous hyperinsulinism in such cases is critical to preventing misdiagnosis and ensuring appropriate treatment.

About this Article -

Written with AI assistance from published research, and reviewed by the Mystum team. See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.1590/0004-2730000002368, Alternate LINK

Title: Hiperinsulinismo Endógeno: Dois Desafios Diagnósticos

Subject: General Medicine

Journal: Arquivos Brasileiros de Endocrinologia & Metabologia

Publisher: FapUNIFESP (SciELO)

Authors: Ana Pires Gonçalves, Fernando Baptista, Ema Nobre, Isabel Do Carmo

Published: 2014-02-01

Everything You Need To Know

1

What is endogenous hyperinsulinism, and why is it a diagnostic challenge?

Endogenous hyperinsulinism is a condition where the body inappropriately overproduces insulin, leading to hypoglycemia. Diagnosing it involves differentiating between various potential causes, which can be challenging because some causes are rare and difficult to identify. Diagnostic delays can have significant consequences, emphasizing the importance of vigilance and a systematic approach to evaluation.

2

What is a proinsulin-producing adenoma, and how is it diagnosed when standard imaging techniques fail?

A proinsulin-producing adenoma is a rare type of tumor, as seen in Case 1, that secretes excessive amounts of proinsulin, a precursor to insulin. This overproduction leads to hypoglycemia. Diagnosing this condition often requires a high degree of clinical suspicion and specific measurement of proinsulin levels, as standard imaging techniques might initially miss these small tumors. Endoscopic ultrasound can be useful when other imaging is unremarkable.

3

What is insulin autoimmune syndrome, and why is it important to consider it when evaluating hyperinsulinism?

Insulin autoimmune syndrome, also known as Hirata disease, is a condition where the body produces antibodies against its own insulin, leading to episodic hypoglycemia. As highlighted in Case 2, this can occur in the context of underlying conditions like multiple myeloma, where myeloma cells produce insulin-binding antibodies. It is important to consider insulin autoimmune syndrome in the differential diagnosis of hyperinsulinism to avoid unnecessary surgical interventions.

4

What is the role of the prolonged fasting test in the diagnostic workup of endogenous hyperinsulinism?

The prolonged fasting test is a diagnostic procedure used to evaluate patients with suspected endogenous hyperinsulinism. During the test, the patient fasts under close monitoring, and blood samples are periodically collected to measure glucose, insulin, C-peptide, and proinsulin levels. In cases of endogenous hyperinsulinism, the test typically reveals inappropriately elevated insulin and C-peptide levels during hypoglycemia, helping to differentiate it from other causes of low blood sugar.

5

Why was endoscopic ultrasound crucial in Case 1 after initial imaging studies were unremarkable?

In Case 1, initial imaging studies like ultrasound, CT, and MRI were unremarkable, but endoscopic ultrasound eventually identified a 12 x 8 mm nodule in the pancreas. This highlights the limitations of standard imaging techniques in detecting small pancreatic tumors and underscores the importance of utilizing more sensitive methods like endoscopic ultrasound when suspicion for a proinsulin-producing adenoma is high. Histopathological analysis of the resected tumor confirmed a well-differentiated adenoma with immunoreactivity for insulin, consistent with a proinsulin-producing adenoma.

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