RARE DISEASE
Insulinoma
Insulinoma
Insulinoma
Drug discovery
2
drugs
With orphan designations
Overview
Insulinomas are rare pancreatic neuroendocrine tumors (incidence 1–4/million/year) causing hyperinsulinemic hypoglycemia via uncontrolled insulin secretion [1][2][17]. Over 90% are benign, solitary, and intrapancreatic [1][6][19], with malignant/metastatic forms seen in 6–15% of cases [1][2][6]. Diagnosis relies on Whipple’s triad (symptoms of hypoglycemia, glucose <55 mg/dL during symptoms, resolution with glucose) [6][14]. Surgical resection remains curative for most indolent cases [3][8][13], while malignant cases require multimodal management [1][8][16].
Therapies
Curative: Surgical enucleation (43%) or pancreatic resection (45%) with 89% cure rate [7][13]
Medical: Diazoxide (first-line), somatostatin analogs, or glucose monitoring for inoperable cases [3][8][16]
Malignant: Debulking, liver-directed therapies (embolization/ablation), and systemic therapies (everolimus, PRRT, chemotherapy) [1][8][16]
Categories: rare endocrine diseases, rare gastroenterological diseases, rare neoplastic diseases
Research Papers
2,872 drug discovery papers about Insulinoma, with 2 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2,872 drug discovery papers about Insulinoma, with 2 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-03 | Adipose Tissue Palmitoylation Cycling Mediates Insulin Resistance and Preservation of β-Cell Function in Mice.
Palmitoylation, the reversible modification of proteins by palmitate, is altered in diabetes. We inactivated acyl protein thioesterase-1 (APT1), a key palmitoylation cycling enzyme, in adipose tissue to study how fat affects systemic metabolism. Given adiposity effects on β-cell failure, we asked if palmitoylation of proteins in fat affects insulin secretion. Adipose APT1-deficient mice had improved glucose metabolism and increased cell-autonomous insulin secretion in two models of insulin resistance, high-fat diet, and aging. Extracellular vesicles from APT1-deficient adipocytes promoted insulin secretion in insulinoma cells. Altering palmitoylation in fat may preserve β-cell function in insulin resistance.
2026-07-15 | Phytochemical Profiling and Multitargeted Biological Activities of Crinum asiaticum L. var. anomalum Baker Leaf: In Vitro and In Silico Insights.
This study investigates the phytochemical and pharmacological profiles of Crinum asiaticum L. var. anomalum Baker from Vietnam. Phytochemical screening identified diverse secondary metabolites, including polyphenols, flavonoids, and alkaloids. Gas chromatography-mass spectrometry analysis of the n-hexane fractions revealed 19 major compounds. While all extracts showed moderate antioxidant activity, the chloroform fraction exhibited superior antidiabetic potential via α-amylase inhibition (IC50 = 83.13 ± 6.67 µg/mL). Furthermore, at non-cytotoxic concentrations (3.13 to 50 µg/mL), this fraction effectively rescued mouse β-TC6 insulinoma cells from thapsigargin. In anti-inflammatory assays, the n-hexane fraction significantly suppressed nitric oxide production in RAW 264.7 macrophages (IC50 = 53.12 ± 1.63 µg/mL). Notably, the extracts displayed remarkable selective anticancer activity, particularly the chloroform fraction against HeLa cervical and HepG2/Huh-7 hepatoma cell lines. In silico ADMET and Lipinski's Rule of Five analyses confirmed that the key bioactive constituents possess favorable pharmacokinetic profiles and drug-likeness. These findings demonstrate C. asiaticum L. var. anomalum Baker as a promising natural source for developing multitarget therapeutic agents against inflammation, diabetes, and cancer.
2026-06-23 | Effect of the FGF1-B promoter on spontaneous beta-cell tumorigenesis in F1B-Tag mice: A robust translational model for insulinoma and metabolic crosstalk.
153 Background: Fibroblast growth factor 1 (FGF1) is a key regulator of glucose homeostasis and β-cell physiology. The F1B-Tag transgenic mouse, utilizing the FGF1-B promoter to drive SV40 T-antigen expression, provides a unique opportunity to study spontaneous tumorigenesis. This study characterizes the F1B-Tag model as a clinically relevant platform for human insulinoma, focusing on the molecular interplay between the FGF1-B promoter and pancreatic β-cell transformation. Methods: F1B-Tag mice were monitored longitudinally to evaluate oncogenic progression. Immunohistochemical (IHC) analysis was performed to co-localize SV40 T-antigen with FGF1 and proliferation markers. Metabolic profiling included blood glucose monitoring, fasting insulin ELISA, and Glucose Tolerance Tests (GTT). Results: F1B-Tag mice developed spontaneous tumors, with pancreatic lesions appearing at approximately 5 months of age. Tumorigenesis was specifically localized to the insulin-secreting β-cells within the pancreatic islets, rather than the ductal cells. IHC confirmed that the FGF1-B promoter actively drives T-antigen expression within these cells, triggering uncontrolled proliferation. Progressed F1B-Tag mice exhibited a statistically significant and marked reduction in both random and fasting blood sugar levels compared to age-matched wild-type (WT) controls. This hypoglycemic state was driven by profound hyperinsulinemia, where fasting plasma insulin levels in F1B-Tag mice were substantially and significantly elevated, reaching nearly twenty-fold higher than WT levels after normalization. GTT revealed a persistent, flattened low-glucose response curve following glucose administration, confirming autonomous and pathological insulin over-secretion. Conclusions: The F1B-Tag mouse is a robust translational model that accurately recapitulates the metabolic disturbances and oncogenic progression of insulinoma. Our findings demonstrate that the FGF1-B promoter is a critical driver in β-cell oncogenesis and glucose-sensing circuits. This model offers a valuable therapeutic screening platform for investigating novel FGF1-targeted therapies and modulating tumor-induced metabolic dysfunction.
2026-06-19 | Insulinoma in pregnancy: a case report and literature review of diagnostic challenges, multidisciplinary management, and therapeutic dilemmas.
Insulinoma during pregnancy is exceedingly rare, with fewer than 30 cases reported worldwide. Diagnosis is often delayed due to overlapping physiological and gestational symptoms, posing significant risks to both mother and fetus. We report a case of a 36-year-old gravida 4 para 2 + 1 woman presenting at 7 weeks' gestation with recurrent symptomatic hypoglycaemia. She re-presented at 12 weeks' gestation with persistent neuroglycopenic symptoms and weight loss. Biochemical evaluation demonstrated inappropriately non-suppressed insulin and C-peptide levels during hypoglycaemia, raising suspicion for endogenous hyperinsulinaemia. Ultrasound was non-diagnostic while magnetic resonance imaging identified a 2.3 x 2.5 cm pancreatic lesion consistent with insulinoma. A multidisciplinary team (MDT) approach involving Endocrinology, Obstetrics & Gynecology (Maternal-Fetal Medicine), Hepatobiliary Surgery, and Radiology guided the management. Due to the tumor size and procedural risks during pregnancy, definitive intervention was deferred while medical therapy with octreotide was initiated, achieving partial glycaemic control. The pregnancy was complicated by fetal growth restriction, necessitating delivery at 34 weeks. Postpartum, she underwent endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA), requiring two sessions before achieving glycaemic stabilization. This case highlights the diagnostic challenges of insulinoma in pregnancy and underscores the importance of MDT-guided individualized management. It also illustrates the limitations of EUS-RFA and medical therapy, particularly in larger tumors, and raises important considerations regarding fetal outcomes.
2026-05-01 | A51-04 Endocrine Mystery in the ICU Revealing an Underlying Insulinoma
Abstract Introduction Insulinoma represents an uncommon pancreatic neuroendocrine tumor, occurring in approximately 1 to 4 cases per million population each year. Its recognition can be delayed in patients with diabetes or critical illness, where metabolic stress and exogenous medications can confuse the biochemical picture. Sulfonylurea exposure can prolong insulin secretion and, in the setting of impaired renal clearance, mask an underlying insulinoma. In pulmonary-critical care practice, hypoglycemia in a patient with obesity hypoventilation syndrome, and respiratory failure presents unique diagnostic and therapeutic challenges. Case Presentation Case of a 54-year-old female with obesity hypoventilation syndrome, severe obstructive sleep apnea, chronic hypercapnic respiratory failure, hypothyroidism, and Type II Diabetes Mellitus that required intensive care unit admission due to acute-on-chronic hypercapnic respiratory failure. While this admission, she developed recurrent fasting and nocturnal hypoglycemia consistent with Wipple's triad. Recent sulfonylurea exposure complicated the diagnostic process in the presence of renal dysfunction, which may have prolonged the duration of hypoglycemia and masked laboratory confirmation of insulinoma. Continuous glucose monitoring (CGM) demonstrated recurrent hypoglycemia despite high-rate dextrose 10% infusion, high-dose glucocorticoids, and octreotide. Diazoxide was held initially due to patient fluid overload and risk of worsening hypoventilation. After aggressive diuresis and clinical stabilization, diazoxide was initiated with carbohydrate-adjusted nutrition, leading to descalation of therapy and resolution of hypoglycemia. Discussion Our cases represent the diagnostic complexity when evaluating hypoglycemia in critically ill patients with pulmonary comorbidities. Obesity hypoventilation-related chronic hypercapnia limited the patient's ability to tolerate prolonged fasting or fluid shifts, and concurrent sulfonylurea exposure confounded the metabolic workup. The need to withhold diazoxide due to volume overload highlights the delicate cardiopulmonary balance required in ICU management. Recognizing the possibility of insulinoma in this context prevented premature attribution of hypoglycemia to medication error or malnutrition. Conclusion Clinicians in critical care must remain alert to rare endocrine causes of recurrent hypoglycemia in complex ICU patients. Sulfonylurea toxicity and impaired renal clearance can mimic or mask insulinoma, delaying diagnosis. A multidisciplinary approach with endocrinology, integration of CGM findings, and cautious metabolic support are key to avoiding neurological complications and directing further evaluation once respiratory status allows. This abstract is funded by: None
cell therapies
2026-06-29 | Artificial Intelligence-Assisted Endoscopic Ultrasound-Guided Ablation of Pancreatic Neuroendocrine Tumors: Toward Precision Diagnosis, Risk Stratification, and Personalized Therapy.
Pancreatic neuroendocrine tumors (pNETs) are increasingly detected at an early stage because of the wider use of cross-sectional imaging and endoscopic ultrasound. Their management remains challenging, particularly for small functioning tumors and selected non-functioning lesions, where the risks of pancreatic surgery must be balanced against tumor biology, symptoms, progression risk, and patient preference. Endoscopic ultrasound (EUS)-guided ablation, particularly radiofrequency ablation, has emerged as a minimally invasive, organ-preserving option for carefully selected patients with small pNETs, especially insulinomas and low-risk non-functioning lesions. However, current evidence is limited by small cohorts, heterogeneous techniques, variable follow-up protocols, and uncertainty regarding long-term oncological outcomes. Artificial intelligence (AI) may enhance this evolving field by supporting EUS-based lesion detection, characterization, grading prediction, risk stratification, patient selection, procedural planning, and post-ablation surveillance. AI-assisted models using EUS images, radiomics, pathology, and multimodal clinical data may help identify patients most likely to benefit from ablation while avoiding inappropriate local therapy in biologically aggressive disease. This review summarizes the current role of EUS-guided ablation for pNETs and explores the emerging potential of AI to support precision diagnosis, individualized risk assessment, and personalized minimally invasive therapy.
2026-05-20 | Insulinoma after Roux-en-Y gastric bypass successfully treated by endoscopic ultrasound-guided radiofrequency ablation.
Post-bariatric hypoglycemia (PBH) can significantly impact patient quality of life and is generally referred to as postprandial hyperinsulinemic hypoglycemia or late dumping. In this report, we present the case of a 55-year-old man with a recent history of Roux-en-Y gastric bypass (RYGB) surgery and multiple admissions owing to hypoglycemic coma postoperatively. Initially, the hypoglycemic episodes were interpreted as being caused by PBH. Due to symptom severity, a fasting test was performed, revealing hypoglycemia and inappropriate hyperinsulinemia, suggestive of an insulinoma. Further computed tomography evaluation revealed a lesion in the pancreatic neck, which could not be demonstrated on gallium-68 (68Ga)-labeled dodecanetetraacetic acid-tyrosine-3-octreotate (DOTATATE) positron emission tomography-computed tomography (PET-CT). Anatomopathological confirmation was pursued using endoscopic ultrasound (EUS)-guided fine needle aspiration through EUS-directed gastrogastrostomy and showed presence of a grade 1 neuroendocrine tumor. We decided to perform EUS-guided radiofrequency ablation (RFA), which resulted in complete resolution of the hypoglycemic episodes. This case report offers an important contribution by demonstrating successful treatment of an insulinoma by RFA via an EUS-guided gastrogastrostomy approach after RYGB, which has not been previously well established. It also underlines the importance of considering alternative causes of recurrent hypoglycemia after bariatric surgery beyond PBH.
2026-01-28 | Endoscopic ultrasound-guided radiofrequency ablation of pancreatic insulinoma.
A man in his mid-30s presented to the emergency department following a motor vehicle accident with critically low blood glucose of 1.1 mmol/L (3.9-5.6 mmol/L) noted by emergency medical service and altered mental status. The patient reported progressive symptoms including tremor, sweating and difficulty concentrating, requiring continuous eating throughout the day, weight gain and hypoglycaemia unawareness.A 72-hour supervised fast confirmed endogenous hyperinsulinaemia, after 5 hours, inappropriately elevated insulin of 26 pmol/L (diagnostic cut-off ≥18 pmol/L) and C-peptide >0.33 nmol/L (expected <0.2 nmol/L) with glucose 2.2 mmol/L (3.9-5.6 mmol/L). While CT and DOTATATE-positron emission tomography were negative, endoscopic ultrasound (EUS) and biopsy identified a 13 mm pancreatic head well-differentiated neuroendocrine tumour.EUS-guided radiofrequency ablation (EUS-guided RFA) achieved immediate symptom resolution with normal postprocedure biochemical profile. In this case, EUS successfully identified the lesion when conventional imaging was negative and EUS-guided RFA resulted in successful treatment in this patient.
2026-01-01 | EUS-Guided Radiofrequency Ablation for Pancreatic Insulinoma: A Case Report
Endogenous hyperinsulinemic hypoglycemia remains a diagnostic challenge requiring precise biochemical and imaging evaluation to determine its etiology. Insulinoma, although rare, is the most common functional pancreatic neuroendocrine tumor. It arises from pancreatic beta cells and is characterized by inappropriate insulin secretion, leading to recurrent hypoglycemia. We report the case of a 40-year-old woman with recurrent symptomatic hypoglycemia in whom Whipple’s triad was documented. Endoscopic ultrasound identified a 13 × 12 mm lesion in the pancreatic neck, consistent with insulinoma. Given the clinical and anatomical characteristics, endoscopic ultrasound-guided radiofrequency ablation was performed as a minimally invasive therapeutic alternative. The patient had a favorable short-term outcome, with complete resolution of symptoms, no residual lesion on imaging at 3 months, and normal fasting glucose, insulin, and C-peptide levels at 4 months.
2025-12-11 | [Interventional endoscopic ultrasound in the hepatopancreatobiliary system : What is possible, what is safe and what is meaningful?].
Interventional endoscopic ultrasound (EUS) has become established as an important diagnostic and therapeutic pillar in diseases of the hepatobiliary and pancreatic system. It complements or replaces conventional strategies and expands the spectrum of endoscopic procedures but requires a high level of expertise and interdisciplinary interpretation of indications. One focus is the treatment of necrotizing pancreatitis: The use of EUS-guided drainage is part of the step-up approach and is superior to surgical procedures. Lumen-apposing metal stents (LAMS) facilitate the access and enable direct necrosectomy but double pigtail stents also retain their role. Pancreatic pseudocysts and postoperative fluid accumulation can also be effectively drained endoscopically. In complex bile duct stenoses, EUS-guided drainage is a back-up method, for example as a rendezvous technique, hepaticogastrostomy or choledochoduodenostomy, especially when an endoscopic retrograde cholangiopancreatography (ERCP) is not technically possible. Similarly, the pancreatic duct can be reached endosonographically, although EUS-guided drainage is only advisable under strict clinical indications. Gallbladder drainage using LAMS is an alternative to percutaneous drainage in severe cholecystitis without surgical options. The EUS gastroenterostomy is increasingly replacing surgical procedures for the treatment of gastric outlet obstructions and also enables the endoscopic ultrasound-directed transgastric ERCP (EDGE) procedure for easier ERCP in an anatomically altered stomach. Other emerging fields include EUS-guided ablation of small insulinomas, endovascular interventions for portal hypertension and celiac plexus block, although the benefits of the latter are limited.
proteins
2026-07-17 | Tetherin enforces an immunometabolic checkpoint that coordinates glycolytic and interferon signaling in adipocytes.
Coordination between innate immune signaling and glucose metabolism is fundamental to organismal homeostasis, yet despite decades of study linking immunity and metabolism, the mechanisms by which metabolic cells restrain antiviral innate signaling while preserving glycolytic competence during overnutrition remain poorly defined. Here we identify Tetherin (BST2) as a unique cell-intrinsic immunometabolic checkpoint that couples restraint of type I interferon (IFN-I) signaling to preservation of glycolytic capacity in adipocytes. Tetherin localizes to endoplasmic reticulum and organizes an interactome enriched for antiviral sensing regulators and glycolytic control nodes in adipocytes. Mechanistically, Tetherin directly engages the ubiquitin-dependent degradation machinery NDFIP1 and RNF128 to terminate IRF3 activation, thereby limiting pro-inflammatory, anti-glycolytic signaling and protecting adipocytes from metabolic dysfunction. In parallel, multiomics integration reveals that Tetherin also acts as a scaffold that binds and spatially organizes and activates PFKFB3 to increase glycolytic capacity and restrain MAVS-IRF3 innate immune signalling. In vivo, adipocyte-specific loss of Tetherin amplifies high sucrose diet and high-fat-diet-induced glucose intolerance and liver steatosis, whereas overexpression of human Tetherin in adipocyte suppresses obesity-driven interferon signaling, restores glycolytic pathway, and improves metabolic homeostasis. Orthogonal perturbations in cancer and insulinoma cells further confirm an immunometabolic role for Tetherin. Together, these findings define Tetherin as a dual node immunometabolic checkpoint that couples restraint of antiviral innate inflammatory signaling to maintenance of glycolytic competence, thereby safeguarding adipocyte metabolic homeostasis.
2026-07-01 | High-yield, standardised automated radiosynthesis process for routine clinical insulinoma PET with [⁶⁸Ga]Ga-NODAGA-exendin-4.
Insulinoma is a rare pancreatic neuroendocrine tumour characterised by inappropriate insulin secretion and recurrent hypoglycaemia. Owing to their small size and intrapancreatic localisation, insulinomas are frequently difficult to detect using conventional anatomical imaging techniques. Functional imaging based on positron emission tomography has therefore gained increasing interest, particularly through targeting of the glucagon-like peptide-1 receptor, which is highly overexpressed in most insulinomas. Among available tracers, gallium-68-labelled NODAGA-exendin-4 has demonstrated excellent diagnostic performance. However, its routine clinical implementation remains limited by the absence of a harmonised, robust and transferable radiosynthesis protocol compatible with hospital radiopharmacy practice. The aim of this work was to optimise and harmonise the automated preparation of gallium-68-labelled NODAGA-exendin-4 by systematically evaluating critical synthesis parameters and validating the optimised process across multiple commercially available gallium-68 generators. Using an automated synthesis module, key variables including precursor amount, labelling temperature and duration, formulation additives, workflow sequence and quality control conditions were investigated. The optimised protocol was subsequently validated using generators from three different manufacturers. Optimisation studies demonstrated that formulation-related parameters, particularly the post-labelling addition of polysorbate 20, resulted in improved radiochemical conversion and reduced residual activity within the synthesis cassette. An optimal precursor amount of 20 µg was identified as a compromise between radiochemical yield and clinical injectability constraints. Radiolabelling at 95 °C for 12 min ensured high conversion while reducing overall synthesis time. Validation runs showed excellent reproducibility, with non-decay-corrected yields ranging from 60 to 73% and decay-corrected yields reaching up to 93%, independent of generator type. Radiochemical purity consistently exceeded 95%, and all quality control parameters complied with established specifications. This study establishes a simplified, efficient and generator-independent automated synthesis of gallium-68-labelled NODAGA-exendin-4. By addressing key translational and regulatory constraints, the proposed protocol provides a practical foundation for the routine clinical implementation of glucagon-like peptide-1 receptor imaging in patients with suspected insulinoma.
2026-06-01 | Development of an automated radiosynthesis for [68Ga]Ga-NODAGA[40Lys]-Exendin-4 in sodium acetate buffer.
[68Ga]Ga-NODAGA[40Lys]-Exendin-4 (68Ga-Ex-4) is a new PET radiopharmaceutical targeting GLP-1-R that showed great specificity and sensitivity in the topographic diagnosis of benign insulinoma. We herein report the development of a new method for 68Ga-Ex-4 radiolabeling in sodium acetate buffer, automated on the miniAllinOne synthesizer. Key parameters were reaction volume, due to low amount of peptide, and pH. At a reaction volume of 2.65 mL and pH 2.9, the reaction yielded 80% of 68Ga-Ex-4. The use of polysorbate and cooling of the solution allows to decrease the adsorption on the reaction vial (from 29 to 2% of total activity remaining on the vial). 68Ga-Ex-4 is purified on a HLB cartridge. Final product was obtained within 40 min, with a mean radiochemical purity of 97% and a radiochemical yield of 67%. We have successfully developed a new radiolabeling method for [68Ga]Ga-NODAGA-[40Lys]Exendin-4, automated on a miniAllinOne synthesizer and using sodium acetate buffer, suitable for clinical application.
2026-05-22 | 68Ga-DOTA-exendin-4 PET/CT for Insulinoma Localization in Patients with Negative or Inconclusive Conventional Imaging.
Insulinomas are the main cause of endogenous hyperinsulinemic hypoglycemia (EHH) in adults, with surgery as the only cure. Pancreas-preserving surgery is preferred, making precise preoperative localization crucial. GLP-1R-targeted imaging, such as [68Ga]Ga-DOTA-exendin-4 PET/CT, outperforms other imaging procedures for insulinoma localization. To investigate the performance and clinical impact of [68Ga]Ga-DOTA-exendin-4 PET/CT for the detection of insulinomas in patients with EHH and prior negative or inconclusive conventional imaging. In this retrospective, real-world, dual-center imaging study, 101 patients with biochemically proven EHH and/or a positive Whipple's triad underwent [68Ga]Ga-DOTA-exendin-4 PET/CT at two tertiary centers between April 2017 and March 2024. Among these, 58 patients with prior negative or inconclusive conventional imaging constituted the primary analysis cohort. Endpoints: Insulinoma detection rate and sensitivity by [68Ga]Ga-DOTA-exendin-4 PET/CT after negative or inconclusive conventional imaging and impact on clinical management. Among the 58 patients with prior negative or inconclusive conventional imaging, [68Ga]Ga-DOTA-exendin-4 PET/CT was positive in 42 patients, corresponding to a detection rate of 72% (95% CI, 59-83%). Thirty patients subsequently underwent PET/CT-guided surgery. Overall, 32 patients had histological verification (including two PET/CT-negative cases), corresponding to a sensitivity of 93.8% (95% CI, 79-99%). In real-world clinical practice, [68Ga]Ga-DOTA-exendin-4 PET/CT provides a high detection rate of 72% for localizing insulinomas, including one case of diffuse nesidioblastosis in patients with EHH and prior negative or inconclusive conventional imaging, thereby enabling PET/CT-guided surgical approaches. These findings underscore the substantial clinical impact of GLP-1R-targeted PET/CT on patient management and prognosis.GLP-1 receptor.
2026-05-14 | GLP-1 Receptor Agonist Associated Unmasking of Insulinoma.
Insulinoma is a rare functional pancreatic neuroendocrine tumour and the most common cause of endogenous hyperinsulinaemic hypoglycaemia in adults. Diagnosis is frequently delayed due to non-specific and intermittent symptoms, and a high index of suspicion is needed. We report the case of a 40-year-old non-diabetic woman who presented with recurrent episodes of weakness shortly after initiation of a glucagon-like peptide-1 receptor agonist (GLP-1RA). Laboratory evaluation demonstrated inappropriately elevated insulin and C-peptide levels during documented hypoglycaemic events, consistent with endogenous hyperinsulinaemia. Autoimmune and exogenous causes were excluded. Imaging studies identified a 2 cm hypervascular pancreatic lesion, with functional imaging confirming somatostatin receptor avidity consistent with an insulin-secreting tumour. The patient was initially treated with diazoxide as a bridge to definitive management. She subsequently underwent laparoscopic distal pancreatectomy, with histopathology confirming a well-differentiated pancreatic neuroendocrine tumour (WHO Grade 1). Following surgery, hypoglycaemia resolved completely. This case highlights the potential of GLP-1 receptor agonist therapy to unmask an insulinoma. Many benign insulinomas exhibit abundant expression of GLP-1 receptors. While a high index of suspicion remains essential, awareness of the emerging association between the incretin-based therapies and unexplained hypoglycaemia may facilitate earlier diagnosis. Hypoglycaemia is a rare but significant clinical event, and thorough evaluation is mandatory.Widely used GLP-1RA medications are glucose-dependent and therefore rarely cause hypoglycaemia; occurrence should prompt clinical suspicion for an underlying cause.Benign insulinomas express high levels of GLP-1 receptors; consequently, GLP-1 RAs may induce otherwise unexplained hypoglycaemia and can be used as tracers to localise difficult to detect tumours.
gene therapies
2026-02-27 | Transcriptomic profiling of insulinomas reveals a new "low-endocrine" subtype with low YY1 expressions.
Insulinoma is the most common functional pancreatic neuroendocrine tumors, typically originating from pancreatic β cells. However, the transcriptional heterogeneity and the regulatory role of transcription factor YY1 remain incompletely understood. High-throughput bulk-RNA sequencing was conducted on insulinoma tumor samples. Unsupervised clustering algorithms were employed to identify molecular subtypes of insulinomas. YY1 mutation status was analyzed by whole-exome sequencing. Functional roles of YY1 were analyzed by Yy1-overexpression and knockdown in INS-1 cell line. Spatial transcriptomic characteristics of insulinoma were analyzed using Visium HD platform. Transcriptomic analysis identified two distinct expression patterns: a low-endocrine subtype and an endocrine subtype. The low-endocrine subtype was characterized by reduced PDX1 and insulin synthesis pathways, with an enrichment in exocrine-related functions. However, these two subtypes exhibited similar clinicopathological features. Notably, while YY1 mutation rates were comparable between the two subtypes, YY1 expression levels were significantly reduced in the low-endocrine subtype. Functional experiments demonstrated that Yy1 levels directly correlated with insulin production, as Yy1 overexpression in INS-1 cells markedly upregulated insulin processing genes and secretory pathways. Yy1 knockdown led to suppression of insulin. Furthermore, spatial transcriptomics confirmed that low-endocrine subtype possessed reduced insulin scores compared to the endocrine subtype. We found a low-endocrine subtype insulinoma with reduced YY1 expression and insulin synthesis transcriptomic signature. This highlights the transcriptomic heterogeneity of insulinomas.
2024-11-24 | Calcium sensing receptor expression is downregulated in gastroenteropancreatic neuroendocrine tumours via epigenetic mechanisms.
Gastroenteropancreatic neuroendocrine tumours (GEP-NETs), which may be hormone secreting (e.g., gastrinomas and insulinomas) or non-secreting (also known as non-functioning NETs) are associated with severe morbidity and have a median overall survival of 75-124 months. Studies have highlighted the importance of epigenetic mechanisms in GEP-NETs pathogenesis, with the most frequently mutated genes being the epigenetic regulators, MEN1, DAXX, and ATRX. However, the consequences of these aberrant epigenetic mechanisms are poorly understood. The calcium sensing receptor (CASR), a G protein coupled-receptor, is epigenetically silenced in cancers, and therefore we examined its role in GEP-NET subtypes. Using RNA-Scope and quantitative PCR analyses in two independent tumour cohorts from Europe (n = 18 patients) and the USA (n = 46 patients) we showed that CASR mRNA is almost completely absent in gastrinomas, insulinomas and non-functioning pancreatic NETs. Furthermore, immunohistochemical staining confirmed a significant reduction in CaSR protein expression in all GEP-NET subtypes, compared to normal islets. DNA methylationEPIC and ATAC-seq analyses in the pancreatic NET cell line QGP-1 showed the CaSR promoter was both hypermethylated and in a region of closed chromatin. Furthermore, transfection of wild type CaSR into QGP-1 cells decreased cell viability, in keeping with the CaSR having a role in cellular proliferation. In summary, our study reveals that CaSR expression is decreased in GEP-NETs and that this reduced expression is likely due to DNA methylation and chromatin changes. Moreover, we demonstrate that transfection of the CaSR into a PNET cell line reduces cell viability, thereby indicating that the CaSR acts as a tumour suppressor in this tumour type.
2024-04-22 | Insufficient TRPM5 Mediates Lipotoxicity-induced Pancreatic β-cell Dysfunction.
While the reduction of transient receptor potential channel subfamily M member 5 (TRPM5) has been reported in islet cells from type 2 diabetic (T2D) mouse models, its role in lipotoxicity-induced pancreatic β-cell dysfunction remains unclear. This study aims to study its role. Pancreas slices were prepared from mice subjected to a high-fat-diet (HFD) at different time points, and TRPM5 expression in the pancreatic β cells was examined using immunofluorescence staining. Glucose-stimulated insulin secretion (GSIS) defects caused by lipotoxicity were mimicked by saturated fatty acid palmitate (Palm). Primary mouse islets and mouse insulinoma MIN6 cells were treated with Palm, and the TRPM5 expression was detected using qRT-PCR and Western blotting. Palm-induced GSIS defects were measured following siRNA-based Trpm5 knockdown. The detrimental effects of Palm on primary mouse islets were also assessed after overexpressing Trpm5 via an adenovirus-derived Trpm5 (Ad-Trpm5). HFD feeding decreased the mRNA levels and protein expression of TRPM5 in mouse pancreatic islets. Palm reduced TRPM5 protein expression in a time- and dose-dependent manner in MIN6 cells. Palm also inhibited TRPM5 expression in primary mouse islets. Knockdown of Trpm5 inhibited insulin secretion upon high glucose stimulation but had little effect on insulin biosynthesis. Overexpression of Trpm5 reversed Palm-induced GSIS defects and the production of functional maturation molecules unique to β cells. Our findings suggest that lipotoxicity inhibits TRPM5 expression in pancreatic β cells both in vivo and in vitro and, in turn, drives β-cell dysfunction.
2022-01-06 | Regulation and function of AP-1 in insulinoma cells and pancreatic β-cells.
Cav1.2 L-type voltage-gated Ca2+ channels play a central role in pancreatic β-cells by integrating extracellular signals with intracellular signaling events leading to insulin secretion and altered gene transcription. Here, we investigated the intracellular signaling pathway following stimulation of Cav1.2 Ca2+ channels and addressed the function of the transcription factor activator protein-1 (AP-1) in pancreatic β-cells of transgenic mice. Stimulation of Cav1.2 Ca2+ channels activates AP-1 in insulinoma cells. Pharmacological and genetic experiments identified c-Jun N-terminal protein kinase as a signal transducer connecting Cav1.2 Ca2+ channel activation with gene transcription. Moreover, the basic region-leucine zipper proteins ATF2 and c-Jun or c-Jun-related proteins were involved in stimulus-transcription coupling. We addressed the functions of AP-1 in pancreatic β-cells analyzing a newly generated transgenic mouse model. These transgenic mice expressed A-Fos, a mutant of c-Fos that attenuates DNA binding of c-Fos dimerization partners. In insulinoma cells, A-Fos completely blocked AP-1 activation following stimulation of Cav1.2 Ca2+ channels. The analysis of transgenic A-Fos-expressing mice revealed that the animals displayed impaired glucose tolerance. Thus, we show here for the first time that AP-1 controls an important function of pancreatic β-cells in vivo, the regulation of glucose homeostasis.
2020-12-30 | Insulinoma-associated protein 1 (INSM1): a potential biomarker and therapeutic target for neuroendocrine tumors.
Insulinoma-associated protein 1 (INSM1), a transcriptional regulator with a zinc-finger DNA-binding domain, has been validated as a cytoplasmic marker for neuroendocrine differentiation of tumor cells. Next to its abundant expression in the fetal pancreas, it is expressed in brain tumors, pheochromocytomas, medullary thyroid carcinomas, insulinomas and pituitary and small-cell lung carcinomas. INSM1 is not expressed in normal adult tissues and/or most non-neuroendocrine tumors. It regulates various downstream signaling pathways, including the Sonic Hedgehog, PI3K/AKT, MEK/ERK1/2, ADK, p53, Wnt, histone acetylation, LSD1, cyclin D1, Ascl1 and N-Myc pathways. Although INSM1 appears to be a subtle and specific biomarker for neuroendocrine tumors, its role in tumor development has remained unclear. Here, we highlight INSMI expression, as well as its diagnostic significance and use as a therapeutic target in various neuroendocrine tumors. Targeting signaling pathways or gene expression alterations associated with INSM1 expression may be instrumental for the design of novel therapeutic strategies for neuroendocrine tumors.
other
2026-08-06 | Ersodetug for Refractory Hypoglycemia Due to Malignant Insulin-Secreting Tumors.
Refractory hypoglycemia is common in malignant insulin-secreting tumors and is associated with substantial morbidity. Ersodetug is a fully human monoclonal antibody that allosterically attenuates insulin receptor signaling with the potential to treat various forms of hyperinsulinism (HI). We retrospectively report outcomes from compassionate use of ersodetug in eight individuals with refractory hypoglycemia due to tumor HI. Ersodetug was administered intravenously at 6 or 9 mg/kg every 1-2 weeks initially, followed by a frequency of every 2-5 weeks, as appropriate. Glycemic, functional, and safety outcomes were analyzed. Eight adults (4 M/4F; 24-74 years; Eastern Cooperative Oncology Group (ECOG) 1-3) received ersodetug for insulin-secreting tumors (metastatic insulinoma, n = 7; cervical neuroendocrine carcinoma, n = 1). No drug-related serious adverse events were observed. Most patients experienced improved glycemic control, including discontinuation of parenteral glucose in 6 of the 7 applicable patients (median, 4.5 days) and a 35.6% relative reduction from baseline in time in hypoglycemia (<70 mg/dL) by continuous glucose monitoring (mean 12.4% to 8.0%; pseudo-median paired change of -3.8 percentage points [90% CI, -8.2 to -1,1; P = 0.02). These glycemic improvements permitted hospital discharge and reductions in other antihypoglycemic therapies beyond glucose infusion rate (pseudo-median change, -2.5; 90% CI, -3.5 to -1.0; P = 0.02), with associated improvements in ECOG status. The median treatment duration with ersodetug (11.5 months, range 5-17) tended to correspond to patient lifespan in the setting of metastatic disease. Ersodetug therapy resulted in reduced hypoglycemia burden, ability to discontinue parenteral glucose infusion, allowing discharge from hospital, use of fewer antihypoglycemic therapies, and improved ECOG performance status in individuals with severe, refractory tumor HI.
2025-10-22 | The role of dinutuximab beta with beta cell function, apoptosis, and proliferation: new approaches to proteomic analysis of insulinoma.
The aim of this study was to investigate gene expressions related to beta cell function, and the altered protein profiles in insulinoma INS-1 cells following DB application, under both cytotoxic and non-cytotoxic conditions, with a focus on cell death and proliferation. Caspase 3 activity, LDH level, Bax, Bcl-2, PCNA, MafA, Nkx6.1, Pdx1, NeuroD1, and Pax6 gene expressions, TOS, TAS, and OSI were demonstrated. Protein profiles were analyzed using LC-MS/MS. The upstream and downstream proteins using the IPA database were determined. ERP29, UBE2V2, UBE2L6, PSMA4, TSMB10, ARF1, NUDCD2, ARF3, IRS1, PTEN, AKT, HSPA8, and Fibronectin levels were shown. The changes were observed in genes depending on pancreatic beta cell function and apoptosis. Bcl2, MafA, Nkx6.1, Pdx1, and NeuroD1 gene levels decreased, while Bax and Pax6 gene levels and TAS and TOS levels increased in the group given STZ + DB. PCNA, Bcl-2, Nkx6.1, Pdx1, and Pax6 gene levels increased, while MafA gene levels decreased in the group given DB. The protein ubiquitination pathway more predominates than the other many signaling pathways. Several proteins not previously associated, or only indirectly linked, with beta cell function, apoptosis, or proliferation were identified and characterized for the first time in insulinoma. These findings provide new insights and potential targets for the treatment of pancreatic cancer.
2025-03-31 | Mutation status in yes-associated protein 1 (YAP1) in an insulinoma cell line Rin-5F.
Previous research indicates that YAP1 mutations may enhance responses to immune checkpoint inhibitors, and this mutation could serve as a novel predictor of response to immunotherapy across various cancers by increasing mutation counts. The insulin-secreting pancreatic cell line Rin-5F is commonly used in pharmacological and toxicological studies. In the present study, the author has examined mutations in the YAP1 gene using genomic DNA and complementary DNA from Rin-5F cells. No mutations in the YAP1 gene were identified in the current investigation. The status of the YAP1 gene in an insulinoma cell line has not been previously documented. According to previous research, YAP1 mutations may be associated with enhanced responses to immune checkpoint inhibitors. Given that there is no mutation of the YAP1 gene in this insulinoma cell line, it is possible that immune checkpoint inhibitors may have a reduced impact on insulinoma. To address this question, further clinical trials of immune checkpoint inhibitors are needed for neuroendocrine tumors, such as insulinomas.
2024-10-01 | 8537 Refractory Hypoglycemia Secondary To Metastatic Insulinoma Treated With Novel Insulin Receptor Antibody - A Case Report
Abstract Disclosure: J. Lloyd: None. S. Abu Omar: None. L. Lester: None. L. Wilson: None. Introduction: Insulinoma is the most common functional pancreatic neuroendocrine tumor, characterized by hypersecretion of insulin, causing hypoglycemia. Insulinomas are mostly benign, however malignant neoplasms account for 5-10 % of cases. Surgical resection is the preferred treatment for solitary tumor, however metastatic insulinoma requires a more aggressive approach with medications to prevent hypoglycemia, resection of primary tumor, resection of metastasis, and chemoembolization. We describe a case of metastatic insulinoma with refractory hypoglycemia despite treatment with multiple medications, surgical resection of tumor, embolization of liver metastasis and successfully treated with a novel monoclonal antibody that blocks insulin receptor. Clinical Case: 43-year-old female was initially diagnosed with metastatic insulinoma in 2021. The primary tumor was pancreatic with metastasis to the liver. She was treated with surgical resection of the primary tumor and three hepatic embolizations for liver metastasis. She required a progressive number of medications to treat frequent, debilitating hypoglycemia. These medications included diazoxide, verapamil, lanreotide then changed to pasireotide, everolimus, and dexamethasone. Despite these treatments, she experienced refractory hypoglycemia and was admitted to the hospital. She required continuous dextrose infusion up to 100ml/hr of D50. Due to the large volume of fluid from dextrose infusion and other medications, she developed severe edema and AKI and required aggressive diuretic regimens and briefly intermittent CRRT. As there were no additional medications to add and prospects for future liver embolization were limited, we requested use of RZ358 through the manufacturer’s Expanded Patient Access program. This medication is a monoclonal antibody that blocks the insulin receptor to counteract the effects of insulin and thereby reduce hypoglycemia. This mechanism of action is unique from medications used to manage insulinoma induced hypoglycemia. She received her first infusion of RZ358 which she tolerated well. She had baseline elevation of ALP due to liver metastasis with further rise after liver embolizations, most recently 4 weeks prior. There was a rise in ALP levels which stabilized after 3 days. She experienced no significant side effects. For the first time in two months, five days after her first infusion of RZ358, the dextrose infusion could be stopped. She received her second infusion of RZ358 one week after first infusion. She was discharged home in a stable condition shortly after the second infusion. Conclusion: The Insulin receptor blocking monoclonal antibody, RZ358, offers a promising approach to patients with metastatic insulinoma who have refractory hypoglycemia despite maximal medical and surgical therapy. Presentation: 6/1/2024
2024-09-14 | UTRs and Ago-2/miR-335 Complex Restricts Amylin Translation in Insulinoma and Human Pancreatic β-Cells.
Amylin promoter and transcriptional factors are well-established, inducible factors in the production of the main amyloidogenic pancreatic hormone, human islet amyloid peptide (hIAPP) or amylin. However, posttranscriptional mechanisms driving hIAPP expression in pancreas remain enigmatic, and hence were explored here. The translational assay revealed that both 5' and 3' untranslated regions (UTRs) of hIAPP restricted expression of the luciferase constructs only in constructs driven by the hIAPP promoter. Bioinformatics analysis revealed several putative seed sequences for a dozen micro RNAs (miRNAs) in hIAPP's 3' UTR. miR-182, miR-335, and miR-495 were the most downregulated miRNAs in stressed human islets exposed to endoplasmic reticulum (ER) or metabolic stressors, thapsigargin (TG) or high glucose (HG). Correspondingly, miR-335 mimics alone or in combination with miR-495 and miR-182 mimics significantly and potently (>3-fold) reduced hIAPP protein expression in HG-treated cultured human islets. siRNA-mediated silencing of Ago2 but not Ago1 significantly stimulated hIAPP expression and secretion from transfected, HG-treated human islets. Conversely, ectopic expression of Ago2 in hIAPP-expressing RIN-m5F cell line driven by CMV promoter reduced hIAPP intracellular protein levels. Collectively, the results point to a novel and synergistic role for hIAPP promoter, 5/3' UTRs and Ago-2/miR-335 complex in post-transcriptional regulation of hIAPP gene expression in normal and metabolically active β-cells.
small molecules
2026-08-03 | Adipose Tissue Palmitoylation Cycling Mediates Insulin Resistance and Preservation of β-Cell Function in Mice.
Palmitoylation, the reversible modification of proteins by palmitate, is altered in diabetes. We inactivated acyl protein thioesterase-1 (APT1), a key palmitoylation cycling enzyme, in adipose tissue to study how fat affects systemic metabolism. Given adiposity effects on β-cell failure, we asked if palmitoylation of proteins in fat affects insulin secretion. Adipose APT1-deficient mice had improved glucose metabolism and increased cell-autonomous insulin secretion in two models of insulin resistance, high-fat diet, and aging. Extracellular vesicles from APT1-deficient adipocytes promoted insulin secretion in insulinoma cells. Altering palmitoylation in fat may preserve β-cell function in insulin resistance.
2026-07-15 | Phytochemical Profiling and Multitargeted Biological Activities of Crinum asiaticum L. var. anomalum Baker Leaf: In Vitro and In Silico Insights.
This study investigates the phytochemical and pharmacological profiles of Crinum asiaticum L. var. anomalum Baker from Vietnam. Phytochemical screening identified diverse secondary metabolites, including polyphenols, flavonoids, and alkaloids. Gas chromatography-mass spectrometry analysis of the n-hexane fractions revealed 19 major compounds. While all extracts showed moderate antioxidant activity, the chloroform fraction exhibited superior antidiabetic potential via α-amylase inhibition (IC50 = 83.13 ± 6.67 µg/mL). Furthermore, at non-cytotoxic concentrations (3.13 to 50 µg/mL), this fraction effectively rescued mouse β-TC6 insulinoma cells from thapsigargin. In anti-inflammatory assays, the n-hexane fraction significantly suppressed nitric oxide production in RAW 264.7 macrophages (IC50 = 53.12 ± 1.63 µg/mL). Notably, the extracts displayed remarkable selective anticancer activity, particularly the chloroform fraction against HeLa cervical and HepG2/Huh-7 hepatoma cell lines. In silico ADMET and Lipinski's Rule of Five analyses confirmed that the key bioactive constituents possess favorable pharmacokinetic profiles and drug-likeness. These findings demonstrate C. asiaticum L. var. anomalum Baker as a promising natural source for developing multitarget therapeutic agents against inflammation, diabetes, and cancer.
2026-06-23 | Effect of the FGF1-B promoter on spontaneous beta-cell tumorigenesis in F1B-Tag mice: A robust translational model for insulinoma and metabolic crosstalk.
153 Background: Fibroblast growth factor 1 (FGF1) is a key regulator of glucose homeostasis and β-cell physiology. The F1B-Tag transgenic mouse, utilizing the FGF1-B promoter to drive SV40 T-antigen expression, provides a unique opportunity to study spontaneous tumorigenesis. This study characterizes the F1B-Tag model as a clinically relevant platform for human insulinoma, focusing on the molecular interplay between the FGF1-B promoter and pancreatic β-cell transformation. Methods: F1B-Tag mice were monitored longitudinally to evaluate oncogenic progression. Immunohistochemical (IHC) analysis was performed to co-localize SV40 T-antigen with FGF1 and proliferation markers. Metabolic profiling included blood glucose monitoring, fasting insulin ELISA, and Glucose Tolerance Tests (GTT). Results: F1B-Tag mice developed spontaneous tumors, with pancreatic lesions appearing at approximately 5 months of age. Tumorigenesis was specifically localized to the insulin-secreting β-cells within the pancreatic islets, rather than the ductal cells. IHC confirmed that the FGF1-B promoter actively drives T-antigen expression within these cells, triggering uncontrolled proliferation. Progressed F1B-Tag mice exhibited a statistically significant and marked reduction in both random and fasting blood sugar levels compared to age-matched wild-type (WT) controls. This hypoglycemic state was driven by profound hyperinsulinemia, where fasting plasma insulin levels in F1B-Tag mice were substantially and significantly elevated, reaching nearly twenty-fold higher than WT levels after normalization. GTT revealed a persistent, flattened low-glucose response curve following glucose administration, confirming autonomous and pathological insulin over-secretion. Conclusions: The F1B-Tag mouse is a robust translational model that accurately recapitulates the metabolic disturbances and oncogenic progression of insulinoma. Our findings demonstrate that the FGF1-B promoter is a critical driver in β-cell oncogenesis and glucose-sensing circuits. This model offers a valuable therapeutic screening platform for investigating novel FGF1-targeted therapies and modulating tumor-induced metabolic dysfunction.
2026-06-19 | Insulinoma in pregnancy: a case report and literature review of diagnostic challenges, multidisciplinary management, and therapeutic dilemmas.
Insulinoma during pregnancy is exceedingly rare, with fewer than 30 cases reported worldwide. Diagnosis is often delayed due to overlapping physiological and gestational symptoms, posing significant risks to both mother and fetus. We report a case of a 36-year-old gravida 4 para 2 + 1 woman presenting at 7 weeks' gestation with recurrent symptomatic hypoglycaemia. She re-presented at 12 weeks' gestation with persistent neuroglycopenic symptoms and weight loss. Biochemical evaluation demonstrated inappropriately non-suppressed insulin and C-peptide levels during hypoglycaemia, raising suspicion for endogenous hyperinsulinaemia. Ultrasound was non-diagnostic while magnetic resonance imaging identified a 2.3 x 2.5 cm pancreatic lesion consistent with insulinoma. A multidisciplinary team (MDT) approach involving Endocrinology, Obstetrics & Gynecology (Maternal-Fetal Medicine), Hepatobiliary Surgery, and Radiology guided the management. Due to the tumor size and procedural risks during pregnancy, definitive intervention was deferred while medical therapy with octreotide was initiated, achieving partial glycaemic control. The pregnancy was complicated by fetal growth restriction, necessitating delivery at 34 weeks. Postpartum, she underwent endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA), requiring two sessions before achieving glycaemic stabilization. This case highlights the diagnostic challenges of insulinoma in pregnancy and underscores the importance of MDT-guided individualized management. It also illustrates the limitations of EUS-RFA and medical therapy, particularly in larger tumors, and raises important considerations regarding fetal outcomes.
2026-05-01 | A51-04 Endocrine Mystery in the ICU Revealing an Underlying Insulinoma
Abstract Introduction Insulinoma represents an uncommon pancreatic neuroendocrine tumor, occurring in approximately 1 to 4 cases per million population each year. Its recognition can be delayed in patients with diabetes or critical illness, where metabolic stress and exogenous medications can confuse the biochemical picture. Sulfonylurea exposure can prolong insulin secretion and, in the setting of impaired renal clearance, mask an underlying insulinoma. In pulmonary-critical care practice, hypoglycemia in a patient with obesity hypoventilation syndrome, and respiratory failure presents unique diagnostic and therapeutic challenges. Case Presentation Case of a 54-year-old female with obesity hypoventilation syndrome, severe obstructive sleep apnea, chronic hypercapnic respiratory failure, hypothyroidism, and Type II Diabetes Mellitus that required intensive care unit admission due to acute-on-chronic hypercapnic respiratory failure. While this admission, she developed recurrent fasting and nocturnal hypoglycemia consistent with Wipple's triad. Recent sulfonylurea exposure complicated the diagnostic process in the presence of renal dysfunction, which may have prolonged the duration of hypoglycemia and masked laboratory confirmation of insulinoma. Continuous glucose monitoring (CGM) demonstrated recurrent hypoglycemia despite high-rate dextrose 10% infusion, high-dose glucocorticoids, and octreotide. Diazoxide was held initially due to patient fluid overload and risk of worsening hypoventilation. After aggressive diuresis and clinical stabilization, diazoxide was initiated with carbohydrate-adjusted nutrition, leading to descalation of therapy and resolution of hypoglycemia. Discussion Our cases represent the diagnostic complexity when evaluating hypoglycemia in critically ill patients with pulmonary comorbidities. Obesity hypoventilation-related chronic hypercapnia limited the patient's ability to tolerate prolonged fasting or fluid shifts, and concurrent sulfonylurea exposure confounded the metabolic workup. The need to withhold diazoxide due to volume overload highlights the delicate cardiopulmonary balance required in ICU management. Recognizing the possibility of insulinoma in this context prevented premature attribution of hypoglycemia to medication error or malnutrition. Conclusion Clinicians in critical care must remain alert to rare endocrine causes of recurrent hypoglycemia in complex ICU patients. Sulfonylurea toxicity and impaired renal clearance can mimic or mask insulinoma, delaying diagnosis. A multidisciplinary approach with endocrinology, integration of CGM findings, and cautious metabolic support are key to avoiding neurological complications and directing further evaluation once respiratory status allows. This abstract is funded by: None
cell therapies
2026-06-29 | Artificial Intelligence-Assisted Endoscopic Ultrasound-Guided Ablation of Pancreatic Neuroendocrine Tumors: Toward Precision Diagnosis, Risk Stratification, and Personalized Therapy.
Pancreatic neuroendocrine tumors (pNETs) are increasingly detected at an early stage because of the wider use of cross-sectional imaging and endoscopic ultrasound. Their management remains challenging, particularly for small functioning tumors and selected non-functioning lesions, where the risks of pancreatic surgery must be balanced against tumor biology, symptoms, progression risk, and patient preference. Endoscopic ultrasound (EUS)-guided ablation, particularly radiofrequency ablation, has emerged as a minimally invasive, organ-preserving option for carefully selected patients with small pNETs, especially insulinomas and low-risk non-functioning lesions. However, current evidence is limited by small cohorts, heterogeneous techniques, variable follow-up protocols, and uncertainty regarding long-term oncological outcomes. Artificial intelligence (AI) may enhance this evolving field by supporting EUS-based lesion detection, characterization, grading prediction, risk stratification, patient selection, procedural planning, and post-ablation surveillance. AI-assisted models using EUS images, radiomics, pathology, and multimodal clinical data may help identify patients most likely to benefit from ablation while avoiding inappropriate local therapy in biologically aggressive disease. This review summarizes the current role of EUS-guided ablation for pNETs and explores the emerging potential of AI to support precision diagnosis, individualized risk assessment, and personalized minimally invasive therapy.
2026-05-20 | Insulinoma after Roux-en-Y gastric bypass successfully treated by endoscopic ultrasound-guided radiofrequency ablation.
Post-bariatric hypoglycemia (PBH) can significantly impact patient quality of life and is generally referred to as postprandial hyperinsulinemic hypoglycemia or late dumping. In this report, we present the case of a 55-year-old man with a recent history of Roux-en-Y gastric bypass (RYGB) surgery and multiple admissions owing to hypoglycemic coma postoperatively. Initially, the hypoglycemic episodes were interpreted as being caused by PBH. Due to symptom severity, a fasting test was performed, revealing hypoglycemia and inappropriate hyperinsulinemia, suggestive of an insulinoma. Further computed tomography evaluation revealed a lesion in the pancreatic neck, which could not be demonstrated on gallium-68 (68Ga)-labeled dodecanetetraacetic acid-tyrosine-3-octreotate (DOTATATE) positron emission tomography-computed tomography (PET-CT). Anatomopathological confirmation was pursued using endoscopic ultrasound (EUS)-guided fine needle aspiration through EUS-directed gastrogastrostomy and showed presence of a grade 1 neuroendocrine tumor. We decided to perform EUS-guided radiofrequency ablation (RFA), which resulted in complete resolution of the hypoglycemic episodes. This case report offers an important contribution by demonstrating successful treatment of an insulinoma by RFA via an EUS-guided gastrogastrostomy approach after RYGB, which has not been previously well established. It also underlines the importance of considering alternative causes of recurrent hypoglycemia after bariatric surgery beyond PBH.
2026-01-28 | Endoscopic ultrasound-guided radiofrequency ablation of pancreatic insulinoma.
A man in his mid-30s presented to the emergency department following a motor vehicle accident with critically low blood glucose of 1.1 mmol/L (3.9-5.6 mmol/L) noted by emergency medical service and altered mental status. The patient reported progressive symptoms including tremor, sweating and difficulty concentrating, requiring continuous eating throughout the day, weight gain and hypoglycaemia unawareness.A 72-hour supervised fast confirmed endogenous hyperinsulinaemia, after 5 hours, inappropriately elevated insulin of 26 pmol/L (diagnostic cut-off ≥18 pmol/L) and C-peptide >0.33 nmol/L (expected <0.2 nmol/L) with glucose 2.2 mmol/L (3.9-5.6 mmol/L). While CT and DOTATATE-positron emission tomography were negative, endoscopic ultrasound (EUS) and biopsy identified a 13 mm pancreatic head well-differentiated neuroendocrine tumour.EUS-guided radiofrequency ablation (EUS-guided RFA) achieved immediate symptom resolution with normal postprocedure biochemical profile. In this case, EUS successfully identified the lesion when conventional imaging was negative and EUS-guided RFA resulted in successful treatment in this patient.
2026-01-01 | EUS-Guided Radiofrequency Ablation for Pancreatic Insulinoma: A Case Report
Endogenous hyperinsulinemic hypoglycemia remains a diagnostic challenge requiring precise biochemical and imaging evaluation to determine its etiology. Insulinoma, although rare, is the most common functional pancreatic neuroendocrine tumor. It arises from pancreatic beta cells and is characterized by inappropriate insulin secretion, leading to recurrent hypoglycemia. We report the case of a 40-year-old woman with recurrent symptomatic hypoglycemia in whom Whipple’s triad was documented. Endoscopic ultrasound identified a 13 × 12 mm lesion in the pancreatic neck, consistent with insulinoma. Given the clinical and anatomical characteristics, endoscopic ultrasound-guided radiofrequency ablation was performed as a minimally invasive therapeutic alternative. The patient had a favorable short-term outcome, with complete resolution of symptoms, no residual lesion on imaging at 3 months, and normal fasting glucose, insulin, and C-peptide levels at 4 months.
2025-12-11 | [Interventional endoscopic ultrasound in the hepatopancreatobiliary system : What is possible, what is safe and what is meaningful?].
Interventional endoscopic ultrasound (EUS) has become established as an important diagnostic and therapeutic pillar in diseases of the hepatobiliary and pancreatic system. It complements or replaces conventional strategies and expands the spectrum of endoscopic procedures but requires a high level of expertise and interdisciplinary interpretation of indications. One focus is the treatment of necrotizing pancreatitis: The use of EUS-guided drainage is part of the step-up approach and is superior to surgical procedures. Lumen-apposing metal stents (LAMS) facilitate the access and enable direct necrosectomy but double pigtail stents also retain their role. Pancreatic pseudocysts and postoperative fluid accumulation can also be effectively drained endoscopically. In complex bile duct stenoses, EUS-guided drainage is a back-up method, for example as a rendezvous technique, hepaticogastrostomy or choledochoduodenostomy, especially when an endoscopic retrograde cholangiopancreatography (ERCP) is not technically possible. Similarly, the pancreatic duct can be reached endosonographically, although EUS-guided drainage is only advisable under strict clinical indications. Gallbladder drainage using LAMS is an alternative to percutaneous drainage in severe cholecystitis without surgical options. The EUS gastroenterostomy is increasingly replacing surgical procedures for the treatment of gastric outlet obstructions and also enables the endoscopic ultrasound-directed transgastric ERCP (EDGE) procedure for easier ERCP in an anatomically altered stomach. Other emerging fields include EUS-guided ablation of small insulinomas, endovascular interventions for portal hypertension and celiac plexus block, although the benefits of the latter are limited.
proteins
2026-07-17 | Tetherin enforces an immunometabolic checkpoint that coordinates glycolytic and interferon signaling in adipocytes.
Coordination between innate immune signaling and glucose metabolism is fundamental to organismal homeostasis, yet despite decades of study linking immunity and metabolism, the mechanisms by which metabolic cells restrain antiviral innate signaling while preserving glycolytic competence during overnutrition remain poorly defined. Here we identify Tetherin (BST2) as a unique cell-intrinsic immunometabolic checkpoint that couples restraint of type I interferon (IFN-I) signaling to preservation of glycolytic capacity in adipocytes. Tetherin localizes to endoplasmic reticulum and organizes an interactome enriched for antiviral sensing regulators and glycolytic control nodes in adipocytes. Mechanistically, Tetherin directly engages the ubiquitin-dependent degradation machinery NDFIP1 and RNF128 to terminate IRF3 activation, thereby limiting pro-inflammatory, anti-glycolytic signaling and protecting adipocytes from metabolic dysfunction. In parallel, multiomics integration reveals that Tetherin also acts as a scaffold that binds and spatially organizes and activates PFKFB3 to increase glycolytic capacity and restrain MAVS-IRF3 innate immune signalling. In vivo, adipocyte-specific loss of Tetherin amplifies high sucrose diet and high-fat-diet-induced glucose intolerance and liver steatosis, whereas overexpression of human Tetherin in adipocyte suppresses obesity-driven interferon signaling, restores glycolytic pathway, and improves metabolic homeostasis. Orthogonal perturbations in cancer and insulinoma cells further confirm an immunometabolic role for Tetherin. Together, these findings define Tetherin as a dual node immunometabolic checkpoint that couples restraint of antiviral innate inflammatory signaling to maintenance of glycolytic competence, thereby safeguarding adipocyte metabolic homeostasis.
2026-07-01 | High-yield, standardised automated radiosynthesis process for routine clinical insulinoma PET with [⁶⁸Ga]Ga-NODAGA-exendin-4.
Insulinoma is a rare pancreatic neuroendocrine tumour characterised by inappropriate insulin secretion and recurrent hypoglycaemia. Owing to their small size and intrapancreatic localisation, insulinomas are frequently difficult to detect using conventional anatomical imaging techniques. Functional imaging based on positron emission tomography has therefore gained increasing interest, particularly through targeting of the glucagon-like peptide-1 receptor, which is highly overexpressed in most insulinomas. Among available tracers, gallium-68-labelled NODAGA-exendin-4 has demonstrated excellent diagnostic performance. However, its routine clinical implementation remains limited by the absence of a harmonised, robust and transferable radiosynthesis protocol compatible with hospital radiopharmacy practice. The aim of this work was to optimise and harmonise the automated preparation of gallium-68-labelled NODAGA-exendin-4 by systematically evaluating critical synthesis parameters and validating the optimised process across multiple commercially available gallium-68 generators. Using an automated synthesis module, key variables including precursor amount, labelling temperature and duration, formulation additives, workflow sequence and quality control conditions were investigated. The optimised protocol was subsequently validated using generators from three different manufacturers. Optimisation studies demonstrated that formulation-related parameters, particularly the post-labelling addition of polysorbate 20, resulted in improved radiochemical conversion and reduced residual activity within the synthesis cassette. An optimal precursor amount of 20 µg was identified as a compromise between radiochemical yield and clinical injectability constraints. Radiolabelling at 95 °C for 12 min ensured high conversion while reducing overall synthesis time. Validation runs showed excellent reproducibility, with non-decay-corrected yields ranging from 60 to 73% and decay-corrected yields reaching up to 93%, independent of generator type. Radiochemical purity consistently exceeded 95%, and all quality control parameters complied with established specifications. This study establishes a simplified, efficient and generator-independent automated synthesis of gallium-68-labelled NODAGA-exendin-4. By addressing key translational and regulatory constraints, the proposed protocol provides a practical foundation for the routine clinical implementation of glucagon-like peptide-1 receptor imaging in patients with suspected insulinoma.
2026-06-01 | Development of an automated radiosynthesis for [68Ga]Ga-NODAGA[40Lys]-Exendin-4 in sodium acetate buffer.
[68Ga]Ga-NODAGA[40Lys]-Exendin-4 (68Ga-Ex-4) is a new PET radiopharmaceutical targeting GLP-1-R that showed great specificity and sensitivity in the topographic diagnosis of benign insulinoma. We herein report the development of a new method for 68Ga-Ex-4 radiolabeling in sodium acetate buffer, automated on the miniAllinOne synthesizer. Key parameters were reaction volume, due to low amount of peptide, and pH. At a reaction volume of 2.65 mL and pH 2.9, the reaction yielded 80% of 68Ga-Ex-4. The use of polysorbate and cooling of the solution allows to decrease the adsorption on the reaction vial (from 29 to 2% of total activity remaining on the vial). 68Ga-Ex-4 is purified on a HLB cartridge. Final product was obtained within 40 min, with a mean radiochemical purity of 97% and a radiochemical yield of 67%. We have successfully developed a new radiolabeling method for [68Ga]Ga-NODAGA-[40Lys]Exendin-4, automated on a miniAllinOne synthesizer and using sodium acetate buffer, suitable for clinical application.
2026-05-22 | 68Ga-DOTA-exendin-4 PET/CT for Insulinoma Localization in Patients with Negative or Inconclusive Conventional Imaging.
Insulinomas are the main cause of endogenous hyperinsulinemic hypoglycemia (EHH) in adults, with surgery as the only cure. Pancreas-preserving surgery is preferred, making precise preoperative localization crucial. GLP-1R-targeted imaging, such as [68Ga]Ga-DOTA-exendin-4 PET/CT, outperforms other imaging procedures for insulinoma localization. To investigate the performance and clinical impact of [68Ga]Ga-DOTA-exendin-4 PET/CT for the detection of insulinomas in patients with EHH and prior negative or inconclusive conventional imaging. In this retrospective, real-world, dual-center imaging study, 101 patients with biochemically proven EHH and/or a positive Whipple's triad underwent [68Ga]Ga-DOTA-exendin-4 PET/CT at two tertiary centers between April 2017 and March 2024. Among these, 58 patients with prior negative or inconclusive conventional imaging constituted the primary analysis cohort. Endpoints: Insulinoma detection rate and sensitivity by [68Ga]Ga-DOTA-exendin-4 PET/CT after negative or inconclusive conventional imaging and impact on clinical management. Among the 58 patients with prior negative or inconclusive conventional imaging, [68Ga]Ga-DOTA-exendin-4 PET/CT was positive in 42 patients, corresponding to a detection rate of 72% (95% CI, 59-83%). Thirty patients subsequently underwent PET/CT-guided surgery. Overall, 32 patients had histological verification (including two PET/CT-negative cases), corresponding to a sensitivity of 93.8% (95% CI, 79-99%). In real-world clinical practice, [68Ga]Ga-DOTA-exendin-4 PET/CT provides a high detection rate of 72% for localizing insulinomas, including one case of diffuse nesidioblastosis in patients with EHH and prior negative or inconclusive conventional imaging, thereby enabling PET/CT-guided surgical approaches. These findings underscore the substantial clinical impact of GLP-1R-targeted PET/CT on patient management and prognosis.GLP-1 receptor.
2026-05-14 | GLP-1 Receptor Agonist Associated Unmasking of Insulinoma.
Insulinoma is a rare functional pancreatic neuroendocrine tumour and the most common cause of endogenous hyperinsulinaemic hypoglycaemia in adults. Diagnosis is frequently delayed due to non-specific and intermittent symptoms, and a high index of suspicion is needed. We report the case of a 40-year-old non-diabetic woman who presented with recurrent episodes of weakness shortly after initiation of a glucagon-like peptide-1 receptor agonist (GLP-1RA). Laboratory evaluation demonstrated inappropriately elevated insulin and C-peptide levels during documented hypoglycaemic events, consistent with endogenous hyperinsulinaemia. Autoimmune and exogenous causes were excluded. Imaging studies identified a 2 cm hypervascular pancreatic lesion, with functional imaging confirming somatostatin receptor avidity consistent with an insulin-secreting tumour. The patient was initially treated with diazoxide as a bridge to definitive management. She subsequently underwent laparoscopic distal pancreatectomy, with histopathology confirming a well-differentiated pancreatic neuroendocrine tumour (WHO Grade 1). Following surgery, hypoglycaemia resolved completely. This case highlights the potential of GLP-1 receptor agonist therapy to unmask an insulinoma. Many benign insulinomas exhibit abundant expression of GLP-1 receptors. While a high index of suspicion remains essential, awareness of the emerging association between the incretin-based therapies and unexplained hypoglycaemia may facilitate earlier diagnosis. Hypoglycaemia is a rare but significant clinical event, and thorough evaluation is mandatory.Widely used GLP-1RA medications are glucose-dependent and therefore rarely cause hypoglycaemia; occurrence should prompt clinical suspicion for an underlying cause.Benign insulinomas express high levels of GLP-1 receptors; consequently, GLP-1 RAs may induce otherwise unexplained hypoglycaemia and can be used as tracers to localise difficult to detect tumours.
gene therapies
2026-02-27 | Transcriptomic profiling of insulinomas reveals a new "low-endocrine" subtype with low YY1 expressions.
Insulinoma is the most common functional pancreatic neuroendocrine tumors, typically originating from pancreatic β cells. However, the transcriptional heterogeneity and the regulatory role of transcription factor YY1 remain incompletely understood. High-throughput bulk-RNA sequencing was conducted on insulinoma tumor samples. Unsupervised clustering algorithms were employed to identify molecular subtypes of insulinomas. YY1 mutation status was analyzed by whole-exome sequencing. Functional roles of YY1 were analyzed by Yy1-overexpression and knockdown in INS-1 cell line. Spatial transcriptomic characteristics of insulinoma were analyzed using Visium HD platform. Transcriptomic analysis identified two distinct expression patterns: a low-endocrine subtype and an endocrine subtype. The low-endocrine subtype was characterized by reduced PDX1 and insulin synthesis pathways, with an enrichment in exocrine-related functions. However, these two subtypes exhibited similar clinicopathological features. Notably, while YY1 mutation rates were comparable between the two subtypes, YY1 expression levels were significantly reduced in the low-endocrine subtype. Functional experiments demonstrated that Yy1 levels directly correlated with insulin production, as Yy1 overexpression in INS-1 cells markedly upregulated insulin processing genes and secretory pathways. Yy1 knockdown led to suppression of insulin. Furthermore, spatial transcriptomics confirmed that low-endocrine subtype possessed reduced insulin scores compared to the endocrine subtype. We found a low-endocrine subtype insulinoma with reduced YY1 expression and insulin synthesis transcriptomic signature. This highlights the transcriptomic heterogeneity of insulinomas.
2024-11-24 | Calcium sensing receptor expression is downregulated in gastroenteropancreatic neuroendocrine tumours via epigenetic mechanisms.
Gastroenteropancreatic neuroendocrine tumours (GEP-NETs), which may be hormone secreting (e.g., gastrinomas and insulinomas) or non-secreting (also known as non-functioning NETs) are associated with severe morbidity and have a median overall survival of 75-124 months. Studies have highlighted the importance of epigenetic mechanisms in GEP-NETs pathogenesis, with the most frequently mutated genes being the epigenetic regulators, MEN1, DAXX, and ATRX. However, the consequences of these aberrant epigenetic mechanisms are poorly understood. The calcium sensing receptor (CASR), a G protein coupled-receptor, is epigenetically silenced in cancers, and therefore we examined its role in GEP-NET subtypes. Using RNA-Scope and quantitative PCR analyses in two independent tumour cohorts from Europe (n = 18 patients) and the USA (n = 46 patients) we showed that CASR mRNA is almost completely absent in gastrinomas, insulinomas and non-functioning pancreatic NETs. Furthermore, immunohistochemical staining confirmed a significant reduction in CaSR protein expression in all GEP-NET subtypes, compared to normal islets. DNA methylationEPIC and ATAC-seq analyses in the pancreatic NET cell line QGP-1 showed the CaSR promoter was both hypermethylated and in a region of closed chromatin. Furthermore, transfection of wild type CaSR into QGP-1 cells decreased cell viability, in keeping with the CaSR having a role in cellular proliferation. In summary, our study reveals that CaSR expression is decreased in GEP-NETs and that this reduced expression is likely due to DNA methylation and chromatin changes. Moreover, we demonstrate that transfection of the CaSR into a PNET cell line reduces cell viability, thereby indicating that the CaSR acts as a tumour suppressor in this tumour type.
2024-04-22 | Insufficient TRPM5 Mediates Lipotoxicity-induced Pancreatic β-cell Dysfunction.
While the reduction of transient receptor potential channel subfamily M member 5 (TRPM5) has been reported in islet cells from type 2 diabetic (T2D) mouse models, its role in lipotoxicity-induced pancreatic β-cell dysfunction remains unclear. This study aims to study its role. Pancreas slices were prepared from mice subjected to a high-fat-diet (HFD) at different time points, and TRPM5 expression in the pancreatic β cells was examined using immunofluorescence staining. Glucose-stimulated insulin secretion (GSIS) defects caused by lipotoxicity were mimicked by saturated fatty acid palmitate (Palm). Primary mouse islets and mouse insulinoma MIN6 cells were treated with Palm, and the TRPM5 expression was detected using qRT-PCR and Western blotting. Palm-induced GSIS defects were measured following siRNA-based Trpm5 knockdown. The detrimental effects of Palm on primary mouse islets were also assessed after overexpressing Trpm5 via an adenovirus-derived Trpm5 (Ad-Trpm5). HFD feeding decreased the mRNA levels and protein expression of TRPM5 in mouse pancreatic islets. Palm reduced TRPM5 protein expression in a time- and dose-dependent manner in MIN6 cells. Palm also inhibited TRPM5 expression in primary mouse islets. Knockdown of Trpm5 inhibited insulin secretion upon high glucose stimulation but had little effect on insulin biosynthesis. Overexpression of Trpm5 reversed Palm-induced GSIS defects and the production of functional maturation molecules unique to β cells. Our findings suggest that lipotoxicity inhibits TRPM5 expression in pancreatic β cells both in vivo and in vitro and, in turn, drives β-cell dysfunction.
2022-01-06 | Regulation and function of AP-1 in insulinoma cells and pancreatic β-cells.
Cav1.2 L-type voltage-gated Ca2+ channels play a central role in pancreatic β-cells by integrating extracellular signals with intracellular signaling events leading to insulin secretion and altered gene transcription. Here, we investigated the intracellular signaling pathway following stimulation of Cav1.2 Ca2+ channels and addressed the function of the transcription factor activator protein-1 (AP-1) in pancreatic β-cells of transgenic mice. Stimulation of Cav1.2 Ca2+ channels activates AP-1 in insulinoma cells. Pharmacological and genetic experiments identified c-Jun N-terminal protein kinase as a signal transducer connecting Cav1.2 Ca2+ channel activation with gene transcription. Moreover, the basic region-leucine zipper proteins ATF2 and c-Jun or c-Jun-related proteins were involved in stimulus-transcription coupling. We addressed the functions of AP-1 in pancreatic β-cells analyzing a newly generated transgenic mouse model. These transgenic mice expressed A-Fos, a mutant of c-Fos that attenuates DNA binding of c-Fos dimerization partners. In insulinoma cells, A-Fos completely blocked AP-1 activation following stimulation of Cav1.2 Ca2+ channels. The analysis of transgenic A-Fos-expressing mice revealed that the animals displayed impaired glucose tolerance. Thus, we show here for the first time that AP-1 controls an important function of pancreatic β-cells in vivo, the regulation of glucose homeostasis.
2020-12-30 | Insulinoma-associated protein 1 (INSM1): a potential biomarker and therapeutic target for neuroendocrine tumors.
Insulinoma-associated protein 1 (INSM1), a transcriptional regulator with a zinc-finger DNA-binding domain, has been validated as a cytoplasmic marker for neuroendocrine differentiation of tumor cells. Next to its abundant expression in the fetal pancreas, it is expressed in brain tumors, pheochromocytomas, medullary thyroid carcinomas, insulinomas and pituitary and small-cell lung carcinomas. INSM1 is not expressed in normal adult tissues and/or most non-neuroendocrine tumors. It regulates various downstream signaling pathways, including the Sonic Hedgehog, PI3K/AKT, MEK/ERK1/2, ADK, p53, Wnt, histone acetylation, LSD1, cyclin D1, Ascl1 and N-Myc pathways. Although INSM1 appears to be a subtle and specific biomarker for neuroendocrine tumors, its role in tumor development has remained unclear. Here, we highlight INSMI expression, as well as its diagnostic significance and use as a therapeutic target in various neuroendocrine tumors. Targeting signaling pathways or gene expression alterations associated with INSM1 expression may be instrumental for the design of novel therapeutic strategies for neuroendocrine tumors.
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2026-08-06 | Ersodetug for Refractory Hypoglycemia Due to Malignant Insulin-Secreting Tumors.
Refractory hypoglycemia is common in malignant insulin-secreting tumors and is associated with substantial morbidity. Ersodetug is a fully human monoclonal antibody that allosterically attenuates insulin receptor signaling with the potential to treat various forms of hyperinsulinism (HI). We retrospectively report outcomes from compassionate use of ersodetug in eight individuals with refractory hypoglycemia due to tumor HI. Ersodetug was administered intravenously at 6 or 9 mg/kg every 1-2 weeks initially, followed by a frequency of every 2-5 weeks, as appropriate. Glycemic, functional, and safety outcomes were analyzed. Eight adults (4 M/4F; 24-74 years; Eastern Cooperative Oncology Group (ECOG) 1-3) received ersodetug for insulin-secreting tumors (metastatic insulinoma, n = 7; cervical neuroendocrine carcinoma, n = 1). No drug-related serious adverse events were observed. Most patients experienced improved glycemic control, including discontinuation of parenteral glucose in 6 of the 7 applicable patients (median, 4.5 days) and a 35.6% relative reduction from baseline in time in hypoglycemia (<70 mg/dL) by continuous glucose monitoring (mean 12.4% to 8.0%; pseudo-median paired change of -3.8 percentage points [90% CI, -8.2 to -1,1; P = 0.02). These glycemic improvements permitted hospital discharge and reductions in other antihypoglycemic therapies beyond glucose infusion rate (pseudo-median change, -2.5; 90% CI, -3.5 to -1.0; P = 0.02), with associated improvements in ECOG status. The median treatment duration with ersodetug (11.5 months, range 5-17) tended to correspond to patient lifespan in the setting of metastatic disease. Ersodetug therapy resulted in reduced hypoglycemia burden, ability to discontinue parenteral glucose infusion, allowing discharge from hospital, use of fewer antihypoglycemic therapies, and improved ECOG performance status in individuals with severe, refractory tumor HI.
2025-10-22 | The role of dinutuximab beta with beta cell function, apoptosis, and proliferation: new approaches to proteomic analysis of insulinoma.
The aim of this study was to investigate gene expressions related to beta cell function, and the altered protein profiles in insulinoma INS-1 cells following DB application, under both cytotoxic and non-cytotoxic conditions, with a focus on cell death and proliferation. Caspase 3 activity, LDH level, Bax, Bcl-2, PCNA, MafA, Nkx6.1, Pdx1, NeuroD1, and Pax6 gene expressions, TOS, TAS, and OSI were demonstrated. Protein profiles were analyzed using LC-MS/MS. The upstream and downstream proteins using the IPA database were determined. ERP29, UBE2V2, UBE2L6, PSMA4, TSMB10, ARF1, NUDCD2, ARF3, IRS1, PTEN, AKT, HSPA8, and Fibronectin levels were shown. The changes were observed in genes depending on pancreatic beta cell function and apoptosis. Bcl2, MafA, Nkx6.1, Pdx1, and NeuroD1 gene levels decreased, while Bax and Pax6 gene levels and TAS and TOS levels increased in the group given STZ + DB. PCNA, Bcl-2, Nkx6.1, Pdx1, and Pax6 gene levels increased, while MafA gene levels decreased in the group given DB. The protein ubiquitination pathway more predominates than the other many signaling pathways. Several proteins not previously associated, or only indirectly linked, with beta cell function, apoptosis, or proliferation were identified and characterized for the first time in insulinoma. These findings provide new insights and potential targets for the treatment of pancreatic cancer.
2025-03-31 | Mutation status in yes-associated protein 1 (YAP1) in an insulinoma cell line Rin-5F.
Previous research indicates that YAP1 mutations may enhance responses to immune checkpoint inhibitors, and this mutation could serve as a novel predictor of response to immunotherapy across various cancers by increasing mutation counts. The insulin-secreting pancreatic cell line Rin-5F is commonly used in pharmacological and toxicological studies. In the present study, the author has examined mutations in the YAP1 gene using genomic DNA and complementary DNA from Rin-5F cells. No mutations in the YAP1 gene were identified in the current investigation. The status of the YAP1 gene in an insulinoma cell line has not been previously documented. According to previous research, YAP1 mutations may be associated with enhanced responses to immune checkpoint inhibitors. Given that there is no mutation of the YAP1 gene in this insulinoma cell line, it is possible that immune checkpoint inhibitors may have a reduced impact on insulinoma. To address this question, further clinical trials of immune checkpoint inhibitors are needed for neuroendocrine tumors, such as insulinomas.
2024-10-01 | 8537 Refractory Hypoglycemia Secondary To Metastatic Insulinoma Treated With Novel Insulin Receptor Antibody - A Case Report
Abstract Disclosure: J. Lloyd: None. S. Abu Omar: None. L. Lester: None. L. Wilson: None. Introduction: Insulinoma is the most common functional pancreatic neuroendocrine tumor, characterized by hypersecretion of insulin, causing hypoglycemia. Insulinomas are mostly benign, however malignant neoplasms account for 5-10 % of cases. Surgical resection is the preferred treatment for solitary tumor, however metastatic insulinoma requires a more aggressive approach with medications to prevent hypoglycemia, resection of primary tumor, resection of metastasis, and chemoembolization. We describe a case of metastatic insulinoma with refractory hypoglycemia despite treatment with multiple medications, surgical resection of tumor, embolization of liver metastasis and successfully treated with a novel monoclonal antibody that blocks insulin receptor. Clinical Case: 43-year-old female was initially diagnosed with metastatic insulinoma in 2021. The primary tumor was pancreatic with metastasis to the liver. She was treated with surgical resection of the primary tumor and three hepatic embolizations for liver metastasis. She required a progressive number of medications to treat frequent, debilitating hypoglycemia. These medications included diazoxide, verapamil, lanreotide then changed to pasireotide, everolimus, and dexamethasone. Despite these treatments, she experienced refractory hypoglycemia and was admitted to the hospital. She required continuous dextrose infusion up to 100ml/hr of D50. Due to the large volume of fluid from dextrose infusion and other medications, she developed severe edema and AKI and required aggressive diuretic regimens and briefly intermittent CRRT. As there were no additional medications to add and prospects for future liver embolization were limited, we requested use of RZ358 through the manufacturer’s Expanded Patient Access program. This medication is a monoclonal antibody that blocks the insulin receptor to counteract the effects of insulin and thereby reduce hypoglycemia. This mechanism of action is unique from medications used to manage insulinoma induced hypoglycemia. She received her first infusion of RZ358 which she tolerated well. She had baseline elevation of ALP due to liver metastasis with further rise after liver embolizations, most recently 4 weeks prior. There was a rise in ALP levels which stabilized after 3 days. She experienced no significant side effects. For the first time in two months, five days after her first infusion of RZ358, the dextrose infusion could be stopped. She received her second infusion of RZ358 one week after first infusion. She was discharged home in a stable condition shortly after the second infusion. Conclusion: The Insulin receptor blocking monoclonal antibody, RZ358, offers a promising approach to patients with metastatic insulinoma who have refractory hypoglycemia despite maximal medical and surgical therapy. Presentation: 6/1/2024
2024-09-14 | UTRs and Ago-2/miR-335 Complex Restricts Amylin Translation in Insulinoma and Human Pancreatic β-Cells.
Amylin promoter and transcriptional factors are well-established, inducible factors in the production of the main amyloidogenic pancreatic hormone, human islet amyloid peptide (hIAPP) or amylin. However, posttranscriptional mechanisms driving hIAPP expression in pancreas remain enigmatic, and hence were explored here. The translational assay revealed that both 5' and 3' untranslated regions (UTRs) of hIAPP restricted expression of the luciferase constructs only in constructs driven by the hIAPP promoter. Bioinformatics analysis revealed several putative seed sequences for a dozen micro RNAs (miRNAs) in hIAPP's 3' UTR. miR-182, miR-335, and miR-495 were the most downregulated miRNAs in stressed human islets exposed to endoplasmic reticulum (ER) or metabolic stressors, thapsigargin (TG) or high glucose (HG). Correspondingly, miR-335 mimics alone or in combination with miR-495 and miR-182 mimics significantly and potently (>3-fold) reduced hIAPP protein expression in HG-treated cultured human islets. siRNA-mediated silencing of Ago2 but not Ago1 significantly stimulated hIAPP expression and secretion from transfected, HG-treated human islets. Conversely, ectopic expression of Ago2 in hIAPP-expressing RIN-m5F cell line driven by CMV promoter reduced hIAPP intracellular protein levels. Collectively, the results point to a novel and synergistic role for hIAPP promoter, 5/3' UTRs and Ago-2/miR-335 complex in post-transcriptional regulation of hIAPP gene expression in normal and metabolically active β-cells.
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Drug Discovery Landscape
2 orphan drug designations for Insulinoma.
2 orphan drug designations for Insulinoma.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Anti-(insulin receptor) human monoclonal antibody | antibodies | EMA | 2024-01-12 | — | Rezolute (Bio) Ireland Limited |
Lys40(NODAGA-68Ga)NH2-exendin-4 | peptides | EMA | 2020-06-26 | — | Stichting Katholieke Universiteit |
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