Unmasking an insulinoma: recurrent Hypoglycemia in a young patient following GLP-1 receptor agonist therapy —A case report

Abstract

Background

Insulinomas are rare, typically benign pancreatic neuroendocrine tumors that cause endogenous hyperinsulinemic hypoglycemia. While usually diagnosed in middle age, their presence in young adults may suggest hereditary syndromes, such as MEN1. While semaglutide and other GLP-1 receptor agonists rarely cause hypoglycemia, they can unmask tumors secreting insulin

Case Presentation

A 25-year-old woman with obesity and polycystic ovary syndrome (PCOS) developed severe hypoglycemia (35 mg/dL) after starting semaglutide. She did not respond to IV dextrose. Labs showed hyperinsulinemia (77.5 mU/L) and elevated C-peptide (19.53 ng/mL). Imaging revealed a pancreatic tail mass, pituitary microadenoma, and ovarian teratoma, raising concern for MEN1. She underwent distal pancreatectomy, splenectomy, and right salpingo-oophorectomy. Glycemia normalized postoperatively. Pathology confirmed a grade 1 pancreatic neuroendocrine tumor (Ki-67 < 1%)

Conclusion

This case emphasizes that hypoglycemia occurring during GLP-1 receptor agonist therapy is not always a drug-related side effect but may result from unmasking of an underlying insulinoma.

1. Introduction

Insulinomas are rare, benign insulin-producing pancreatic neuroendocrine tumors with an incidence of 1–4 cases per million annually [1]. They are typically diagnosed in middle-aged adults and slightly more prevalent in females [2]. Clinically, insulinomas present with neuroglycopenic symptoms such as confusion, dizziness, palpitations and sweating. Diagnosis relies on Whipple’s triad: symptoms of hypoglycemia, plasma glucose < 55 mg/dl, and symptom relief after glucose administration [3], as well as biochemical evidence of endogenous hyperinsulinemia during hypoglycemia [4].

Although most insulinomas are sporadic, 5–10% are associated with Multiple Endocrine Neoplasia Type 1 (MEN1), an autosomal dominant disorder caused by mutations in the MEN1 gene [1, 5]. MEN1 is characterized by tumors in the parathyroid glands, anterior pituitary, and gastroentero-pancreatic tract. MEN1-related insulinomas often present earlier, may be multifocal, and have higher recurrence rates, thereby carrying a worse prognosis [3].

GLP-1 receptor agonists, such as semaglutide, are widely used in the treatment of obesity and diabetes. They stimulate glucose-dependent insulin secretion and have a low risk of hypoglycemia [6, 7]. However, in rare cases, they may unmask insulinomas. We report a young woman with obesity who developed severe hypoglycemia after initiating semaglutide, leading to the diagnosis of an insulinoma and a pituitary microadenoma suggestive of MEN1.

2. Case report

A 25-year-old woman with a history of PCOS, metabolic syndrome, and morbid obesity (BMI 44.3 kg/m²) presented to the emergency department after a syncopal episode preceded by sweating, tremors, and weakness. One week earlier, she was prescribed semaglutide 0.25 mg weekly, orlistat 120 mg, and spironolactone 100 mg. The episode occurred shortly after the first dose of semaglutide, raising concern for medication-related adverse effects.

Upon arrival, her blood glucose was 35 mg/dl and all outpatient medications were discontinued. Although transient normalization of glucose levels was achieved with dextrose infusion (92–116 mg/dl), these improvements were short-lived, and recurrent episodes continued to occur, prompting ICU admission. Hydrocortisone was administered empirically to exclude adrenal insufficiency as a potential cause of hypoglycemia, but it had no effect. An endocrine workup was initiated to evaluate endogenous hyperinsulinemia and adrenal insufficiency.

During the first five days of hospitalization, at least four symptomatic episodes of hypoglycemia occurred (35–67 mg/dl), each time the dextrose infusion was tapered, accompanied by nausea, vomiting, tremors, and altered sensorium. Lactate increased from 12.6 to 18.3 mg/dl, indicating metabolic stress.

Biochemical results prior dextrose administration showed:

• Insulin: 77.5 mU/l

• C-peptide: 19.53 ng/ml

• Proinsulin: 62 pmol/l

• HbA1c: 4.7%

• Cortisol and ACTH: normal

• Serum calcium: 9.0 mg/dl

• Intact PTH: 42.4 pg/ml

Findings were consistent with an insulinoma.

Abdominal MRI revealed a 3.3 × 3.5 cm pancreatic tail mass, suggestive of a neuroendocrine tumor (Fig. 1). Pelvic MRI demonstrated a 4.9 × 5.2 cm right ovarian mass, suggestive of a teratoma (Fig. 2). A pituitary MRI showed a 5 × 7 mm lesion in the adenohypophysis, consistent with a pituitary microadenoma (Fig. 3). Findings raised suspicion of MEN1. Additional hormonal testing revealed mildly elevated prolactin (70.25 ng/ml).

Figure 1.

Composite figure showing two magnetic resonance imaging (MRI) sequences of the abdomen with contrast, demonstrating a mass at the pancreatic tail (red arrows). (A) Axial contrast-enhanced MRI (B), coronal T2-weighted MRI.

Figure 2.

Composite figure showing T2-weighted contrast-enhanced magnetic resonance imaging (MRI) of the pelvis, demonstrating a mass at the right ovary (red arrows). (A) Axial view (B), coronal view.

Figure 3.

Coronal T1-weighted contrast-enhanced magnetic resonance imaging of the brain showing a hypointense lesion at the anterior pituitary, consistent with a pituitary microadenoma (red arrow).

Before surgery, recurrent hypoglycemia was managed with continuous dextrose infusion, intermittent boluses, and close glucose monitoring. Oral intake was poorly tolerated, so the patient relied mainly on intravenous glucose (Table 1). On the 13th day after admission, the patient underwent a laparoscopic distal pancreatectomy, total splenectomy, and right salpingo-oophorectomy after multidisciplinary coordination and completion of preoperative evaluations. The pituitary lesion was managed conservatively with surveillance. Postoperatively, glucose normalized within 24 hours, recovery was uneventful, and none of her previous medications were resumed at discharge.

Table 1.

Summary of preoperative clinical management and interventions.

Time	Intervention	Indication	Dose/Route	Response
ED Arrival	Point-of-care glucose test	Altered mental status/suspected hypoglycemia	Result: 35 mg/dL	Critical hypoglycemia confirmed
ED	Dextrose 10% infusion	Initial glucose correction	81 cc/hr IV	Temporary rise in glucose
Shortly after	Dextrose 50% bolus	Severe hypoglycemia	1 amp IV stat	Transient normalization
Post-bolus	Dextrose 10% infusion resumed	Maintenance of glucose	81 cc/hr IV	Glucose reached 92–116 mg/dl temporarily
ED/ICU	Hydrocortisone trial	Suspected adrenal insufficiency	Dose unspecified	No effect on glucose levels
ED/ICU	Insulin rate adjustment	Empiric insulin suppression strategy- assessed effect by withholding exogenous insulin	N/A	No exogenous insulin administered; hypoglycemia recurred, suggesting endogenous hyperinsulinemia
ICU	Endocrine work-up initiated	Recurrent hypoglycemia despite glucose and steroid therapy	Labs: insulin, C-peptide, cortisol, ACTH, etc.	To evaluate for endogenous hyperinsulinemia and adrenal insufficiency

ED = Emergency Department; ICU =Intensive Care Unit; IV = Intravenous; ACTH = Adrenocorticotropic hormone.

Histopathology confirmed a grade 1 pancreatic neuroendocrine tumor (Fig. 4). Immunohistochemistry revealed positivity for synaptophysin, chromogranin, and PCK AE1/AE3, with Ki-67 < 1%, and negative CD45 and desmin, which supported the diagnosis of a low-grade neuroendocrine neoplasm of pancreatic origin (Fig. 5).

Figure 4.

Histopathological findings of a pancreatic neuroendocrine tumor. (A) Low-power photomicrograph of pancreatic tissue showing well-differentiated neuroendocrine tumor with trabecular and nesting architecture. (B) Higher magnification view highlighting glandular and organoid arrangements, composed of uniform cuboidal cells with round nuclei and moderated cytoplasm, without mitotic activity or atypia.

Figure 5.

Immunohistochemical profile confirming a pancreatic neuroendocrine tumor.

3. Discussion

Insulinomas are rare insulin-secreting pancreatic neuroendocrine tumors causing recurrent hypoglycemia, more frequent in women [1, 2]. Around 5%–10% occur in the context of MEN1, a hereditary syndrome characterized by tumors of the parathyroid glands, anterior pituitary, and gastroentero-pancreatic tract [5].

Our patient developed recurrent hypoglycemia shortly after initiating semaglutide. Although GLP-1 receptor agonists are generally considered safe, isolated reports describe unmasking of insulinomas after exposure to these agents [8]. This phenomenon may occur because GLP-1 receptors are frequently expressed on insulinoma cells, and their stimulation by semaglutide can enhance insulin secretion, revealing an otherwise subclinical tumor. In metabolically complex patients with chronic insulin resistance, such as those with obesity and PCOS, chronic insulin resistance may blunt counterregulatory responses, allowing tumor-induced hypoglycemia to remain unnoticed until therapy modifies metabolic balance [8]. The transient rise in lactate likely reflected impaired glucose utilization and anaerobic metabolism secondary to prolonged hypoglycemia.

Biochemical testing confirmed endogenous hyperinsulinemia. Imaging revealed a lesion in the tail of the pancreas, a pituitary microadenoma and an ovarian teratoma. Although ovarian teratomas are unrelated to MEN1, the coexistence of pancreatic and pituitary lesions in a young woman raised suspicion for MEN1 [4, 9].

A definitive diagnosis of insulinoma relies on histopathologic confirmation following surgical resection. In this case, Histopathology confirmed a well-differentiated grade 1 pancreatic neuroendocrine tumor positive for synaptophysin and chromogranin, with Ki-67 < 1%, consistent with a low-grade insulinoma [3]. MEN1 genetic testing was not performed due to limited availability and financial constraints, representing a limitation of this report.

Reports of insulinoma unmasked by GLP-1 receptor agonists remain extremely limited, and cases involving semaglutide are exceedingly rare. The absence of GLP-1 receptor immunohistochemistry, also due to financial limitations, represents another constraint. Early recognition, thorough hormonal and imaging assessments, allow timely intervention and long-term surveillance. This case reinforces the importance of personalized evaluation and vigilance when unexpected effects arise during metabolic therapy in young adults.

Conflict of interest

The authors declare no conflicts of interest.

Funding

No funding was received.

Ethical approval

Approved by CEDIMAT Ethics Committee (IRB00014368CEI-78).

Consent

Written informed consent was obtained.

Guarantor

Nicole Baldera-Rodriguez accepts full responsibility for the content of this case report.