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.
Insulinoma ; Glucose Tolerance Test

Insulinoma-associated protein-2 (IA-2) is a transmembrane glycoprotein belonging to the tyrosine phosphatase-like protein family as well as an important autoantigen in the diagnosis of type 1 diabetes. IA-2 products have been marketed in Europe and the United States. At present, commercially available IA-2 antigens are either the recombinant IA-2ic domain or the IA-2 naturally extracted from bovine islets. However, the recombinant IA-2 antigen displays weak positive in clinic practice, which often results in occasional detection failures, thus cannot completely replace the naturally extracted IA-2 antigen. In this study, an HEK293 expression system was used to explore the production of recombinant IA-2. An IA-2 transmembrane fragment (IA-2 TMF) located at amino acid position 449-979, also known as the natural membrane protein form of IA-2, was produced in HEK293 through transfection, and both the expression conditions and dissolution conditions of the membrane protein were also optimized. The purified membrane protein yield was 0.78 mg/L cell culture. Subsequently, the antigen activity of IA-2 TMF was compared with RSR rhIA-2 through enzyme linked immunosorbent assay. The serum of 77 type 1 diabetes patients and 32 healthy volunteers were detected. Receiver operating characteristic curve (ROC) curve was used to characterize the sensitivity and specificity of the test results. The results showed that the sensitivity of IA-2 TMF was 71.4% (55/77), while the sensitivity of RSR rhIA-2 was 63.6% (49/77), and the specificity of both antigens were all 100%. There was no significant difference in specificity between the two antigens, but the sensitivity of IA-2 TMF was appreciably better than that of the imported gold standard RSR rhIA-2 antigen. In conclusion, the recombinant IA-2 TMF produced in HEK293 cells can be used as a raw material to develop in vitro diagnostic reagents for type 1 diabetes.
Humans ; Animals ; Cattle ; HEK293 Cells ; Insulinoma ; Diabetes Mellitus, Type 1/genetics* ; Recombinant Proteins ; Membrane Proteins ; Pancreatic Neoplasms

Objective To determine the appropriate averaging strategy for pancreatic perfusion datasets to create images for routine reading of insulinoma.Methods Thirty-nine patients undergoing pancreatic perfusion CT in Peking Union Medical College Hospital and diagnosed as insulinoma by pathology were enrolled in this retrospective study.The time-density curve of abdominal aorta calculated by software dynamic angio was used to decide the timings for averaging.Five strategies,by averaging 3,5,7,9 and 11 dynamic scans in perfusion,all including peak enhancement of the abdominal aorta,were investigated in the study.The image noise,pancreas signal-to-noise ratio(SNR),lesion contrast and lesion contrast-to-noise ratio(CNR)were recorded and compared.Besides,overall image quality and insulinoma depiction were also compared.ANOVA and Friedman's test were performed.Results The image noise decreased and the SNR of pancreas increased with the increase in averaging time points(all P<0.001).The lesion contrast(69.81±41.35)averaged from 5 scans showed no significant difference compared with that(72.77±45.25)averaged from 3 scans(P=0.103),both of which were higher than that in other groups(all P≤0.001).The lesion CNRs of the last four groups showed no significant difference(all P>0.99)and were higher than that of the first group(all P<0.05).There was no significant difference in overall image quality among the 5 groups(P=0.977).Conclusions Image averaged from 5 scans showed moderate image noise,pancreas SNR and relatively high lesion contrast and lesion CNR.Therefore,it is advised to be used in image averaging to detect insulinoma.
Contrast Media ; Humans ; Insulinoma/diagnostic imaging* ; Pancreas/diagnostic imaging* ; Pancreatic Neoplasms/diagnostic imaging* ; Perfusion ; Radiographic Image Interpretation, Computer-Assisted ; Reading ; Retrospective Studies ; Signal-To-Noise Ratio

To prospectively evaluate the correlation between intravoxel incoherent motion (IVIM)-derived parameters and CT perfusion parameters as well as the pathological grade in insulinoma. A total of 55 patients with suspected insulinoma undergoing IVIM and CT perfusion scans were prospectively enrolled. The images were post-processed to obtain IVIM parameters including apparent diffusion coefficient (ADC),diffusion (D),perfusion correlated diffusion (D*),and f,and CT perfusion parameters including blood flow (BF),blood volume (BV),and permeability (PM). The pathological specimens were stained to obtain pathological parameters including the grading,ki-67 index,and the mitotic count. The IVIM derived parameters of normal pancreas including head,body,and tail as well as that of the pancreatic insulinoma were compared. The correlation between IVIM parameters and CT perfusion parameters as well as the pathological parameters was analyzed. ADC and D values of pancreatic tail were significantly lower than those of the pancreatic head and neck (all <0.001). There were significant differences in all IVIM parameters between insulinoma and normal pancreas (all <0.001). The ADC and f value of the normal pancreas was positively correlated with BF (=0.437,=0.003;=0.357,=0.010). There is no correlation between the remaining IVIM parameters and the CT perfusion parameters as well as between IVIM parameters and pathological parameters (all >0.05). IVIM parameters differ at different anatomical parts of normal pancreas. IVIM parameters can distinguish normal pancreatic parenchyma from insulinoma. The ADC value is weakly correlated with BF.
Diffusion Magnetic Resonance Imaging ; Humans ; Insulinoma ; diagnostic imaging ; Motion ; Pancreatic Neoplasms ; diagnostic imaging ; Reproducibility of Results ; Tomography, X-Ray Computed

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder. A 44-year-old man visited second Xiangya Hospital, Central South University due to hypoglycemia. He was eventually diagnosed as MEN1. A novel homozygous frameshift for c.640-643delCAGA (p.V215Mfs*13) of MEN1 gene was identified in the patient. After MDT (Multiple Disciplinary Team), open bilateral exploration with total parathyroidectomy and autotransplantation as well as partial pancreatectomy excision of all the macroscopic pancreatic tumors were performed at the same time. The patient recovered well. Individualized diagnosis and treatment are important for MEN1 patients.
Adult ; Humans ; Insulinoma ; Male ; Multiple Endocrine Neoplasia Type 1 ; Pancreatic Neoplasms ; Parathyroid Neoplasms ; Parathyroidectomy

No abstract available.
Insulinoma ; Liver

BACKGROUND: The nuclear receptor peroxisome proliferator-activator gamma (PPARγ) is a useful therapeutic target for obesity and diabetes, but its role in protecting β-cell function and viability is unclear. METHODS: To identify the potential functions of PPARγ in β-cells, we treated mouse insulinoma 6 (MIN6) cells with the PPARγ agonist pioglitazone in conditions of lipotoxicity, endoplasmic reticulum (ER) stress, and inflammation. RESULTS: Palmitate-treated cells incubated with pioglitazone exhibited significant improvements in glucose-stimulated insulin secretion and the repression of apoptosis, as shown by decreased caspase-3 cleavage and poly (adenosine diphosphate [ADP]-ribose) polymerase activity. Pioglitazone also reversed the palmitate-induced expression of inflammatory cytokines (tumor necrosis factor α, interleukin 6 [IL-6], and IL-1β) and ER stress markers (phosphor-eukaryotic translation initiation factor 2α, glucose-regulated protein 78 [GRP78], cleaved-activating transcription factor 6 [ATF6], and C/EBP homologous protein [CHOP]), and pioglitazone significantly attenuated inflammation and ER stress in lipopolysaccharide- or tunicamycin-treated MIN6 cells. The protective effect of pioglitazone was also tested in pancreatic islets from high-fat-fed KK-Ay mice administered 0.02% (wt/wt) pioglitazone or vehicle for 6 weeks. Pioglitazone remarkably reduced the expression of ATF6α, GRP78, and monocyte chemoattractant protein-1, prevented α-cell infiltration into the pancreatic islets, and upregulated glucose transporter 2 (Glut2) expression in β-cells. Moreover, the preservation of β-cells by pioglitazone was accompanied by a significant reduction of blood glucose levels. CONCLUSION: Altogether, these results support the proposal that PPARγ agonists not only suppress insulin resistance, but also prevent β-cell impairment via protection against ER stress and inflammation. The activation of PPARγ might be a new therapeutic approach for improving β-cell survival and insulin secretion in patients with diabetes mellitus
Animals ; Apoptosis ; Blood Glucose ; Caspase 3 ; Chemokine CCL2 ; Cytokines ; Diabetes Mellitus ; Endoplasmic Reticulum Stress* ; Endoplasmic Reticulum* ; Glucose Transport Proteins, Facilitative ; Humans ; Inflammation* ; Insulin ; Insulin Resistance ; Insulin-Secreting Cells ; Insulinoma ; Interleukin-6 ; Islets of Langerhans ; Mice ; Necrosis ; Obesity ; Peptide Initiation Factors ; Peroxisomes ; Repression, Psychology ; Transcription Factors

BACKGROUND: Emerging evidence suggests that sphingolipids may be involved in type 2 diabetes. However, the exact signaling defect through which disordered sphingolipid metabolism induces β-cell dysfunction remains unknown. The current study demonstrated that sphingosine-1-phosphate (S1P), the product of sphingosine kinase (SphK), is an essential factor for maintaining β-cell function and survival via regulation of mitochondrial action, as mediated by prohibitin (PHB). METHODS: We examined β-cell function and viability, as measured by mitochondrial function, in mouse insulinoma 6 (MIN6) cells in response to manipulation of cellular S1P and PHB levels. RESULTS: Lack of S1P induced by sphingosine kinase inhibitor (SphKi) treatment caused β-cell dysfunction and apoptosis, with repression of mitochondrial function shown by decreases in cellular adenosine triphosphate content, the oxygen consumption rate, the expression of oxidative phosphorylation complexes, the mitochondrial membrane potential, and the expression of key regulators of mitochondrial dynamics (mitochondrial dynamin-like GTPase [OPA1] and mitofusin 1 [MFN1]). Supplementation of S1P led to the recovery of mitochondrial function and greatly improved β-cell function and viability. Knockdown of SphK2 using small interfering RNA induced mitochondrial dysfunction, decreased glucose-stimulated insulin secretion (GSIS), and reduced the expression of PHB, an essential regulator of mitochondrial metabolism. PHB deficiency significantly reduced GSIS and induced mitochondrial dysfunction, and co-treatment with S1P did not reverse these trends. CONCLUSION: Altogether, these data suggest that S1P is an essential factor in the maintenance of β-cell function and survival through its regulation of mitochondrial action and PHB expression.
Adenosine Triphosphate ; Animals ; Apoptosis ; GTP Phosphohydrolases ; Insulin ; Insulin-Secreting Cells ; Insulinoma ; Membrane Potential, Mitochondrial ; Metabolism ; Mice ; Mitochondria ; Mitochondrial Dynamics ; Oxidative Phosphorylation ; Oxygen Consumption ; Phosphotransferases ; Repression, Psychology ; RNA, Small Interfering ; Sphingolipids ; Sphingosine

Insulin autoimmune syndrome (IAS) is characterized by spontaneous hypoglycemia, extremely high serum insulin levels, and high titers of autoantibodies against endogenous insulin, in the absence of exogenous insulin injection. IAS often occurs following exposure to sulfhydryl-containing drugs, including alpha-lipoic acid (ALA). A 30-year-old woman without diabetes visited our outpatient clinic with recurrent hypoglycemia. She had been taken ALA for weight reduction since 3 weeks ago. Further hypoglycemia work up revealed very high insulin levels, C-Peptide levels and positive insulin antibodies. And conventional imaging examinations were negative for insulinoma or other pancreatic tumors. Finally, the diagnosis of Insulin autoimmune syndrome (IAS) was made. Following the cessation of ALA, hypoglycemia improved, with no medication, and the patient experienced no further hypoglycemic attacks over the next month. The use of ALA as a nutritional supplement is increasing. We report a case of IAS associated with ALA in a non-diabetic patient.
Adult ; Ambulatory Care Facilities ; Autoantibodies ; C-Peptide ; Diagnosis ; Female ; Humans ; Hypoglycemia ; Insulin Antibodies ; Insulin* ; Insulinoma ; Thioctic Acid* ; Weight Loss

BACKGROUND: The increase in circulating free fatty acid (FFA) levels is a major factor that induces malfunction in pancreatic β-cells. We evaluated the effect of FFAs reconstituted according to the profile of circulating fatty acids found in obese adolescents on the viability and function of the murine insulinoma cell line (mouse insulinoma [MIN6]). METHODS: From fatty acids obtained commercially, plasma-FFA profiles of three different youth populations were reconstituted: obese with metabolic syndrome; obese without metabolic syndrome; and normal weight without metabolic syndrome. MIN6 cells were treated for 24 or 48 hours with the three FFA profiles, and glucose-stimulated insulin secretion, cell viability, mitochondrial function and antioxidant activity were evaluated. RESULTS: The high FFA content and high polyunsaturated ω6/ω3 ratio, present in plasma of obese adolescents with metabolic syndrome had a toxic effect on MIN6 cell viability and function, increasing oxidative stress and decreasing glucose-dependent insulin secretion. CONCLUSION: These results could help to guide nutritional management of obese young individuals, encouraging the increase of ω-3-rich food consumption in order to reduce the likelihood of deterioration of β-cells and the possible development of type 2 diabetes mellitus.
Adolescent* ; Cell Line ; Cell Survival ; Diabetes Mellitus, Type 2 ; Fatty Acids* ; Fatty Acids, Nonesterified ; Humans ; In Vitro Techniques* ; Insulin ; Insulin-Secreting Cells ; Insulinoma ; Obesity ; Oxidative Stress ; Plasma*