VNN1, a potential biomarker for pancreatic cancer-associated new-onset diabetes, aggravates paraneoplastic islet dysfunction by increasing oxidative stress

e16265 Background: Pancreatic cancer (PaCa) is the third leading cause of cancer death in the United States despite its low incidence rate, owing to a 5-year survival rate of 10%. It is often asymptomatic in early stage, resulting in the majority of diagnoses occurring when cancer has already metastasized to distant organs. Late diagnosis deprives patients of potentially curative treatments such as surgery and impacts survival rates. Diabetes can be an early symptom of PaCa. Indeed, 25% of PaCa patients had a preceding diabetes diagnosis. Among all people with new onset diabetes (NOD), 0.85% will be diagnosed with PaCa within 3 years, which represents 6-8 fold increased risk for PaCa compared to the general population. Surveillance of the NOD population for PaCa presents an opportunity to shift PaCa diagnosis to earlier stage by finding it sooner. Methods: Whole blood was obtained from a cohort of 117 PaCa patients as well as 800 non-cancer controls with and without NOD. Plasma was processed to isolate cfDNA and 5hmC and low pass whole genome libraries were generated and sequenced. The EpiDetect assay combines 5hmC and whole genome sequencing data and were generated using Bluestar Genomics’s technology platform. Results: To investigate whether PaCa can be detected in plasma, we interrogated plasma-derived cfDNA epigenomic and genomic signal from PaCa patients and non-cancer controls. We first trained stacked ensemble models on PaCa and non-cancer samples utilizing 5hmC, fragmentation and CNV-based biomarkers from cfDNA. These models performed stably with a median of 72.8% sensitivity and 90.1% specificity measured across 25 outer fold iterations using the training data set, which was composed of 50% early stage (Stages I & II) disease. The final binomial ensemble model was trained using all of the training data, yielding an area under the receiver operating characteristic curve (auROC) of 0.9, with 75% sensitivity and 89% specificity. This model was then tested on an independent validation data set from 33 PaCa patients (24 with diabetes, 15 of which was NOD) and 202 non-cancer control patients (76 with diabetes, 51 of which was NOD) and yielded a classification performance auROC of 0.9 with 67% sensitivity at 92% specificity. Lastly, model performance in the subset of patient cohort with NOD only had an auROC of 0.87 with 60% sensitivity at 88% specificity. Conclusions: Our results indicate that 5hmC profiles along with CNV and fragmentation patterns from cfDNA can be used to detect PaCa in plasma-derived cfDNA. Overall, model performance was stable and consistent between the training and independent validation datasets. A larger clinical study is under development to investigate the utility of the model described in this pilot study in identifying occult PaCa within the NOD population, with the aim of shifting diagnosis to early stage and potentially improving patient outcomes.

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Impact of Pancreatic Cancer and Subsequent Resection on Glycemic Control in Diabetic and Nondiabetic Patients

The American Surgeon ◽

10.1177/000313481107700823 ◽

2011 ◽

Vol 77 (8) ◽

pp. 1032-1037 ◽

Cited By ~ 7

Author(s):

Michael A. White ◽

Steven C. Agle ◽

Hannah M. Fuhr ◽

James H. Mehaffey ◽

Brett H. Waibel ◽

...

Keyword(s):

Pancreatic Cancer ◽

Glycemic Control ◽

Cancer Diagnosis ◽

Univariate Analysis ◽

Cell Mass ◽

University Teaching ◽

Partial Pancreatectomy ◽

Onset Diabetes ◽

Number Of Factors ◽

New Onset

The incidence of new onset or worsening diabetes is surprisingly low in patients after partial pancreatectomy for cancer, leading us to question what factors predict diminished glycemic control in those undergoing resection. All patients undergoing pancreatectomy for cancer at a large, rural university teaching hospital between 1996 and 2010 were identified. The incidence of new onset, or worsening, existing diabetes was determined based on pre and postoperative medication requirement. Univariate analysis was undertaken to identify factors that predict worsened glycemic control. One hundred and one (1 total, 79 Whipple, 21 distal) patients were identified, 41 per cent of which had preexisting diabetes. Nearly half of existing diabetics manifested an increased medication requirement prior to their cancer diagnosis. New onset diabetes occurred in 20 per cent of postoperative patients. Of established diabetics, 34 per cent had either improved glycemic control (9/41) or were cured (5/41) despite the reduction of islet cell mass that occurred with surgery. On univariate analysis, only prolonged hospitalization was associated with worsened glycemic control. Diminished glycemic control is a frequent presenting symptom of pancreatic cancer. Worsened or new onset diabetes is associated with length of stay, which can be influenced by a number of factors including complications and comorbidities.

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Plasma Malondialdehyde and Risk of New-Onset Diabetes after Transplantation in Renal Transplant Recipients: A Prospective Cohort Study

Journal of Clinical Medicine ◽

10.3390/jcm8040453 ◽

2019 ◽

Vol 8 (4) ◽

pp. 453 ◽

Cited By ~ 2

Author(s):

Manuela Yepes-Calderón ◽

Camilo Sotomayor ◽

António Gomes-Neto ◽

Rijk Gans ◽

Stefan Berger ◽

...

Keyword(s):

Oxidative Stress ◽

Renal Transplant ◽

Cox Proportional Hazards ◽

Renal Transplant Recipients ◽

Transplant Recipients ◽

Dietary Antioxidants ◽

Onset Diabetes ◽

Plasma Malondialdehyde ◽

New Onset

New-onset diabetes after transplantation (NODAT) is a frequent complication in renal transplant recipients (RTR). Although oxidative stress has been associated with diabetes mellitus, data regarding NODAT are limited. We aimed to prospectively investigate the long-term association between the oxidative stress biomarker malondialdehyde (measured by high-performance liquid chromatography) and NODAT in an extensively phenotyped cohort of non-diabetic RTR with a functioning graft ≥1 year. We included 516 RTR (51 ± 13 years-old, 57% male). Median plasma malondialdehyde (MDA) was 2.55 (IQR, 1.92–3.66) µmol/L. During a median follow-up of 5.3 (IQR, 4.6–6.0) years, 56 (11%) RTR developed NODAT. In Cox proportional-hazards regression analyses, MDA was inversely associated with NODAT, independent of immunosuppressive therapy, transplant-specific covariates, lifestyle, inflammation, and metabolism parameters (HR, 0.55; 95% CI, 0.36–0.83 per 1-SD increase; p < 0.01). Dietary antioxidants intake (e.g., vitamin E, α-lipoic acid, and linoleic acid) were effect-modifiers of the association between MDA and NODAT, with particularly strong inverse associations within the subgroup of RTR with relatively higher dietary antioxidants intake. In conclusion, plasma MDA concentration is inversely and independently associated with long-term risk of NODAT in RTR. Our findings support a potential underrecognized role of oxidative stress in post-transplantation glucose homeostasis.

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Early diagnosis of pancreatic cancer with metabolite biomarkers in new-onset diabetes mellitus-New Onset of Diabetes in the Elderly Study (NODES)

Pancreatology ◽

10.1016/j.pan.2019.05.295 ◽

2019 ◽

Vol 19 ◽

pp. S111

Author(s):

Dóra Illés ◽

Emese Ivány ◽

Gábor Holzinger ◽

Klára Kosár ◽

Gábor Zsóri ◽

...

Keyword(s):

Diabetes Mellitus ◽

Pancreatic Cancer ◽

Early Diagnosis ◽

The Elderly ◽

Onset Diabetes ◽

Onset Of Diabetes ◽

New Onset Diabetes Mellitus ◽

New Onset

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Paraneoplastic β Cell Dedifferentiation in Nondiabetic Patients with Pancreatic Cancer

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/clinem/dgz224 ◽

2019 ◽

Vol 105 (4) ◽

pp. e1489-e1503 ◽

Cited By ~ 3

Author(s):

Yichen Wang ◽

Qicheng Ni ◽

Jiajun Sun ◽

Min Xu ◽

Jing Xie ◽

...

Keyword(s):

Pancreatic Cancer ◽

Endocrine Cells ◽

Fasting Blood Glucose ◽

Ductal Adenocarcinoma ◽

Benign Tumors ◽

Β Cell ◽

Cell Dedifferentiation ◽

Glucose Transporter 2 ◽

Onset Diabetes ◽

New Onset

Abstract Context Beta-cell dedifferentiation was recently proposed as a mechanism of β-cell dysfunction, but whether it can be a trigger of β-cell failure preceding hyperglycemia in humans is uncertain. Pancreatic cancer can cause new-onset diabetes, yet the underlying mechanism is unknown. Objective To investigate whether β-cell dedifferentiation is present in nondiabetic pancreatic ductal adenocarcinoma (PDAC) patients, we examined pancreatic islets from 15 nondiabetic patients with benign tumors (control) and 15 nondiabetic PDAC patients. Design We calculated the number of hormone-negative endocrine cells and evaluated important markers of β-cell dedifferentiation and function in the paraneoplastic islets. We assessed tumor-related inflammatory changes under the pancreatic cancer microenvironment and their influence on β-cell identity. Results We found nearly 10% of nonhormone expressing endocrine cells in nondiabetic PDAC subjects. The PDAC islets were dysfunctional, evidenced by low expression of Glucose transporter 2 (GLUT2) and Urocortin3 (UCN3), and concomitant upregulation of Aldehyde Dehydrogenase 1 Family Member A3 (ALDH1A3) expression and proinsulin accumulation. Pancreatic cancer caused paraneoplastic inflammation with enhanced tissue fibrosis, monocytes/macrophages infiltration, and elevated inflammatory cytokines. Moreover, we detected β-cell dedifferentiation and defects in GSIS in islets exposed to PANC-1 (a cell line established from a pancreatic carcinoma of ductal origin from a 56-year-old Caucasian male)-conditioned medium. In a larger cohort, we showed high prevalence of new-onset diabetes in PDAC subjects, and fasting blood glucose (FBG) was found to be an additional useful parameter for early diagnosis of PDAC. Conclusions Our data provide a rationale for β-cell dedifferentiation in the pathogenesis of pancreatic cancer–associated diabetes. We propose that β-cell dedifferentiation can be a trigger for β-cell failure in humans, before hyperglycemia occurs.

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