Insulinoma

Although diabetes results in part from a deficiency of normal pancreatic beta cells, inducing human beta cells to regenerate is difficult. Reasoning that insulinomas hold the "genomic recipe" for beta cell expansion, we surveyed 38 human insulinomas to obtain insights into therapeutic pathways for beta cell regeneration. An integrative analysis of whole-exome and RNA-sequencing data was employed to extensively characterize the genomic and molecular landscape of insulinomas relative to normal beta cells. Here, we show at the pathway level that the majority of the insulinomas display mutations, copy number variants and/or dysregulation of epigenetic modifying genes, most prominently in the polycomb and trithorax families. Importantly, these processes are coupled to co-expression network modules associated with cell proliferation, revealing candidates for inducing beta cell regeneration. Validation of key computational predictions supports the concept that understanding the molecular complexity of insulinoma may be a valuable approach to diabetes drug discovery.Diabetes results in part from a deficiency of functional pancreatic beta cells. Here, the authors study the genomic and epigenetic landscapes of human insulinomas to gain insight into possible pathways for therapeutic beta cell regeneration, highlighting epigenetic genes and pathways.

Receptors for the incretin glucagon-like peptide-1 (GLP-1R) have been found overexpressed in selected types of human tumors and may, therefore, play an increasingly important role in endocrine gastrointestinal tumor management. In particular, virtually all benign insulinomas express GLP-1R in high density. Targeting GLP-1R with indium-111, technetium-99m or gallium-68-labeled exendin-4 offers a new approach that permits the successful localization of small benign insulinomas. It is likely that this new non-invasive technique has the potential to replace the invasive localization of insulinomas by selective arterial stimulation and venous sampling. In contrast to benign insulinomas, malignant insulin-secreting neuroendocrine tumors express GLP-1R in only one-third of the cases, while they more often express the somatostatin subtype 2 receptors. Importantly, one of the two receptors appears to be always overexpressed. In special cases of endogenous hyperinsulinemic hypoglycemia (EHH), that is, in the context of MEN-1 or adult nesidioblastosis GLP-1R imaging is useful whereas in postprandial hypoglycemia in the context of bariatric surgery, GLP-1R imaging is probably not helpful. This review focuses on the potential use of GLP-1R imaging in the differential diagnosis of EHH.

Insulin-producing pancreatic neuroendocrine tumors (PanNETs)/insulinomas are generally considered to be indolent tumors with an excellent prognosis after complete resection. However, some insulinomas have a poor prognosis due to relapses and metastatic disease. Recently, studies in non-functional PanNETs indicated that behavior can be stratified according to alpha- and beta-cell differentiation, as defined by expression of the transcription factors ARX and PDX1, respectively. It is unknown whether similar mechanisms play a role in insulinomas. Therefore, we determined ARX and PDX1 expression in a cohort of 35 sporadic primary insulinomas and two liver metastases of inoperable primary insulinomas. In addition, WHO grade and loss of ATRX or DAXX were determined by immunohistochemistry, and alternative lengthening of telomeres (ALT) and CDKN2A status by fluorescence in situ hybridization. These findings were correlated with tumor characteristics and clinical follow-up data. In total, five out of 37 insulinoma patients developed metastatic disease. Metastatic insulinomas were all larger than 3 cm, whereas the indolent insulinomas were smaller (p value < 0.05). All three primary insulinomas that metastasized showed ARX expression, 2/3 showed ALT, and 1/3 had a homozygous deletion of CDKN2A as opposed to absence of ARX expression, ALT, or CDKN2A deletions in the 32 non-metastatic cases. The two liver metastases also showed ARX expression and ALT (2/2). The presence of ARX expression, which is usually absent in beta-cells, and genetic alterations not seen in indolent insulinomas strongly suggest a distinct tumorigenic mechanism in malignant insulinomas, with similarities to non-functional PanNETs. These observations may inform future follow-up strategies after insulinoma surgery.

ContextInsulinomas 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.ObjectiveTo 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.MethodsIn 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.ResultsAmong 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%).ConclusionIn 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.