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:
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.
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.
2026-07-17 | 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.
2026-07-15 | 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.
2026-07-01 | 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.
2026-08-06 | 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.
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.
2026-07-17 | 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.
2026-07-15 | 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.
2026-07-01 | 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.
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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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