A Systematic Review of the Accuracy of Insulin and C-peptide Secretion Ratios During the Oral Glucose Tolerance Test to Diagnose Insulinoma.

Background: Insulinoma is one of the causes of recurrent hypoglycemia, one of the chief complaints for emergency department admission. The gold standard in diagnosing insulinoma is a 72-hour fasting test which is inconvenient and inefficient as it requires hospitalization. Research has found that measurement of insulin and C-peptide during OGTT may help diagnose insulinoma. We aimed to assess the diagnostic value of OGTT in diagnosing insulinoma. Methodology: The literature search was conducted on 19 August 2022 using several databases (MEDLINE, Scopus, Embase, and ScienceDirect). All studies that measured OGTT as diagnostic tools in diagnosing insulinoma and 72-hour fasting test as reference standard were included. The quality assessment of the selected studies was based on the Centre of Evidence-Based Medicine University of Oxford and the Quality Assessment of Diagnostic Accuracy-2 tool (QUADAS-2). Analysis of the included studies was performed qualitatively. This study was registered on PROSPERO (CRD42022360205). Results: A total of two case-control studies (106 patients) were included, which were at risk of bias and low concern of applicability. Both studies demonstrated that the combination of insulin and C-peptide levels measured during OGTT had high specificity, sensitivity, positive predictive value, and negative predictive value in diagnosing insulinoma compared to the reference standard. A logistic regression model of 8.305 - (0.441 × insulin 2-h/0-h) - (1.679 × C-peptide 1-h/0-h) >0.351 has the highest diagnostic value in one study (AUC 0.97, Sensitivity 86.5%, Specificity 95.2%, PPV 94.1, NPV 88.9). Conclusion: The measurement of 0-h and 2-h insulin and C-peptide levels during 2-h OGTT was found in two small case-control studies with a total of 106 patients to have good sensitivity and specificity. However, due to these limitations, future research is still needed to validate the potential use of OGTT for the diagnosis of insulinoma.

Differences in intratumor innate lymphoid cell composition between orthotopic and spontaneous pancreatic mouse models.

Pancreatic cancer remains an unmet medical need. Late diagnosis and the lack of efficient treatment significantly impact the prognosis of patients suffering from pancreatic cancer. Improving patient outcomes requires a deeper comprehension of the tumor ecosystem. To achieve this, a thorough exploration of the tumor microenvironment using pre-clinical models that accurately replicate human disease is imperative, particularly in understanding the dynamics of immune cell subsets. Surprisingly, the impact of model variations on the composition of the tumor microenvironment has been largely neglected. In this study, we introduce an orthotopic model of pancreatic ductal adenocarcinoma and a spontaneous model of insulinoma. Our findings reveal striking differences in the innate lymphoid cell infiltrate, highlighting the importance of considering model-specific influences when investigating the tumor microenvironment.

Recurrent Hypoglycemia After Total Gastrectomy: A Case Report and Literature Analysis.

BACKGROUND Hypoglycemia is a common complication following total gastrectomy, primarily caused by dumping syndrome and severe malnutrition, with late dumping syndrome being particularly significant. However, for recurrent fasting hypoglycemia, the possibility of insulinoma should be considered. Hypoglycemia caused by insulinoma can lead to severe consequences, including seizures and even death. Thus, it is crucial to differentially diagnose hypoglycemia occurring after total gastrectomy. CASE REPORT In this report, we present the case of a 36-year-old Chinese woman who underwent total gastrectomy for gastric cancer and subsequently received chemotherapy. Four months after surgery, she began experiencing recurrent seizures, and multiple tests confirmed hypoglycemia. A series of laboratory and imaging examinations ultimately led to a diagnosis of insulinoma. After surgical resection of the tumor, the patient's hypoglycemic symptoms resolved, and pathology results confirmed an insulinoma. CONCLUSIONS This case report highlights the rapid weight loss and severe hypoglycemia observed in a patient only 4 months after total gastrectomy for gastric cancer. Although dumping syndrome was initially suspected based on the clinical course, the final diagnosis turned out to be insulinoma. The case underscores the importance of comprehensive evaluation and appropriate diagnostic investigations for patients experiencing hypoglycemia after total gastrectomy. Furthermore, the case suggests that the increased levels of enteroglucagon following changes in the gastrointestinal tract resulting from total gastrectomy may promote the development of insulinomas. This case report also contributes to the existing literature regarding atypical presentations of insulinomas and their association with gastric resection.

SAP deletion promotes malignant insulinoma progression by inducing CXCL12 secretion from CAFs via the CXCR4/p38/ERK signalling pathway.

Malignant insulinoma is an extremely rare type of functioning pancreatic neuroendocrine tumour with a high degree of malignancy and a high incidence of metastasis. However, it is still unclear how malignant insulinomas develop and metastasize. Serum amyloid P component (SAP), a member of the pentraxin protein family, is an acute-phase protein secreted by liver cells. The role of SAP in insulinoma and the related mechanism are still unknown. To determine the effect of SAP on insulinoma, we crossed Rip1-Tag2 mice, which spontaneously develop insulinoma, and SAP knockout (KO) mice to generate Rip1-Tag2;SAP-/- mice. We found that SAP deletion significantly promoted the growth, invasion and metastasis of malignant insulinoma through C-X-C motif chemokine ligand 12 (CXCL12) secreted by cancer-associated fibroblasts (CAFs). Further study showed that SAP deletion promoted CXCL12 secretion by CAFs through the CXCR4/p38/ERK signalling pathway. These findings reveal a novel role and mechanism of SAP in malignant insulinoma and provide direct evidence that SAP may be a therapeutic agent for this disease.

Outcomes of endoscopic ultrasound-guided ablation and minimally invasive surgery in the treatment of pancreatic insulinoma: a systematic review and meta-analysis.

Background and aims: Most pancreatic insulinomas can be treated by minimally invasive modalities. The aim of this meta-analysis was to assess the clinical outcomes of endoscopic ultrasound (EUS)-guided ablation and minimally invasive surgery (MIS) in the treatment of pancreatic insulinoma. Materials and methods: Online databases were searched for relevant studies. The primary aim was to compare the rates of adverse events (AEs) and the secondary aims were to compare the clinical and technical success rates, length of hospital stays, and symptom recurrence rates between EUS and MIS approaches. Results: Eight studies with 150 patients were identified that reported EUS-guided ablation outcomes, forming the EUS group, and 9 studies with 236 patients reported MIS outcomes, forming the MIS group. The pooled median age of the included patients in the EUS group was greater than that of the MIS group (64.06 vs. 44.98 years old, p < 0.001). Also, the technical success rate was significantly higher in the EUS group (100% vs. 96.6%, p = 0.025), while the clinical success was significantly higher (6%) in the MIS group (94% vs. 98.7%, p = 0.021). The AE rates (18.7% vs. 31.1%, p = 0.012) and severe AE rates (1.3% vs. 7.9%, p = 0.011) were significantly lower in the EUS group. The median length of hospital stay in the EUS group (2.68 days, 95% CI: 1.88-3.48, I2 = 60.3%) was significantly shorter than in the MIS group (7.40 days, 95% CI: 6.22-8.58, I2 = 42.2%, p < 0.001). The recurrence rate was significantly higher in the EUS group (15.3% vs. 1.3%, p < 0.001). Conclusions: EUS-guided ablation is associated with a lower AE rate and a shorter length of hospital stay, but a higher recurrence rate for the treatment of insulinoma compared with MIS. The EUS approach may be an alternative, even first-line, treatment for poor surgery candidates.

Preoperative pancreatic stent placement before the enucleation of insulinoma located in the head and neck of the pancreas in proximity to the main pancreatic duct: study protocol for a multicentre randomised clinical trial in Chinese tertiary medical centres.

INTRODUCTION: The surgical intervention approach to insulinomas in proximity to the main pancreatic duct remains controversial. Standard pancreatic resection is recommended by several guidelines; however, enucleation (EN) still attracts surgeons with less risk of late exocrine/endocrine insufficiency, despite a higher postoperative pancreatic fistula (POPF) rate. Recently, the efficacy and safety of preoperative pancreatic stent placement before the EN have been demonstrated. Thus, a multicentre open-label study is being conducted to evaluate the efficacy and safety of stent placement in improving the outcome of EN of insulinomas in proximity to the main pancreatic duct. METHODS AND ANALYSIS: This is a prospective, randomised, open-label, superiority clinical trial conducted at multiple tertiary centres in China. The major eligibility criterion is the presence of insulinoma located in the head and neck of the pancreas in proximity (≤2 mm) to the main pancreatic duct. Blocked randomisation will be performed to allocate patients into the stent EN group and the direct EN group. Patients in the stent EN group will go through stent placement by the endoscopist within 24 hours before the EN surgery, whereas other patients will receive EN surgery directly. The primary outcome is the assessment of the superiority of stent placement in reducing POPF rate measured by the International Study Group of Pancreatic Surgery standard. Both interventions will be performed in an inpatient setting and regular follow-up will be performed. The primary outcome (POPF rate) will be tested for superiority with the Χ2 test. The difference in secondary outcomes between the two groups will be analysed using appropriate tests. ETHICS AND DISSEMINATION: The study has been approved by the Peking Union Medical College Hospital Institutional Review Board (K23C0195), Ruijin Hospital Ethics Committee (2023-314), Peking University First Hospital Ethics Committee (2024033-001), Institutional Review Board of Xuanwu Hospital of Capital Medical University (2023223-002), Ethics Committee of the First Affiliated Hospital of Xi'an Jiaotong University (XJTU1AF2023LSK-473), Institutional Review Board of Tongji Medical College Tongji Hospital (TJ-IRB202402059), Ethics Committee of Tongji Medical College Union Hospital (2023-0929) and Shanghai Cancer Center Institutional Review Board (2309282-16). The results of the study will be published in an international peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT05523778.

Induction of islet autoimmunity to defective ribosomal product of the insulin gene as neoantigen after anti-cancer immunotherapy leading to autoimmune diabetes.

Introduction: The autoimmune response in type 1 diabetes (T1D), in which the beta cells expressing aberrant or modified proteins are killed, resembles an effective antitumor response. Defective ribosomal protein products in tumors are targets of the anti-tumor immune response that is unleashed by immune checkpoint inhibitor (ICI) treatment in cancer patients. We recently described a defective ribosomal product of the insulin gene (INS-DRiP) that is expressed in stressed beta cells and targeted by diabetogenic T cells. T1D patient-derived INS-DRiP specific T cells can kill beta cells and are present in the insulitic lesion. T cells reactive to INS-DRiP epitopes are part of the normal T cell repertoire and are believed to be kept in check by immune regulation without causing autoimmunity. Method: T cell autoreactivity was tested using a combinatorial HLA multimer technology measuring a range of epitopes of islet autoantigens and neoantigen INS-DRiP. INS-DRiP expression in human pancreas and insulinoma sections was tested by immunohistochemistry. Results: Here we report the induction of islet autoimmunity to INS-DRiP and diabetes after ICI treatment and successful tumor remission. Following ICI treatment, T cells of the cancer patient were primed against INS-DRiP among other diabetogenic antigens, while there was no sign of autoimmunity to this neoantigen before ICI treatment. Next, we demonstrated the expression of INS-DRiP as neoantigen in both pancreatic islets and insulinoma by staining with a monoclonal antibody to INS-DRiP. Discussion: These results bridge cancer and T1D as two sides of the same coin and point to neoantigen expression in normal islets and insulinoma that may serve as target of both islet autoimmunity and tumor-related autoimmunity.

Genetic disorders and insulinoma/glucagonoma.

Insulinoma and glucagonoma are two rare functioning neoplasms of the neuroendocrine cells of the pancreas, respectively, characterized by an uncontrolled over-secretion of insulin or glucagon, responsible for the development of the hypoglycemic syndrome and the glucagonoma syndrome. They prevalently arise as sporadic tumors; only about 10% of cases develop in the context of rare inherited tumor syndromes, such as multiple endocrine neoplasia type 1 (MEN1), neurofibromatosis type 1 (NF1), and tuberous sclerosis complex (TSC), being the result of an autosomal-dominant germline heterozygous loss-of-function mutation in a tumor-suppressor gene. Here, we reviewed the main epidemiological and clinical aspects of insulinoma and glucagonoma in the context of genetic syndromes.

[Current views on the treatment of insulinoma].

RELEVANCE: Insulinoma is the most common hormonally active neuroendocrine tumor (NET) of the pancreas. In recent years, there has been a trend towards an increase in the incidence of NET especially insulinoma. AIM: Summarizing and analyzing current data on various approaches to the treatment of insulinoma. Our review includes a comprehensive assessment of the advantages and disadvantages of currently available insulinoma treatment methods in comparison with past experience, as well as a review of promising methods that are not currently widely used. MATERIALS AND METHODS: Analysis of literature from such databases as scientific electronic library elibrary.ru, Pubmed, Google Scholar, MedLine, Scopus and Web of Science. RESULTS: The most common treatment for insulinoma is surgery. For patients with high operative risk, alternative methods such as alcohol ablation, radiofrequency ablation, and tumor embolization may be used. Medications include the use of somatostatin analogues, diazoxide. The literature describes the potential benefit of the use of beta-blockers, phenytoin, glucagon, however, in clinical trials, these drugs have not demonstrated a significant effect. For the treatment of malignant and metastatically advanced insulinoma, targeted therapy (primarily Everolimus), chemotherapy, as well as embolization (including chemoembolization, radioembolization), radiofrequency ablation (RFA), microwave ablation and cryoablation, ultrasound ablation (HIFU), laser ablation, brachytherapy, irreversible electroporation are used. CONCLUSION: The study of new drugs is an important task for scientists, among medications the most promising are new generations of somatostatin analogues, targeted drugs and chemotherapy drugs. The rare frequency of insulinoma makes it difficult to conduct randomized controlled trials and prospective studies. That is why physicians and scientists need to maintain close contacts with each other and take into account the experience of treating each patient with such disease, which will help develop effective treatment algorithms in the future.

Balancing efficacy and adverse reactions using everolimus in a patient with metastatic malignant insulinoma: Case report.

INTRODUCTION: Malignant insulinoma is a rare neuroendocrine tumor responsible for excessive insulin secretion and life-threatening hypoglycemia episodes. Computed tomography (CT) of the abdomen can identify a pancreatic tumor corresponding to insulinoma. Loco-regional metastases define the metastatic cases. The first-line therapeutic approach is surgery, while other medical treatments like diazoxide and everolimus play also a role. These treatments have shown efficacy in regulating blood glucose and, to some extent, controlling tumor progression. CASE PRESENTATION: We present the case of a 48-year-old female who was admitted for severe hypoglycemia episodes. She presented neuroglycopenic symptoms without any other clinical features. High levels of C-peptide and insulin during severe hypoglycemia confirmed the presence of endogenous hyperinsulinism. The CT scan of the abdomen confirmed the existence of an insulinoma along with several hepatic metastases. Surgery was proposed as a first-line approach. However, due to the persistent occurrence of severe hypoglycemia episodes, other treatment options were necessary such as diazoxide and everolimus. Diazoxide caused a significant improvement in the patient's blood glucose levels. Nonetheless, glycemic control was unsustainable, obligating the switch to everolimus, which showed better control of blood glucose levels with challenging management due to the appearance of grade 3 stomatitis as a side effect. The patient died 1 year after the diagnosis due to tumor progression. CONCLUSION: Balancing the benefits of enhanced glycemic control with the difficulties posed by side effect management of everolimus underscores the need to carefully consider both efficacy and potential adverse events.

Short fasting test as a reliable and effective tool to diagnose insulinoma.

PURPOSE: The diagnosis of insulinoma can be challenging, requiring documentation of hypoglycaemia associated with non-suppressed insulin and C-peptide, often achieved during a prolonged 72 h fast performed in inpatient setting. Our goal is to predict weather a shorter outpatient fasting test initiated overnight and prolonged up until 24 h could be a sensitive method for diagnosing insulinoma. METHODS: We conducted a retrospective monocentric study on subjects admitted to our Unit of Endocrinology from 2019 to 2022 for clinical suspicion of insulinoma and underwent the short fasting test. A comparison between the short test group and the group of subjects who underwent the standard prolonged fasting test (from 2003 to 2018) has also been performed. The short fasting test was initiated by the patient overnight at home and proceeded the following day in outpatient setting (Day Hospital). As in the standard protocol, symptoms and capillary blood glucose (CBG) were strictly monitored. Venous blood was drawn for glycaemia, insulin and C-peptide at admission and at established intervals, in case of symptoms of hypoglycaemia or if CBG ≤ 45 mg/dl, when the fast would be suspended. RESULTS: The final sample consisted of 37 patients, with mean age of 44.5 ± 12.6 years (17-74). Short and standard tests were performed in 15 and 22 subjects, respectively. Diagnostic values for insulinoma were observed in 12 patients: in 5/15 who underwent the short fasting test, in 6/22 who underwent the prolonged test and in 1 patient who was initially negative on the short test and subsequently showed diagnostic values during the prolonged test. The diagnosis of insulinoma was achieved in 11/12 cases within 24 h of the beginning of the fast (91.7%). CONCLUSIONS: A short fasting test could be a valid, sensitive and reliable first-line workup in diagnosing insulinoma.

Purification of time-resolved insulin granules reveals proteomic and lipidomic changes during granule aging.

Endocrine cells employ regulated exocytosis of secretory granules to secrete hormones and neurotransmitters. Secretory granule exocytosis depends on spatiotemporal variables such as proximity to the plasma membrane and age, with newly generated granules being preferentially released. Despite recent advances, we lack a comprehensive view of the molecular composition of insulin granules and associated changes over their lifetime. Here, we report a strategy for the purification of insulin secretory granules of distinct age from insulinoma INS-1 cells. Tagging the granule-resident protein phogrin with a cleavable CLIP tag, we obtain intact fractions of age-distinct granules for proteomic and lipidomic analyses. We find that the lipid composition changes over time, along with the physical properties of the membrane, and that kinesin-1 heavy chain (KIF5b) as well as Ras-related protein 3a (RAB3a) associate preferentially with younger granules. Further, we identify the Rho GTPase-activating protein (ARHGAP1) as a cytosolic factor associated with insulin granules.

Endoscopic ultrasound-guided radiofrequency ablation of pancreatic insulinoma: a state of the art review.

INTRODUCTION: Insulinomas are the most common functional pancreatic neuroendocrine tumors (PNETs) that lead to incapacitating hypoglycemia. Guidelines recommend surgical resection as the mainstay of management. However, surgery is fraught with complications, causing significant peri/post-operative morbidity. Since insulinomas are usually benign, solitary, small (<2 cm), and do not need lymphadenectomy, hence, in this regard, endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is now being increasingly performed, to circumvent these adverse events and impairment of pancreatic function. AREAS COVERED: A comprehensive literature search was undertaken across various databases (PubMed/MEDLINE, Embase, Scopus), with no language restriction, for relevant articles (case series, reviews, case reports) pertaining to EUS-RFA for insulinoma and PNETs, till October 2023. In this review, we have explicated the role of EUS-RFA for insulinoma management, detailing thoroughly its mechanism of action, EUS-RFA devices with data on its safety and efficacy, and an algorithmic approach for its management. EXPERT OPINION: EUS-RFA is being advocated as a 'mini-invasive' option with the potential to replace surgery as a first-line approach for benign, sporadic, solitary, and small (<2 cm) insulinomas. Under real-time guidance, EUS-RFA has immense precision, is safe, predictable, with acceptable safety profile. Presently, it is being frequently performed for high-risk or inoperable candidates. Current need-of-the-hour is a randomized controlled trial to substantiate its role in the therapeutic algorithm for insulinoma management.

ETV5 Silencing Produces Mesenchymal to Epithelial Transition in INS-1 (832/13) Cell Line.

ETV5 has been described to be involved in the epithelial to mesenchymal transition (EMT) mainly in cancer. It is known that EMT provokes cytoskeleton remodeling, improving cellular migratory, and invasive capabilities. Moreover, overexpression of ETV5 has been correlated to cancer development and this gene has been implicated in cell proliferation. However, little is known about the downregulation of ETV5 expression in a pancreatic cell line and the inverse mesenchymal to epithelial transition (MET). Therefore, we studied the implications of ETV5 silencing over the phenotype of the insulinoma INS-1 (832/13) cell line and described the MET by partial ETV5 silencing in the INS-1 (832/13) cell line. The downregulation of ETV5 expression was obtained by using ETV5 siRNA in the insulinoma rat cell line, INS-1 (832/13). Then, ETV5 knockdown provoked a MET phenotype observed by crystal violet staining and verified by immunohistochemistry against E-cadherin. Wound healing assay showed no migration, and F-actin stain revealed rearrangement of actin microfilaments. In addition, TGFß1 and TGFß3 were downregulated in the absence of ETV5. ETV5 silencing induces epithelial phenotype by downregulating TGFß1 and TGFß3 in INS-1 (832/13) cell line.

A rare case report of reversible glucose counterregulation in an insulinoma patient with type 2 diabetes.

CONTEXT: Insulinoma is a neuroendocrine tumor derived from pancreatic ß -cells whose clinical manifestation is recurrent hypoglycemia. Insulinoma in a patient with preexisting diabetes is extraordinarily rare, and the unmasking of type 2 diabetes (T2DM) after insulinoma surgery is even rarer. CASE REPORT: This article reports a 49-year-old male patient with insulinoma that masked the diagnosis of T2DM. The patient was admitted to the hospital with symptoms of hypoglycemia, such as repeated sweating, palpitations, and asthenia for over 4 years. The patient was diagnosed with insulinoma after completing relevant examinations. The emergence of hyperglycemia after the removal of insulinoma is attributable to the coexistence of T2DM. Surprisingly, a reversible decrease in cortisol levels was observed during the diagnostic process. We searched the previously published reports of this type of case from PubMed to determine why type 2 diabetes was covered by insulinoma and why glucocorticoids decreased. CONCLUSIONS: The diagnosis of T2DM in the patient after surgery may be related to increased food intake and insulin resistance induced by hyperinsulinemia caused by long-term hypoglycemia. The reversible decrease in cortisol levels, not adrenocortical insufficiency during the diagnostic process, may be caused by a transient abnormality in glucose counterregulation.

Genotype-histotype-phenotype correlations in hyperinsulinemic hypoglycemia.

Hyperinsulinemic hypoglycemia (HH) of pancreatic origin includes congenital hyperinsulinism (CHI), insulinoma, insulinomatosis, and adult-onset non-insulinoma persistent hyperinsulinemic hypoglycemia syndrome (NI-PHHS). In this review, we describe the genotype-histotype-phenotype correlations in HH and their therapeutic implications. CHI can occur from birth or later on in life. Histologically, diffuse CHI shows diffuse beta cell hypertrophy with a few giant nuclei per islet of Langerhans, most frequently caused by loss-of-function mutations in ABCC8 or KCNJ11. Focal CHI is histologically characterized by focal adenomatous hyperplasia consisting of confluent hyperplastic islets, caused by a paternal ABCC8/KCNJ11 mutation combined with paternal uniparental disomy of 11p15. CHI in Beckwith-Wiedemann syndrome is caused by mosaic changes in the imprinting region 11p15.4-11p15.5, leading to segmental or diffuse overgrowth of endocrine tissue in the pancreas. Morphological mosaicism of pancreatic islets is characterized by occurence of hyperplastic (type 1) islets in one or a few lobules and small (type 2) islets in the entire pancreas. Other rare genetic causes of CHI show less characteristic or unspecific histology. HH with a predominant adult onset includes insulinomas, which are pancreatic insulin-producing endocrine neoplasms, in some cases with metastatic potential. Insulinomas occur sporadically or as part of multiple endocrine neoplasia type 1 due to MEN1 mutations. MAFA mutations may histologically lead to insulinomatosis with insulin-producing neuroendocrine microadenomas or neuroendocrine neoplasms. NI-PHHS is mainly seen in adults and shows slight histological changes in some patients, which have been defined as major and minor criteria. The genetic cause is unknown in most cases. The diagnosis of HH, as defined by genetic, histological, and phenotypic features, has important implications for patient management and outcome.

TMEM219 regulates the transcription factor expression and proliferation of beta cells.

Pancreatic beta cells replenishment is considered the next therapeutic option for type 1 diabetes; while stimulating endogenous beta cells proliferation is the "holy grail" for those patients with exhausted beta cell mass. Here we are demonstrating that the pro-apoptotic receptor TMEM219 is expressed in fetal pancreas, in beta cell precursors and in in vitro embryonic-derived endocrine progenitors. TMEM219 signaling negatively regulates beta cells at early stages and induces Caspase 8-mediated cell death. Pharmacological blockade of TMEM219 further rescued beta cell precursor and proliferation markers, and decreased cell death, both in islets and in in vitro-derived endocrine progenitors, allowing for beta cell preservation. While addressing the upstream controlling TMEM219 expression, we determined the TMEM219 miRNet; indeed, one of those miRNAs, miR-129-2, is highly expressed in human islets, particularly in patients at risk or with established type 1 diabetes. miR-129-2 mimic downregulated TMEM219 expression in islets, in in vitro embryonic-derived endocrine progenitors and in highly proliferating insulinoma-derived cells. Moreover, miR-129-2 inhibitor induced a TMEM219 overexpression in insulinoma-derived cells, which restored cell proliferation and functional markers, thus acting as endogenous regulator of TMEM219 expression. The TMEM219 upstream regulator miR129-2 controls the fate of beta cell precursors and may unleash their regenerative potentials to replenish beta cells in type 1 diabetes.