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McDonnell D, Afolabi PR, Niazi U, Wilding S, Griffiths GO, Swann JR, Byrne CD, Hamady ZZ. Metabolite Changes Associated with Resectable Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2025; 17:1150. [PMID: 40227642 PMCID: PMC11988049 DOI: 10.3390/cancers17071150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2025] [Revised: 03/24/2025] [Accepted: 03/28/2025] [Indexed: 04/15/2025] Open
Abstract
INTRODUCTION Pancreatic ductal adenocarcinoma (PDAC) is insidious, with only 15-20% of those diagnosed suitable for surgical resection as it is either too advanced and has invaded local structures or has already spread to distant sites. The associated tumor microenvironment provides a protective shield which limits the efficacy of chemotherapeutic agents, but also impairs the delivery of nutrients required for the PDAC cells. To compensate for this, metabolic adaptions occur to provide alternative sources of fuel. The aim of this study is to explore metabolomic differences between participants with resectable PDAC compared to healthy volunteers (HV). The objectives were to use nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) to determine if resectable PDAC induces sufficient metabolic adaptations and variations which could be used to discriminate between the two groups. METHODS Plasma samples were collected from fasted individuals with resectable PDAC (n = 23, median age 68 [IQR 56-75], 69.6% male) and HV (n = 24, median age 63 [IQR 58-71], 54.2% male). Samples were analyzed using NMR and the Biocrates MxP Quant 500 kit at University Hospital Southampton. RESULTS NMR spectroscopy identified six independent metabolites that significantly discriminated between the PDAC and HV groups, including elevated plasma concentrations of 3-hydroxybutyrate and citrate, with decreased amounts of glutamine and histidine. MS analysis identified 84 metabolites with a significant difference between the PDAC and HV cohorts. The metabolites with a fold change (FC) > 1.5 in the PDAC population were conjugated bile acids (taurocholic acid, glycocholic acid, and glycochenodexoycholic acid). DISCUSSION In conclusion, using metabolomics, biochemical differences between resectable PDAC and HV were detected. These differences indicate metabolic plasticity and utilization of alternative fuel sources.
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Affiliation(s)
- Declan McDonnell
- Human Development & Health, University of Southampton, Southampton SO16 6YD, UK; (P.R.A.); (U.N.); (Z.Z.H.)
- Department of General Surgery, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK
| | - Paul R. Afolabi
- Human Development & Health, University of Southampton, Southampton SO16 6YD, UK; (P.R.A.); (U.N.); (Z.Z.H.)
| | - Umar Niazi
- Human Development & Health, University of Southampton, Southampton SO16 6YD, UK; (P.R.A.); (U.N.); (Z.Z.H.)
| | - Sam Wilding
- Cancer Research UK Southampton Clinical Trials Unit, University of Southampton, Southampton SO16 6YD, UK
| | - Gareth O. Griffiths
- Department of General Surgery, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK
- Cancer Research UK Southampton Clinical Trials Unit, University of Southampton, Southampton SO16 6YD, UK
| | - Jonathan R. Swann
- Human Development & Health, University of Southampton, Southampton SO16 6YD, UK; (P.R.A.); (U.N.); (Z.Z.H.)
| | - Christopher D. Byrne
- Human Development & Health, University of Southampton, Southampton SO16 6YD, UK; (P.R.A.); (U.N.); (Z.Z.H.)
- Department of General Surgery, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK
| | - Zaed Z. Hamady
- Human Development & Health, University of Southampton, Southampton SO16 6YD, UK; (P.R.A.); (U.N.); (Z.Z.H.)
- Department of General Surgery, University Hospital Southampton NHS Foundation Trust, Southampton SO16 6YD, UK
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Chen HJ, Hu Y, Ma JH. Relationship between imaging changes of the pancreas and islet beta-cell function. World J Radiol 2024; 16:717-721. [PMID: 39801662 PMCID: PMC11718522 DOI: 10.4329/wjr.v16.i12.717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 11/21/2024] [Accepted: 12/20/2024] [Indexed: 12/27/2024] Open
Abstract
Imaging changes in the pancreas can provide valuable information about the status of islet beta-cell function in different pancreatic diseases, such as diabetes, pancreatitis, pancreatic cancer, fatty pancreas, and insulinoma. While imaging cannot directly measure beta-cell function; it can be used as a marker of disease progression and a tool to guide therapeutic interventions. As imaging technologies continue to advance, they will likely play an increasingly important role in diagnosing, monitoring, and managing diabetes.
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Affiliation(s)
- Hong-Jing Chen
- Department of Endocrinology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi 214000, Jiangsu Province, China
| | - Yun Hu
- Department of Endocrinology, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi 214000, Jiangsu Province, China
| | - Jian-Hua Ma
- Department of Endocrinology, Nanjing First Hospital, Nanjing Medical University, Nanjing 210000, Jiangsu Province, China
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Song Y, Jiang L, Han Y, Zhang S, Li S. Triglyceride-glucose index and glycemic dynamics in pancreatic ductal adenocarcinoma: implications for disease progression and prognosis. J Transl Med 2024; 22:708. [PMID: 39080703 PMCID: PMC11290143 DOI: 10.1186/s12967-024-05524-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 07/20/2024] [Indexed: 08/02/2024] Open
Abstract
BACKGROUND To elucidate the relationship between the triglyceride-glycemic index (TyG) and clinical characteristics of pancreatic ductal adenocarcinoma (PDAC). METHODS A total of 1,594 individuals diagnosed with pancreatic and periampullary neoplasms were categorized into four groups: PDAC-early (n = 403), locally advanced PDAC (LAPC, n = 315), PDAC-late with distant metastasis (n = 371), and other tumor types (n = 505). TyG-high was defined as a TyG index greater than 8.81 in males and 8.73 in females. RESULTS The prevalence of TyG-high status was highest in PDAC-early (68.48%), followed by LAPC (53.33%), and lowest in PDAC-late (44.47%). TyG-high status significantly predicted worse PDAC prognosis (P = 0.0166), particularly in PDAC-late (P = 0.0420). Despite similar blood glucose levels across PDAC groups (P = 0.897), PDAC-early patients showed significantly higher rates of glycemic disturbances (56.33% vs. 32.28%) and TyG-high status (68.48% vs. 47.13%) compared to those with other tumors. Progressive increases in glycemic disturbances and TyG-high status were observed from benign to pre-malignant lesions and PDAC-early. PDAC-early patients at the pancreatic head exhibited higher rates of glycemic disturbances (58.12% vs. 33.33%, P < 0.0001), larger pancreatic duct diameters (0.4056 cm vs. 0.3398 cm, P = 0.0043), and poorer prognosis compared to periampullary cancers, although the TyG-high rate and body mass index were similar. CONCLUSION The TyG index exhibits a complex association with PDAC stages, profoundly shaping glycemic profiles. At the initial stages of PDAC, a notable elevation in TyG-high status and glycemic disturbances is observed. However, in advanced PDAC, while the TyG-high rate diminishes, abnormal glucose levels persist.
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Affiliation(s)
- Yunda Song
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou, 510060, China
- Department of Pancreatobiliary Surgery, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Lingmin Jiang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou, 510060, China
- Department of Pancreatobiliary Surgery, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Yuanxia Han
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou, 510060, China
- Department of Pancreatobiliary Surgery, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China
| | - Subo Zhang
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou, 510060, China.
| | - Shengping Li
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou, 510060, China.
- Department of Pancreatobiliary Surgery, Sun Yat-sen University Cancer Center, No. 651 Dongfeng Road East, Guangzhou, 510060, People's Republic of China.
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Mulindwa F, Castelnuovo B, Brusselaers N, Bollinger R, Yendewa G, Amutuhaire W, Mukashaka C, Schwarz JM. Should dolutegravir always be withheld in people with HIV on dolutegravir with incident diabetes mellitus? A case report. RESEARCH SQUARE 2023:rs.3.rs-3218404. [PMID: 37674704 PMCID: PMC10479436 DOI: 10.21203/rs.3.rs-3218404/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/08/2023]
Abstract
Dolutegravir (DTG), an integrase strand transfer inhibitor is currently the recommended first and second line anti-retroviral therapy (ART) anchor agent by the World Health Organization. This followed widespread reports of primary resistance to non-nucleoside reverse transcriptase inhibitors. Despite its very good side effect profile, there have been multiple case reports of ART experienced patients developing hyperglycemia within weeks to a few months after switching to DTG preceded by weight loss. At population level, however, dolutegravir as well as other integrase inhibitors have been demonstrated to have a reduced risk of incident diabetes mellitus (T2DM) compared to other HIV drug classes. Following multiple similar reports of accelerated hyperglycemia in Uganda during the first pilot year of DTG use, the Uganda Ministry of Health recommended withholding dolutegravir in all patients who develop diabetes. Whether this recommendation should be applied to all patients with incident T2DM remains to be demonstrated. We present a clinical case of an HIV positive ART naïve man who was diagnosed with T2DM after 36 weeks on dolutegravir. We describe changes in blood glucose, glycated hemoglobin, insulin resistance and pancreatic beta cell function before and after withholding DTG. We demonstrated that he was phenotypically different from the reported cases of accelerated hyperglycemia and he continued to have worsening insulin resistance despite withholding DTG. His blood glucose improved with dietary T2DM management. It is possible he had an inherent risk of developing T2DM independent of his exposure to DTG. This put in question whether DTG should universally be withheld in PLHIV with incident T2DM in Uganda.
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Chen G, Tan C, Liu X, Wang X, Tan Q, Chen Y. Associations between Systemic Immune-Inflammation Index and Diabetes Mellitus Secondary to Pancreatic Ductal Adenocarcinoma. J Clin Med 2023; 12:756. [PMID: 36769405 PMCID: PMC9917636 DOI: 10.3390/jcm12030756] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Revised: 01/08/2023] [Accepted: 01/09/2023] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND There is a high prevalence of diabetes mellitus (DM) in patients with pancreatic ductal adenocarcinoma (PDAC). An inflammatory response is considered as a potential mechanism involved in the process. The systemic immune-inflammation (SII) index is an integrated and novel inflammatory indicator developed in recent years. The purpose of this study was to determine the relationship between the SII and DM secondary to PDAC. METHOD Patients with a confirmed diagnosis of PDAC were analyzed in this cross-sectional study. Anthropometric measures, glucose-related data (including fasting glucose, 2 h OGTT, glycated hemoglobin, fasting insulin, and fasting c-peptide), tumor characteristics (tumor volumes, location and stages), and the periphery blood inflammatory index (white blood cell count, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and SII) were recorded. The inflammation index was analyzed for its association with glucose-related parameters. Multivariable logistic regression analysis was used to analyze the association between SII levels and DM secondary to PDAC. RESULTS Blood cell results showed that the white blood cell count, neutrophils, lymphocytes, monocytes, platelets, the neutrophil-to-lymphocyte ratio, and platelet-to-lymphocyte ratio were higher in patients with diabetes. It was worth noting that SII significantly increased in patients with diabetes secondary to PDAC (4.41 vs. 3.19, p < 0.0001). Multivariable logistic regression analysis showed that SII (OR: 2.024, 95%CI: 1.297, 3.157, p = 0.002) and age (OR: 1.043, 95%CI: 1.01, 1.077, p = 0.011) were the risk factors for DM secondary to PDAC after adjusting for covariates. According to Spearmen correlation analysis, SII was positively correlated with fasting glucose (r = 0.345, p < 0.0001), 2 h OGTT (r = 0.383, p < 0.0001), HbA1c (r = 0.211, p = 0.005), fasting insulin (r = 0.435, p < 0.0001), fasting C-peptide (r = 0.420, p < 0.0001), and HOMA2-IR (r = 0.491, p < 0.0001). CONCLUSIONS In conclusion, SII is significantly increased among patients with DM secondary to PDAC and is associated with the DM in patients with PDAC (OR: 2.382, 95% CI: 1.157, 4.903, p = 0.019). Additionally, SII is significantly correlated with insulin resistance. We are the first to investigate the relationship between SII and diabetes secondary to PDAC and further confirm the role of an inflammatory response in this process. More studies need to be designed to clarify how inflammatory responses participate.
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Affiliation(s)
| | | | | | | | | | - Yonghua Chen
- Department of Pancreatic Surgery, West China Hospital of Sichuan University, Chengdu 610041, China
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Tsuchiya T, Saisho Y, Inaishi J, Sasaki H, Sato M, Nishikawa M, Masugi Y, Yamada T, Itoh H. Increased alpha cell to beta cell ratio in patients with pancreatic cancer. Endocr J 2022; 69:1407-1414. [PMID: 35934795 DOI: 10.1507/endocrj.ej22-0170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
The development of pancreatic cancer (PC) is associated with worsening of glucose tolerance. However, there is limited information about the effects of PC on islet morphology. The aim of this study was to elucidate changes in alpha and beta cell mass in patients with PC. We enrolled 30 autopsy cases with death due to PC (9 with diabetes; DM) and 31 age- and BMI-matched autopsy cases without PC (controls, 12 with DM). Tumor-free pancreatic sections were stained for insulin and glucagon, and fractional beta cell (BCA) and alpha cell area (ACA) were quantified. In addition, expression of de-differentiation markers, i.e., ALDH1A3 and UCN3, was qualitatively evaluated. The pancreas of subjects with PC showed atrophic and fibrotic changes. There was no significant difference in BCA in subjects with PC compared to controls (1.53 ± 1.26% vs. 0.95 ± 0.42%, p = 0.07). However, ACA and ACA to BCA ratio were significantly higher in subjects with PC compared to controls (2.48 ± 2.39% vs. 0.53 ± 0.26% and 1.94 ± 1.93 vs. 0.59 ± 0.26, respectively, both p < 0.001). Increased ACA to BCA ratio was observed in subjects with PC irrespective of the presence of DM. Qualitative evaluation of ALDH1A3 and UCN3 expression showed no significant difference between the groups. In conclusion, in subjects with PC, alpha to beta cell mass ratio is increased, which may contribute to the increased risk of worsening glucose metabolism. Further studies are warranted to elucidate the mechanisms of increased alpha to beta cell mass in patients with PC.
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Affiliation(s)
- Tami Tsuchiya
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yoshifumi Saisho
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
- Saisho Diabetes Clinic, Tokyo 164-0001, Japan
| | - Jun Inaishi
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
- Center for Preventive Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Hironobu Sasaki
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
- Center for Preventive Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Midori Sato
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Masaru Nishikawa
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Yohei Masugi
- Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Taketo Yamada
- Department of Pathology, Keio University School of Medicine, Tokyo 160-8582, Japan
- Department of Pathology, Saitama Medical University, Saitama 350-0495, Japan
| | - Hiroshi Itoh
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan
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Ashok G, Miryala SK, Saju MT, Anbarasu A, Ramaiah S. FN1 encoding fibronectin as a pivotal signaling gene for therapeutic intervention against pancreatic cancer. Mol Genet Genomics 2022; 297:1565-1580. [PMID: 35982245 DOI: 10.1007/s00438-022-01943-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 08/08/2022] [Indexed: 10/15/2022]
Abstract
The delayed diagnosis of pancreatic cancer has resulted in rising mortality rate and low survival rate that can be circumvented using potent theranostics biomarkers. The treatment gets complicated with delayed detection resulting in lowered 5-year relative survival rate. In our present study, we employed systems biology approach to identify central genes that play crucial roles in tumor progression. Pancreatic cancer genes collected from various databases were used to construct a statistically significant interactome with 812 genes that was further analysed thoroughly using topological parameters and functional enrichment analysis. The significant genes in the network were then identified based on the maximum degree parameter. The overall survival analysis indicated through hazard ratio [HR] and gene expression [log Fold Change] across pancreatic adenocarcinoma revealed the critical role of FN1 [HR 1.4; log2(FC) 5.748], FGA [HR 0.78; log2(FC) 1.639] FGG [HR 0.9; log2(FC) 1.597], C3 [HR 1.1; log2(FC) 2.637], and QSOX1 [HR 1.4; log2(FC) 2.371]. The functional significance of the identified hub genes signified the enrichment of integrin cell surface interactions and proteoglycan syndecan-mediated cell signaling. The differential expression, low overall survival and functional significance of FN1 gene implied its possible role in controlling metastasis in pancreatic cancer. Furthermore, alternate splice variants of FN1 gene showed 10 protein coding transcripts with conserved cell attachment site and functional domains indicating the variants' potential role in pancreatic cancer. The strong association of the identified hub-genes can be better directed to design potential theranostics biomarkers for metastasized pancreatic tumor.
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Affiliation(s)
- Gayathri Ashok
- Medical and Biological Computing Laboratory, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.,Department of Bio-Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Sravan Kumar Miryala
- Medical and Biological Computing Laboratory, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.,Department of Bio-Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Megha Treesa Saju
- Medical and Biological Computing Laboratory, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.,Department of Bio-Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Anand Anbarasu
- Medical and Biological Computing Laboratory, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.,Department of Biotechnology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Sudha Ramaiah
- Medical and Biological Computing Laboratory, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India. .,Department of Bio-Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.
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Kumar S, Santos RJ, McGuigan AJ, Singh U, Johnson P, Kunzmann AT, Turkington RC. The Role of Circulating Protein and Metabolite Biomarkers in the Development of Pancreatic Ductal Adenocarcinoma (PDAC): A Systematic Review and Meta-analysis. Cancer Epidemiol Biomarkers Prev 2022; 31:1090-1102. [PMID: 34810209 PMCID: PMC9377754 DOI: 10.1158/1055-9965.epi-21-0616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 08/19/2021] [Accepted: 11/08/2021] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, and this is attributed to it being diagnosed at an advanced stage. Understanding the pathways involved in initial development may improve early detection strategies. This systematic review assessed the association between circulating protein and metabolite biomarkers and PDAC development. METHODS A literature search until August 2020 in MEDLINE, EMBASE, and Web of Science was performed. Studies were included if they assessed circulating blood, urine, or salivary biomarkers and their association with PDAC risk. Quality was assessed using the Newcastle-Ottawa scale for cohort studies. Random-effects meta-analyses were used to calculate pooled relative risk. RESULTS A total of 65 studies were included. Higher levels of glucose were found to be positively associated with risk of developing PDAC [n = 4 studies; pooled relative risk (RR): 1.61; 95% CI: 1.16-2.22]. Additionally, an inverse association was seen with pyridoxal 5'-phosphate (PLP) levels (n = 4 studies; RR: 0.62; 95% CI: 0.44-0.87). Meta-analyses showed no association between levels of C-peptide, members of the insulin growth factor signaling pathway, C-reactive protein, adiponectin, 25-hydroxyvitamin D, and folate/homocysteine and PDAC risk. Four individual studies also reported a suggestive positive association of branched-chain amino acids with PDAC risk, but due to differences in measures reported, a meta-analysis could not be performed. CONCLUSIONS Our pooled analysis demonstrates that higher serum glucose levels and lower levels of PLP are associated with risk of PDAC. IMPACT Glucose and PLP levels are associated with PDAC risk. More prospective studies are required to identify biomarkers for early detection.
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Affiliation(s)
- Swati Kumar
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom
| | - Ralph J. Santos
- Centre for Public Health, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom
| | - Andrew J. McGuigan
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom
| | - Urvashi Singh
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom
| | - Peter Johnson
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom
| | - Andrew T. Kunzmann
- Centre for Public Health, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom
| | - Richard C. Turkington
- Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom
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Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an intractable cancer and a leading cause of cancer deaths worldwide. Over 90% of patients die within 1 year of diagnosis. Deaths from PDAC are increasing and it remains a cancer of substantial unmet need. A number of factors contribute to its poor prognosis: namely, late presentation, early metastases and limited systemic therapy options because of chemoresistance. A variety of research approaches underway are aimed at improving patient survival. Here, we review high-risk groups and efforts for early detection. We examine recent developments in the understanding of complex molecular and metabolic alterations which accompany PDAC. We explore artificial intelligence and biological targets for therapy and examine the role of tumour stroma and the immune microenvironment. We also review recent developments with respect to the PDAC microbiome. It is hoped that current research efforts will translate into earlier diagnosis, improvements in treatment and better outcomes for patients.
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Affiliation(s)
- Martyn C Stott
- Department of Molecular & Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Sherrington Building, Liverpool, UK
| | - Lucy Oldfield
- Department of Molecular & Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Sherrington Building, Liverpool, UK
| | - Jessica Hale
- Department of Molecular & Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Sherrington Building, Liverpool, UK
| | - Eithne Costello
- Department of Molecular & Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Sherrington Building, Liverpool, UK
| | - Christopher M Halloran
- Department of Molecular & Clinical Cancer Medicine, Institute of Systems, Molecular and Integrative Biology, University of Liverpool, Sherrington Building, Liverpool, UK
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Bao J, Liu D, Sun J, Su X, Cheng H, Qi L, Zhang Y, Lv Y, Ye Z, Yu X, Wei Q, Qiu Y, Su J, Li L. Pancreatic cancer-associated diabetes mellitus is characterized by reduced β-cell secretory capacity, rather than insulin resistance. Diabetes Res Clin Pract 2022; 185:109223. [PMID: 35149166 DOI: 10.1016/j.diabres.2022.109223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 10/19/2021] [Accepted: 01/28/2022] [Indexed: 11/24/2022]
Abstract
AIMS The early distinction of pancreatic cancer associated diabetes (PaCDM) in patients with elderly diabetes is critical. However, PaCDM and type 2 diabetes mellitus (T2DM) remain indistinguishable. We aim to address the differences between the pancreatic and gut endocrine hormones of patients with PaCDM and T2DM. METHODS A total of 44 participants underwent mixed meal tolerance test (MMTT). Fasting and postprandial concentrations of insulin, C-peptide, glucagon, pancreatic polypeptide (PP), glucagon-like peptide-1 (GLP-1), and gastric inhibitory peptide (GIP) were measured. Insulin sensitivity and secretion indices were calculated. One-way ANOVA with post-hoc analysis was used for statistical analysis. RESULTS Insulin and C-peptide responses to MMTT were blunted in PaCDM patients compared with T2DM. Baseline concentrations and AUCs differed. PaCDM patients showed lower insulin secretion capacity but better insulin sensitivity than T2DM patients. The peak concentration and AUC of PP in T2DM group were higher than healthy controls, but in accordance with PaCDM. PaCDM patients presented lower baseline GLP-1 concentration than T2DM patients. No between-group differences were found for glucagon and GIP. CONCLUSIONS PaCDM patients had a lower baseline and postprandial insulin and C-peptide secretion than T2DM patients. Reduced insulin secretion and improved peripheral sensitivity were found in PaCDM patients compared with T2DM.
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Affiliation(s)
- Jiantong Bao
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Dechen Liu
- Department of Endocrinology, School of Medicine, and Department of Clinical Science and Research, Zhongda Hospital, Southeast University, Nanjing, China
| | - Jinfang Sun
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China.
| | - Xianghui Su
- Department of Endocrinology, Changji Branch, First Affiliated Hospital of Xinjiang Medical University, Xinjiang 831100, China
| | - Hao Cheng
- Department of Hepatobiliary and Pancreatic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Liang Qi
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Yidi Zhang
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Yingqi Lv
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Zheng Ye
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Xuebing Yu
- Department of Endocrinology, Changzhou Jintan District People's Hospital, School of Medicine in Jiangsu University, Changzhou, China
| | - Qiong Wei
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Yudong Qiu
- Department of Hepatobiliary and Pancreatic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Jianhua Su
- Changzhou Jintan District People's Hospital, School of Medicine in Jiangsu University, Changzhou, China
| | - Ling Li
- Department of Endocrinology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
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11
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Zhu B, Qu S. The Relationship Between Diabetes Mellitus and Cancers and Its Underlying Mechanisms. Front Endocrinol (Lausanne) 2022; 13:800995. [PMID: 35222270 PMCID: PMC8873103 DOI: 10.3389/fendo.2022.800995] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Accepted: 01/12/2022] [Indexed: 12/27/2022] Open
Abstract
Epidemiological studies suggest associations between diabetes mellitus and some cancers. The risk of a number of cancers appears to be increased in diabetes mellitus. On the other hand, some cancer and cancer therapies could lead to diabetes mellitus. Genetic factors, obesity, inflammation, oxidative stress, hyperglycemia, hyperinsulinemia, cancer therapies, insulin and some oral hypoglycemic drugs appear to play a role in the crosstalk between diabetes mellitus and cancers. This review summarized the associations between various types of diabetes and cancers and updated available evidence of underlying mechanisms between diabetes and cancers.
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Affiliation(s)
| | - Shen Qu
- Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, School of Medicine, Tongji University, Shanghai, China
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12
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Perera CJ, Falasca M, Chari ST, Greenfield JR, Xu Z, Pirola RC, Wilson JS, Apte MV. Role of Pancreatic Stellate Cell-Derived Exosomes in Pancreatic Cancer-Related Diabetes: A Novel Hypothesis. Cancers (Basel) 2021; 13:5224. [PMID: 34680372 PMCID: PMC8534084 DOI: 10.3390/cancers13205224] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 09/27/2021] [Accepted: 10/14/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating condition characterised by vague symptomatology and delayed diagnosis. About 30% of PDAC patients report a history of new onset diabetes, usually diagnosed within 3 years prior to the diagnosis of cancer. Thus, new onset diabetes, which is also known as pancreatic cancer-related diabetes (PCRD), could be a harbinger of PDAC. Diabetes is driven by progressive β cell loss/dysfunction and insulin resistance, two key features that are also found in PCRD. Experimental studies suggest that PDAC cell-derived exosomes carry factors that are detrimental to β cell function and insulin sensitivity. However, the role of stromal cells, particularly pancreatic stellate cells (PSCs), in the pathogenesis of PCRD is not known. PSCs are present around the earliest neoplastic lesions and around islets. Given that PSCs interact closely with cancer cells to drive cancer progression, it is possible that exosomal cargo from both cancer cells and PSCs plays a role in modulating β cell function and peripheral insulin resistance. Identification of such mediators may help elucidate the mechanisms of PCRD and aid early detection of PDAC. This paper discusses the concept of a novel role of PSCs in the pathogenesis of PCRD.
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Affiliation(s)
- Chamini J. Perera
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney 2052, Australia; (C.J.P.); (Z.X.); (R.C.P.); (J.S.W.)
- Ingham Institute for Applied Medical Research, Sydney 2170, Australia
| | - Marco Falasca
- Metabolic Signalling Group, Curtin Health Innovation Research Institute, Curtin Medical School, Curtin University, Perth 6102, Australia;
| | - Suresh T. Chari
- M.D Anderson Cancer Centre, Department of Gastroenterology, Hepatology and Nutrition, University of Texas, Houston, TX 75083, USA;
| | - Jerry R. Greenfield
- St Vincent Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney 2052, Australia;
- Healthy Ageing, Garvan Institute of Medical Research, Darlinghurst 2830, Australia
- Department of Diabetes and Endocrinology, St Vincent’s Hospital, Darlinghurst 3065, Australia
| | - Zhihong Xu
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney 2052, Australia; (C.J.P.); (Z.X.); (R.C.P.); (J.S.W.)
- Ingham Institute for Applied Medical Research, Sydney 2170, Australia
| | - Romano C. Pirola
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney 2052, Australia; (C.J.P.); (Z.X.); (R.C.P.); (J.S.W.)
| | - Jeremy S. Wilson
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney 2052, Australia; (C.J.P.); (Z.X.); (R.C.P.); (J.S.W.)
- Ingham Institute for Applied Medical Research, Sydney 2170, Australia
| | - Minoti V. Apte
- Pancreatic Research Group, South Western Sydney Clinical School, Faculty of Medicine and Health, UNSW Sydney, Sydney 2052, Australia; (C.J.P.); (Z.X.); (R.C.P.); (J.S.W.)
- Ingham Institute for Applied Medical Research, Sydney 2170, Australia
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13
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Roy A, Sahoo J, Kamalanathan S, Naik D, Mohan P, Kalayarasan R. Diabetes and pancreatic cancer: Exploring the two-way traffic. World J Gastroenterol 2021; 27:4939-4962. [PMID: 34497428 PMCID: PMC8384733 DOI: 10.3748/wjg.v27.i30.4939] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 06/16/2021] [Accepted: 07/07/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) is often associated with a poor prognosis. Long-standing diabetes mellitus is considered as an important risk factor for its development. This risk can be modified by the use of certain antidiabetic medications. On the other hand, new-onset diabetes can signal towards an underlying PC in the elderly population. Recently, several attempts have been made to develop an effective clinical tool for PC screening using a combination of history of new-onset diabetes and several other clinical and biochemical markers. On the contrary, diabetes affects the survival after treatment for PC. We describe this intimate and complex two-way relationship of diabetes and PC in this review by exploring the underlying pathogenesis.
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Affiliation(s)
- Ayan Roy
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
- Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, Jodhpur 342005, India
| | - Jayaprakash Sahoo
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Sadishkumar Kamalanathan
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Dukhabandhu Naik
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Pazhanivel Mohan
- Department of Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Raja Kalayarasan
- Department of Surgical Gastroenterology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
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14
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Gyawali M, Venkatesan N, Ogeyingbo OD, Bhandari R, Botleroo RA, Kareem R, Ahmed R, Elshaikh AO. Magic of a Common Sugar Pill in Cancer: Can Metformin Raise Survival in Pancreatic Cancer Patients? Cureus 2021; 13:e16916. [PMID: 34367843 PMCID: PMC8343553 DOI: 10.7759/cureus.16916] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 08/04/2021] [Indexed: 12/14/2022] Open
Abstract
Pancreatic cancer is one of the common cancers globally, with a poor survival outcome. Metformin, a popular anti-diabetic drug, has gained popularity for its use in the chemoprevention of cancer. However, results regarding the survival benefit of metformin in pancreatic cancer have been unpredictable. In this review, we aim to analyze the use of metformin in pancreatic cancer patients with pre-existing diabetes mellitus for survival benefit. We systematically conducted a literature search in PubMed, Science Direct, and Scopus databases to collect the relevant articles and reviewed them. Eventually, 11 quality appraised articles were included accessing overall survival as the primary outcome. Our results concluded that metformin can efficaciously improve survival in pancreatic cancer patients with coexisting diabetes mellitus, but the results are still incongruent. Hence, further prospective studies and clinical trials are essential to provide a strong evidence-based recommendation that will help prolong the lifespan of patients.
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Affiliation(s)
- Mallika Gyawali
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Nanditha Venkatesan
- Internal Medicine, All India Institute of Medical Sciences, Raipur, IND.,Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Opemipo D Ogeyingbo
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.,Internal Medicine, Saint James School of Medicine, Park Ridge, USA.,Public Health, Walden University, Minneapolis, USA
| | - Renu Bhandari
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA.,Internal Medicine, Manipal College of Medical Sciences, Pokhara, NPL
| | - Rinky A Botleroo
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Roaa Kareem
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Rowan Ahmed
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Abeer O Elshaikh
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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15
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Kumar S, Jach D, Macfarlane W, Crnogorac-Jurcevic T. A 3-Dimensional Coculture Model to Visualize and Monitor Interaction Between Pancreatic Cancer and Islet β Cells. Pancreas 2021; 50:982-989. [PMID: 34629448 DOI: 10.1097/mpa.0000000000001865] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES To facilitate exploring a link between pancreatic ductal adenocarcinoma (PDAC) and diabetes mellitus, we constructed a novel 3-dimensional (3D) in vitro coculturing system for studying interactions between PDAC and islet cells. METHODS Adopting a 3D rotary cell culture system, we have cocultured several PDAC cell lines and MIN6 islet β cells. The cellular morphology and viability of both cell types were investigated by time-lapse imaging, confocal and scanning electron microscopy, and immunohistochemistry. RESULTS The developed coculture method enabled the formation of 3D PDAC and β-cell spheroids (pseudo islets). We showed that surface morphology and growth of cultured cells mimicked their in vivo appearance. In addition, the coculture demonstrated the affinity of the PDAC cells to grow around and invade the pseudo islets. CONCLUSIONS Using rotary cell culture system, we have established a simple in vitro 3D pancreatic model. It is a flexible culture system that can easily be expanded with the addition of various stromal/neural components to further mimic in vivo conditions, thus enabling holistic investigation of the endocrine and exocrine pancreas.
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MESH Headings
- Animals
- Carcinoma, Pancreatic Ductal/metabolism
- Carcinoma, Pancreatic Ductal/pathology
- Cell Communication
- Cell Culture Techniques, Three Dimensional/methods
- Cell Line, Tumor
- Cell Survival
- Coculture Techniques/methods
- Humans
- Immunohistochemistry
- Insulin-Secreting Cells/metabolism
- Insulin-Secreting Cells/pathology
- Mice
- Microscopy, Confocal
- Microscopy, Electron, Scanning
- Pancreatic Neoplasms/metabolism
- Pancreatic Neoplasms/pathology
- Spheroids, Cellular/metabolism
- Spheroids, Cellular/pathology
- Spheroids, Cellular/ultrastructure
- Time-Lapse Imaging/methods
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Affiliation(s)
- Sandeep Kumar
- From the Advance Therapy Unit, NHS Blood and Transplant, Barnsley
| | - Daria Jach
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London
| | - Wendy Macfarlane
- School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, United Kingdom
| | - Tatjana Crnogorac-Jurcevic
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London
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16
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Serum Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor-binding Protein 2 as a Novel Biomarker in the Detection of Pancreatic Adenocarcinoma. J Clin Gastroenterol 2020; 54:e83-e88. [PMID: 31851103 DOI: 10.1097/mcg.0000000000001297] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Insulin-like growth factor 1 (IGF-1) and insulin-like growth factor-binding protein 2 (IGFBP-2) are proteins that belong to the IGF axis, which is involved in glucose and lipid metabolism and may as well promote carcinogenesis. GOALS The aim of this study was to evaluate the serum concentration levels of IGF-1 and IGFBP-2 in patients with newly diagnosed pancreatic adenocarcinoma (PDAC) to verify their possible role in the diagnosis of the disease. STUDY The study included 69 patients with PDAC and 20 healthy controls. The concentrations of IGF-1 and IGFBP-2 were estimated by means of ELISA. The study protocol was approved by the Bioethics Committee at the Medical University of Lodz in Poland. RESULTS PDAC patients compared with controls have a significantly lower mean serum IGF-1 level (45.83±30.03 vs. 70.66±60.57 ng/mL; P<0.0001). In contrast, in PDAC patients, the mean IGFBP-2 level was significantly higher compared with the control group (225.06±86.37 vs. 51.92±29.40 ng/mL; P<0.0001). The results show that, at the 0.01 sensitivity level, the IGF-1/IGFBP-2 ratio <0.85 points indicates PDAC presence. At this level of sensitivity, the test has a specificity of 0.097 (α=0.01; β=0.097; IGF-1/IGFBP-2≤0.85). CONCLUSIONS Our results show that IGF-1 to IGFBP-2 ratio ≤0.85 may be a powerful PDAC indicator. Further studies in this area in a larger patient group are necessary to confirm our findings.
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17
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Liao W, Chen P, Huang C, Chang Y, Huang B, Chang C, Wu M, Chow L. Relationship between pancreatic cancer-associated diabetes and cachexia. J Cachexia Sarcopenia Muscle 2020; 11:899-908. [PMID: 32100478 PMCID: PMC7432579 DOI: 10.1002/jcsm.12553] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 01/22/2020] [Accepted: 02/03/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Pancreatic cancer-associated diabetes mellitus (PCDM) is a paraneoplastic phenomenon characterized by worsening hyperglycaemia and weight loss. Galectin-3 and S100A9, mediators of PCDM, have pro-inflammatory functions and might thereby induce systemic inflammation and cachexia. We aimed to examine whether PCDM directly mediates cachexia. METHODS Consecutive pancreatic cancer (PC) patients with and without PCDM (n = 88 each) with complete information were included. Cachexia was defined as weight loss >5% within 6 months or weight loss >2% and body mass index <20 kg/m2 or sarcopenia. Skeletal muscle mass was measured with lumbar skeletal muscle index (SMI) using computed tomography images. Cachexia-related parameters (prevalence of cachexia, weight loss, and SMI) were compared between patients with and without PCDM. Relations between cachexia-related parameters and fasting blood glucose or serum levels of galectin-3 and S100A9 were analysed by Spearman correlation and logistic regression analyses. RESULTS One hundred two (58.0%) patients had cachexia at diagnosis. No significant differences existed between patients with and without PCDM in prevalence of cachexia (64.8% vs. 51.1%, P = 0.093), percentage of weight loss (median 6.8 vs. 4.0, P = 0.085), and SMI (median 45.8 vs. 45.3 cm2 /m2 in men, P = 0.119; 34.9 vs. 36.3 cm2 /m2 in women, P = 0.418). In patients with cachexia, the percentage of weight loss and SMI were also similar between patients with and without PCDM. In patients with PCDM, fasting blood glucose was comparable between patients with and without cachexia (P = 0.458) and did not correlate with the percentage of weight loss (P = 0.085) or SMI (P = 0.797 in men and 0.679 in women). Serum S100A9 level correlated with fasting blood glucose (correlation coefficient 0.213, P = 0.047) but not with the percentage of weight loss (P = 0.977) or SMI (P = 0.247 in men and 0.458 in women). Serum galectin-3 level also did not correlate with the percentage of weight loss (P = 0.226) and SMI (P = 0.201 in men and 0.826 in women). Primary tumour size was associated with cachexia (adjusted odds ratio per 1 cm increase 1.28, 95% confidence interval 1.02-1.60, P = 0.034), whereas PCDM, fasting blood glucose, and levels of galectin-3 and S100A9 were not predictors of cachexia. CONCLUSIONS Neither fasting blood glucose nor levels of galectin-3 and S100A9 were associated with cachexia-related parameters. Mediators of PCDM and hyperglycaemia do not directly mediate PC-induced cachexia.
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Affiliation(s)
- Wei‐Chih Liao
- Division of Gastroenterology and Hepatology, Department of Internal MedicineNational Taiwan University Hospital, National Taiwan University College of MedicineTaipeiTaiwan
- Internal Medicine, College of MedicineNational Taiwan UniversityTaipeiTaiwan
| | - Peng‐Ruei Chen
- Graduate Institute of Biochemistry and Molecular Biology, College of MedicineNational Taiwan UniversityTaipeiTaiwan
| | - Cheng‐Chieh Huang
- Graduate Institute of Biochemistry and Molecular Biology, College of MedicineNational Taiwan UniversityTaipeiTaiwan
| | - Yen‐Tzu Chang
- Graduate Institute of Biochemistry and Molecular Biology, College of MedicineNational Taiwan UniversityTaipeiTaiwan
| | - Bo‐Shih Huang
- Graduate Institute of Biochemistry and Molecular Biology, College of MedicineNational Taiwan UniversityTaipeiTaiwan
| | - Chin‐Chen Chang
- Department of Medical ImagingNational Taiwan University Hospital, National Taiwan University College of MedicineTaipeiTaiwan
- Department and Graduate Institute of Forensic MedicineNational Taiwan University College of MedicineTaipeiTaiwan
| | - Ming‐Shiang Wu
- Division of Gastroenterology and Hepatology, Department of Internal MedicineNational Taiwan University Hospital, National Taiwan University College of MedicineTaipeiTaiwan
- Internal Medicine, College of MedicineNational Taiwan UniversityTaipeiTaiwan
| | - Lu‐Ping Chow
- Graduate Institute of Biochemistry and Molecular Biology, College of MedicineNational Taiwan UniversityTaipeiTaiwan
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18
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Ueberberg S, Nauck MA, Uhl W, Montemurro C, Tannapfel A, Clark A, Meier JJ. Islet Amyloid in Patients With Diabetes Due to Exocrine Pancreatic Disorders, Type 2 Diabetes, and Nondiabetic Patients. J Clin Endocrinol Metab 2020; 105:5818378. [PMID: 32271378 DOI: 10.1210/clinem/dgaa176] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Accepted: 04/08/2020] [Indexed: 01/06/2023]
Abstract
BACKGROUND Amyloid deposits are a typical finding in pancreatic islets from patients with type 2 diabetes. Whether this is linked to the pathogenesis of type 2 diabetes is currently unknown. Therefore, we compared the occurrence of islet amyloid in patients with type 2 diabetes, diabetes secondary to pancreatic disorders, and nondiabetic individuals. PATIENTS AND METHODS Pancreatic tissue from 15 nondiabetic patients, 22 patients with type 2 diabetes, and 11 patients with diabetes due to exocrine pancreatic disorders (chronic pancreatitis, pancreatic carcinoma) were stained for insulin, amyloid, and apoptosis. β-cell area, amyloid deposits, and β-cell apoptosis were quantified by morphometric analysis. RESULTS The proportion of islets containing amyloid deposits was significantly higher in both type 2 diabetes and diabetes due to exocrine pancreatic disorders than in healthy subjects. Islets with both amyloid and apoptosis were observed more frequently in type 2 diabetes and significantly more so in diabetes due to exocrine pancreatic disorders. In both diabetic groups, apoptotic ß-cells were found significantly more frequently in islets with more prominent amyloid deposits. CONCLUSIONS The occurrence of amyloid deposits in both type 2 diabetes and diabetes secondary to exocrine pancreatic disorders suggests that islet amyloid formation is a common feature of diabetes mellitus of different etiologies and may be associated with a loss of pancreatic ß-cells.
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Affiliation(s)
- Sandra Ueberberg
- Diabetes Division St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
| | - Michael A Nauck
- Diabetes Division St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
| | - Waldemar Uhl
- Department of General and Visceral Surgery, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
| | - Chiara Montemurro
- Diabetes Division St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
- David Geffen School of Medicine, University of California, Los Angeles, CA, US
| | | | - Anne Clark
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Juris J Meier
- Diabetes Division St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
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19
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Nagpal SJS, Kandlakunta H, Her T, Sharma A, Sannapaneni S, Smyrk TC, Velamala P, Garg SK, Rakshit K, Majumder S, Chari S, Matveyenko A. Pancreatic ductal adenocarcinoma is associated with a unique endocrinopathy distinct from type 2 diabetes mellitus. Pancreatology 2020; 20:929-935. [PMID: 32620407 DOI: 10.1016/j.pan.2020.05.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 05/10/2020] [Accepted: 05/13/2020] [Indexed: 12/11/2022]
Abstract
INTRODUCTION The majority of patients with pancreatic ductal adenocarcinoma (PC) display either impaired fasting glucose/glucose intolerance or overt diabetes. However, the pathophysiologic basis of this association remains largely unexplained. METHODS In this case-control study we aimed to study the morphological changes in the islets of patients with PC, compared to control patients with and without type 2 diabetes mellitus (T2DM). T2DM controls and PC cases had a lower β-cell area and average islet size and density compared to non-T2DM controls (p < 0.05). RESULTS Compared to both T2DM and non-T2DM controls, mean α-cell area was significantly lower and β/α-ratio was higher in PC cases (p < 0.05). Furthermore, whereas islets in T2DM controls were characterized by disrupted islet architecture and presence of islet amyloid aggregates, islet composition in PC islets was not significantly different compared to non-T2DM controls (p > 0.05 vs. Control). CONCLUSIONS Our data shows that PC is associated with a unique pattern of islet pathology characterized by preserved architecture, absence of amyloid aggregates, and relative α-cell loss indicating that distinct mechanisms are likely involved in the pathophysiology of islet failure in PC-induced DM. Insights into the mechanisms mediating β-cell failure in PC can be important for our understanding of pathophysiology of PC.
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Affiliation(s)
- Sajan Jiv Singh Nagpal
- Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA; Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, UChicago Medicine, Chicago, IL, USA
| | - Harika Kandlakunta
- Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Tracy Her
- Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Ayush Sharma
- Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Shilpa Sannapaneni
- Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Thomas C Smyrk
- Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Pruthvi Velamala
- Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Sushil K Garg
- Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Kuntol Rakshit
- Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Shounak Majumder
- Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Suresh Chari
- Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA; Department of Gastroenterology, Hepatology and Nutrition, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Aleksey Matveyenko
- Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine and Science, Rochester, MN, USA; Department of Medicine, Division of Endocrinology, Metabolism, Diabetes, and Nutrition, Mayo Clinic College of Medicine and Science, Rochester, MN, USA.
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20
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Principe DR, Rana A. Updated risk factors to inform early pancreatic cancer screening and identify high risk patients. Cancer Lett 2020; 485:56-65. [PMID: 32389710 DOI: 10.1016/j.canlet.2020.04.022] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 04/06/2020] [Accepted: 04/23/2020] [Indexed: 02/07/2023]
Abstract
Pancreatic adenocarcinoma (PDAC) is associated with poor clinical outcomes and incomplete responses to conventional therapy. Therefore, there is an unmet clinical need to better understand the predisposing factors for pancreatic cancer in hopes of providing early screening to high-risk patients. While select risk factors such as age, race, and family history, or predisposing syndromes are unavoidable, there are several new and established risk factors that allow for intervention, namely by counseling patients to make the appropriate lifestyle modifications. Here, we discuss the best-studied risk factors for PDAC such as tobacco use and chronic pancreatitis, as well as newly emerging risk factors including select nutritional deficits, bacterial infections, and psychosocial factors. As several of these risk factors appear to be additive or synergistic, by understanding their relationships and offering coordinated, multidisciplinary care to high-risk patients, it may be possible to reduce pancreatic cancer incidence and improve clinical outcomes through early detection.
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Affiliation(s)
- Daniel R Principe
- Medical Scientist Training Program, University of Illinois College of Medicine, Chicago, IL, USA; Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL, USA.
| | - Ajay Rana
- Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, IL, USA; Jesse Brown VA Medical Center, Chicago, IL, USA.
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21
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Wang Y, Ni Q, Sun J, Xu M, Xie J, Zhang J, Fang Y, Ning G, Wang Q. Paraneoplastic β Cell Dedifferentiation in Nondiabetic Patients with Pancreatic Cancer. J Clin Endocrinol Metab 2020; 105:5645541. [PMID: 31781763 DOI: 10.1210/clinem/dgz224] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2019] [Accepted: 11/27/2019] [Indexed: 12/13/2022]
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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Affiliation(s)
- Yichen Wang
- Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commision of the PR China, Shanghai Institute of Endocrine and Metabolic Disease, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qicheng Ni
- Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commision of the PR China, Shanghai Institute of Endocrine and Metabolic Disease, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiajun Sun
- Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commision of the PR China, Shanghai Institute of Endocrine and Metabolic Disease, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Min Xu
- Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commision of the PR China, Shanghai Institute of Endocrine and Metabolic Disease, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jing Xie
- Department of Pathology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jun Zhang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuan Fang
- Research Institute of Pancreatic Disease, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guang Ning
- Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commision of the PR China, Shanghai Institute of Endocrine and Metabolic Disease, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qidi Wang
- Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commision of the PR China, Shanghai Institute of Endocrine and Metabolic Disease, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Sino-French Research Center for Life Sciences and Genomics, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
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22
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Barreto SG, Michael MZ, Keating DJ. Islets and pancreatic ductal adenocarcinoma - An opportunity for translational research from the 'Bench to the Bedside'. Pancreatology 2020; 20:385-390. [PMID: 32057682 DOI: 10.1016/j.pan.2020.02.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 01/15/2020] [Accepted: 02/01/2020] [Indexed: 02/06/2023]
Abstract
The islet-acinar axis is of prime importance to the optimal functioning of the human pancreas. Not only is this inter-relationship important for normal physiological processes, it is also relevant in diseased states, including chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC). Early experiments, nearly 4 decades ago, explored the role of islets in the development and progression of PDAC. These led to further studies that provided compelling evidence to support the role of islets and their hormones in PDAC. This association presents oncologists with therapeutic options not only for managing, but potentially preventing PDAC, a cancer that is well known for its poor patient outcomes. This review will discuss the accumulated evidence regarding the role of islets and their hormones in PDAC and highlight areas for future research.
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Affiliation(s)
- Savio G Barreto
- Division of Surgery and Perioperative Medicine, Flinders Medical Centre, Bedford Park, Adelaide, South Australia, Australia; College of Medicine and Public Health, Flinders University, South Australia, Australia.
| | - Michael Z Michael
- Division of Surgery and Perioperative Medicine, Flinders Medical Centre, Bedford Park, Adelaide, South Australia, Australia; College of Medicine and Public Health, Flinders University, South Australia, Australia
| | - Damien J Keating
- College of Medicine and Public Health, Flinders University, South Australia, Australia
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23
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Goldberg R, Meirovitz A, Abecassis A, Hermano E, Rubinstein AM, Nahmias D, Grinshpun A, Peretz T, Elkin M. Regulation of Heparanase in Diabetes-Associated Pancreatic Carcinoma. Front Oncol 2019; 9:1405. [PMID: 31921662 PMCID: PMC6914686 DOI: 10.3389/fonc.2019.01405] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 11/27/2019] [Indexed: 12/18/2022] Open
Abstract
While at least six types of cancer have been associated with diabetes, pancreatic ductal adenocarcinoma (PDAC) and diabetes exhibit a unique bidirectional relationship. Recent reports indicate that majority of PDAC patients display hyperglycemia, and ~50% have concurrent diabetes. In turn, hyperglycemic/diabetic state in PDAC patients fosters enhanced growth and dissemination of the tumor. Heparanase enzyme (the sole mammalian endoglycosidase degrading glycosaminoglycan heparan sulfate) is tightly implicated in PDAC progression, aggressiveness, and therapy resistance. Overexpression of heparanase is a characteristic feature of PDAC, correlating with poor prognosis. However, given the lack of heparanase expression in normal pancreatic tissue, the regulatory mechanisms responsible for induction of the enzyme in PDAC have remained largely unknown. Previously reported inducibility of heparanase gene by diabetic milieu components in several non-cancerous cell types prompted us to hypothesize that in the setting of diabetes-associated PDAC, hyperglycemic state may induce heparanase overexpression. Here, utilizing a mouse model of diet-induced metabolic syndrome/diabetes, we found accelerated PDAC progression in hyperglycemic mice, occurring along with induction of heparanase in PDAC. In vitro, we demonstrated that advanced glycation end-products (AGE), which are largely thought as oxidative derivatives resulting from chronic hyperglycemia, and the receptor for AGE (RAGE) are responsible for heparanase induction in PDAC cells. These findings underscore the new mechanism underlying preferential expression of heparanase in pancreatic cancer. Moreover, taken together with the well-established causal role of the enzyme in PDAC progression, our findings indicate that heparanase may sustain (at least in part) reciprocal causality between diabetes and pancreatic tumorigenesis.
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Affiliation(s)
- Rachel Goldberg
- Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Amichay Meirovitz
- Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Alexia Abecassis
- Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Esther Hermano
- Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Ariel M Rubinstein
- Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Daniela Nahmias
- Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Albert Grinshpun
- Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Tamar Peretz
- Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Michael Elkin
- Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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24
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Liao WC, Huang BS, Yu YH, Yang HH, Chen PR, Huang CC, Huang HY, Wu MS, Chow LP. Galectin-3 and S100A9: Novel Diabetogenic Factors Mediating Pancreatic Cancer-Associated Diabetes. Diabetes Care 2019; 42:1752-1759. [PMID: 31262951 DOI: 10.2337/dc19-0217] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 06/12/2019] [Indexed: 02/03/2023]
Abstract
OBJECTIVE Pancreatic cancer-associated diabetes (PCDM) is a paraneoplastic phenomenon accounting for 1% of new-onset diabetes. We aimed to identify the mediators of PCDM and evaluate their usefulness in distinguishing PCDM from type 2 diabetes. RESEARCH DESIGN AND METHODS Secreted proteins of MIA PaCa-2 cells were identified by proteomics, and those with ≥10-fold overexpression in transcriptome analysis were assessed by bioinformatics and glucose uptake assay to identify candidate factors. Expression of factors was compared between tumors with and without PCDM by immunohistochemistry. Serum levels were measured in a training set including PC with and without PCDM, type 2 diabetes, pancreatitis, other pancreatic/peripancreatic tumors, and control subjects (n = 50 each). Cutoff values for differentiation between PCDM and type 2 diabetes from the training set were validated in a test set (n = 41 each). RESULTS Galectin-3 and S100A9 were overexpressed in tumors with PCDM and dose-dependently suppressed insulin-stimulated glucose uptake in C2C12 myotubes. In the training set, serum galectin-3 and S100A9 levels were exclusively increased in patients with PCDM and distinguished PCDM from type 2 diabetes (area under the curve [AUC] galectin-3: 0.73 [95% CI 0.64-0.83]; S100A9: 0.79 [95% CI 0.70-0.87]). Similar results were observed in the test set (AUC galectin-3: 0.83 [95% CI 0.74-0.92]; S100A9: 0.77 [95% CI 0.67-0.87]), with sensitivity and specificity 72.1% and 86.1%, respectively, for galectin-3 and 69.8% and 58.1% for S100A9 in differentiating between PCDM and type 2 diabetes. CONCLUSIONS Galectin-3 and S100A9 are overexpressed in PCDM tumors and mediate insulin resistance. Galectin-3 and S100A9 distinguish PCDM from type 2 diabetes in subjects with new-onset diabetes.
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Affiliation(s)
- Wei-Chih Liao
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.,Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Bo-Shih Huang
- Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ya-Han Yu
- Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hsin-Hua Yang
- Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Peng-Ruei Chen
- Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Cheng-Chieh Huang
- Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hsin-Yi Huang
- Department of Pathology, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Ming-Shiang Wu
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan .,Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Lu-Ping Chow
- Graduate Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
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25
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Singhi AD, Koay EJ, Chari ST, Maitra A. Early Detection of Pancreatic Cancer: Opportunities and Challenges. Gastroenterology 2019; 156:2024-2040. [PMID: 30721664 PMCID: PMC6486851 DOI: 10.1053/j.gastro.2019.01.259] [Citation(s) in RCA: 479] [Impact Index Per Article: 79.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 01/08/2019] [Accepted: 01/15/2019] [Indexed: 12/17/2022]
Abstract
Most patients with pancreatic ductal adenocarcinoma (PDAC) present with symptomatic, surgically unresectable disease. Although the goal of early detection of PDAC is laudable and likely to result in significant improvement in overall survival, the relatively low prevalence of PDAC renders general population screening infeasible. The challenges of early detection include identification of at-risk individuals in the general population who would benefit from longitudinal surveillance programs and appropriate biomarker and imaging-based modalities used for PDAC surveillance in such cohorts. In recent years, various subgroups at higher-than-average risk for PDAC have been identified, including those with familial risk due to germline mutations, a history of pancreatitis, patients with mucinous pancreatic cysts, and elderly patients with new-onset diabetes. The last 2 categories are discussed at length in terms of the opportunities and challenges they present for PDAC early detection. We also discuss current and emerging imaging modalities that are critical to identifying early, potentially curable PDAC in high-risk cohorts on surveillance.
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Affiliation(s)
- Aatur D Singhi
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Eugene J Koay
- Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas; Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Suresh T Chari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
| | - Anirban Maitra
- Sheikh Ahmed Center for Pancreatic Cancer Research, University of Texas MD Anderson Cancer Center, Houston, Texas; Department of Translational Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas
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26
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Sah RP, Sharma A, Nagpal S, Patlolla SH, Sharma A, Kandlakunta H, Anani V, Angom RS, Kamboj AK, Ahmed N, Mohapatra S, Vivekanandhan S, Philbrick KA, Weston A, Takahashi N, Kirkland J, Javeed N, Matveyenko A, Levy MJ, Mukhopadhyay D, Chari ST. Phases of Metabolic and Soft Tissue Changes in Months Preceding a Diagnosis of Pancreatic Ductal Adenocarcinoma. Gastroenterology 2019; 156:1742-1752. [PMID: 30677401 PMCID: PMC6475474 DOI: 10.1053/j.gastro.2019.01.039] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 12/13/2018] [Accepted: 01/11/2019] [Indexed: 12/29/2022]
Abstract
BACKGROUND & AIMS Identifying metabolic abnormalities that occur before pancreatic ductal adenocarcinoma (PDAC) diagnosis could increase chances for early detection. We collected data on changes in metabolic parameters (glucose, serum lipids, triglycerides; total, low-density, and high-density cholesterol; and total body weight) and soft tissues (abdominal subcutaneous fat [SAT], adipose tissue, visceral adipose tissue [VAT], and muscle) from patients 5 years before the received a diagnosis of PDAC. METHODS We collected data from 219 patients with a diagnosis of PDAC (patients) and 657 healthy individuals (controls) from the Rochester Epidemiology Project, from 2000 through 2015. We compared metabolic profiles of patients with those of age- and sex-matched controls, constructing temporal profiles of fasting blood glucose, serum lipids including triglycerides, cholesterol profiles, and body weight and temperature for 60 months before the diagnosis of PDAC (index date). To construct the temporal profile of soft tissue changes, we collected computed tomography scans from 68 patients, comparing baseline (>18 months before diagnosis) areas of SAT, VAT, and muscle at L2/L3 vertebra with those of later scans until time of diagnosis. SAT and VAT, isolated from healthy individuals, were exposed to exosomes isolated from PDAC cell lines and analyzed by RNA sequencing. SAT was collected from KRAS+/LSLG12D P53flox/flox mice with PDACs, C57/BL6 (control) mice, and 5 patients and analyzed by histology and immunohistochemistry. RESULTS There were no significant differences in metabolic or soft tissue features of patients vs controls until 30 months before PDAC diagnosis. In the 30 to 18 months before PDAC diagnosis (phase 1, hyperglycemia), a significant proportion of patients developed hyperglycemia, compared with controls, without soft tissue changes. In the 18 to 6 months before PDAC diagnosis (phase 2, pre-cachexia), patients had significant increases in hyperglycemia and decreases in serum lipids, body weight, and SAT, with preserved VAT and muscle. In the 6 to 0 months before PDAC diagnosis (phase 3, cachexia), a significant proportion of patients had hyperglycemia compared with controls, and patients had significant reductions in all serum lipids, SAT, VAT, and muscle. We believe the patients had browning of SAT, based on increases in body temperature, starting 18 months before PDAC diagnosis. We observed expression of uncoupling protein 1 (UCP1) in SAT exposed to PDAC exosomes, SAT from mice with PDACs, and SAT from all 5 patients but only 1 of 4 controls. CONCLUSIONS We identified 3 phases of metabolic and soft tissue changes that precede a diagnosis of PDAC. Loss of SAT starts 18 months before PDAC identification, and is likely due to browning. Overexpression of UCP1 in SAT might be a biomarker of early-stage PDAC, but further studies are needed.
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MESH Headings
- Adipocytes/metabolism
- Adipocytes/pathology
- Animals
- Blood Glucose/metabolism
- Body Temperature
- Body Weight
- Cachexia/etiology
- Carcinoma, Pancreatic Ductal/blood
- Carcinoma, Pancreatic Ductal/complications
- Carcinoma, Pancreatic Ductal/diagnosis
- Carcinoma, Pancreatic Ductal/genetics
- Case-Control Studies
- Cells, Cultured
- Cholesterol, HDL/blood
- Cholesterol, LDL/blood
- Exosomes
- Humans
- Hyperglycemia/blood
- Hyperglycemia/etiology
- Intra-Abdominal Fat/diagnostic imaging
- Intra-Abdominal Fat/pathology
- Mice
- Middle Aged
- Muscle, Skeletal/diagnostic imaging
- Pancreatic Neoplasms/blood
- Pancreatic Neoplasms/complications
- Pancreatic Neoplasms/diagnosis
- Pancreatic Neoplasms/genetics
- RNA, Messenger/metabolism
- Retrospective Studies
- Subcutaneous Fat, Abdominal/diagnostic imaging
- Subcutaneous Fat, Abdominal/pathology
- Time Factors
- Tomography, X-Ray Computed
- Triglycerides/blood
- Uncoupling Protein 1/genetics
- Up-Regulation
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Affiliation(s)
- Raghuwansh P Sah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Ayush Sharma
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Sajan Nagpal
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Sri Harsha Patlolla
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Anil Sharma
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, Florida
| | - Harika Kandlakunta
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Vincent Anani
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Ramcharan Singh Angom
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, Florida
| | - Amrit K Kamboj
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Nazir Ahmed
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Sonmoon Mohapatra
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Sneha Vivekanandhan
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Jacksonville, Florida
| | | | - Alexander Weston
- Department of Radiology Informatics, Mayo Clinic, Rochester, Minnesota
| | | | - James Kirkland
- Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota
| | - Naureen Javeed
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
| | - Aleksey Matveyenko
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota
| | - Michael J Levy
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | | | - Suresh T Chari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
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27
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Bhattamisra SK, Siang TC, Rong CY, Annan NC, Sean EHY, Xi LW, Lyn OS, Shan LH, Choudhury H, Pandey M, Gorain B. Type-3c Diabetes Mellitus, Diabetes of Exocrine Pancreas - An Update. Curr Diabetes Rev 2019; 15:382-394. [PMID: 30648511 DOI: 10.2174/1573399815666190115145702] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 11/02/2018] [Accepted: 01/08/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND The incidence of diabetes is increasing steeply; the number of diabetics has doubled over the past three decades. Surprisingly, the knowledge of type 3c diabetes mellitus (T3cDM) is still unclear to the researchers, scientist and medical practitioners, leading towards erroneous diagnosis, which is sometimes misdiagnosed as type 1 diabetes mellitus (T1DM), or more frequently type 2 diabetes mellitus (T2DM). This review is aimed to outline recent information on the etiology, pathophysiology, diagnostic procedures, and therapeutic management of T3cDM patients. METHODS The literature related to T3cDM was thoroughly searched from the public domains and reviewed extensively to construct this article. Further, existing literature related to the other forms of diabetes is reviewed for projecting the differences among the different forms of diabetes. Detailed and updated information related to epidemiological evidence, risk factors, symptoms, diagnosis, pathogenesis and management is structured in this review. RESULTS T3cDM is often misdiagnosed as T2DM due to the insufficient knowledge differentiating between T2DM and T3cDM. The pathogenesis of T3cDM is explained which is often linked to the history of chronic pancreatitis, pancreatic cancer. Inflammation, and fibrosis in pancreatic tissue lead to damage both endocrine and exocrine functions, thus leading to insulin/glucagon insufficiency and pancreatic enzyme deficiency. CONCLUSION Future advancements should be accompanied by the establishment of a quick diagnostic tool through the understanding of potential biomarkers of the disease and newer treatments for better control of the diseased condition.
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Affiliation(s)
- Subrat Kumar Bhattamisra
- Department of Life Sciences, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Tiew Chin Siang
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Chieng Yi Rong
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Naveenya Chetty Annan
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Esther Ho Yung Sean
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Lim Wen Xi
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Ong Siu Lyn
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Liew Hui Shan
- School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Hira Choudhury
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Manisha Pandey
- Department of Pharmaceutical Technology, School of Pharmacy, International Medical University, Bukit Jalil 57000, Kuala Lumpur, Malaysia
| | - Bapi Gorain
- School of Pharmacy, Taylor's University, 1, Jalan Taylors, 47500 Subang Jaya, Selangor, Malaysia
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28
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Nagpal SJS, Bamlet WR, Kudva YC, Chari ST. Comparison of Fasting Human Pancreatic Polypeptide Levels Among Patients With Pancreatic Ductal Adenocarcinoma, Chronic Pancreatitis, and Type 2 Diabetes Mellitus. Pancreas 2018; 47:738-741. [PMID: 29771765 PMCID: PMC6139029 DOI: 10.1097/mpa.0000000000001077] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES Human pancreatic polypeptide (HPP) is a hormone secreted by the ventral pancreas. While postprandial HPP levels have been studied in chronic pancreatitis (CP) and pancreatic ductal adenocarcinoma (PDAC), there are limited data on fasting HPP in these diseases. METHODS Fasting serum HPP was measured in the following groups of patients: CP with diabetes mellitus (DM) (n = 16), CP without DM (n = 34), PDAC with new-onset DM (n = 50), PDAC without DM (n = 49), new-onset type 2 DM (n = 50), and controls without DM (n = 49). Sixty-six had type 3c DM (CP with DM, n = 16; PDAC with new-onset DM, n = 50). RESULTS Median fasting HPP levels (in picograms per milliliter) were similar among all groups. Median (interquartile range) HPP levels in new-onset type 2 DM (n = 50; 288.3 [80.1-1072.1]) were similar to those in type 3c DM (n = 66; 242.3 [64.9-890.9]) (P = 0.71). In PDAC (n = 99), HPP values were similar in pancreatic head (n = 75) versus body/tail (n = 24) tumors (245.3 [64.3-1091.3] vs 334.7 [136.1-841.5]; P = 0.95), regardless of DM. CONCLUSIONS Fasting HPP levels are similar in CP, PDAC, and controls regardless of glycemic status.
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Affiliation(s)
| | - William R. Bamlet
- From the Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester MN
| | - Yogish C. Kudva
- From the Division of Endocrinology, Mayo Clinic, Rochester MN
| | - Suresh T. Chari
- From the Division of Gastroenterology, Hepatology, Mayo Clinic, Rochester MN
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29
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Frič P, Šedo A, Škrha J, Bušek P, Laclav M, Škrha P, Zavoral M. Early detection of sporadic pancreatic cancer: time for change. Eur J Gastroenterol Hepatol 2017; 29:885-891. [PMID: 28471824 DOI: 10.1097/meg.0000000000000904] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Sporadic pancreatic cancer amounts to ∼90% of all pancreatic cancers. It is a gloomy depressive disease and the most recalcitrant malignancy, with a very low 5-year survival (3-6%). At present, diagnostic methods are commonly applied, as used half a century ago, after the appearance of local and systemic symptoms (abdominal and back pain, cholestasis, painless jaundice, fatigue, anorexia, weight loss, anemia, peripheral phlebitis, and cachexia). Unfortunately, these symptoms are harbingers of an advanced disease. The subsequent imaging methods may offer additional information on the location, size, and morphology of the lesion, but they do not influence the prognosis. Radical surgery may be offered to 15-20% of patients. The relapses after surgery are frequent and chemotherapy may be palliative. Preventive programs represent the only possibility of improvement. We propose the first multistep and multidisciplinary preventive program for early detection of sporadic pancreatic cancer for the differential identification of average-risk patients who probably have the disease from those who do not.
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Affiliation(s)
- Přemysl Frič
- aDepartment of Medicine/Gastroenterology, Military University Hospital bInstitute of Biochemistry and Experimental Oncology cLaboratory of Endocrinology and Metabolism, General University Hospital, First Faculty of Medicine dSecond Department of Medicine, University Hospital, Third Faculty of Medicine, Charles University, Prague, Czech Republic
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Lower plasma levels of glucose-dependent insulinotropic peptide (GIP) and pancreatic polypeptide (PP) in patients with ductal adenocarcinoma of the pancreas and their relation to the presence of impaired glucoregulation and weight loss. Pancreatology 2016; 17:89-94. [PMID: 28027898 DOI: 10.1016/j.pan.2016.12.004] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2016] [Revised: 11/14/2016] [Accepted: 12/15/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND The changes in gastrointestinal hormones associated with pancreatic ductal adenocarcinoma (PDAC) in patients with impaired glucoregulation have yet to be evaluated. The aim of this study was to determine plasma concentrations of selected gastrointestinal hormones in PDAC patients with and without diabetes and to compare them with levels found in Type 2 diabetic patients without cancer. METHODS In this study we examined plasma concentrations of glucose-dependent insulinotropic peptide (GIP), glucagon-like peptide 1 (GLP-1), pancreatic polypeptide (PP), peptide YY (PYY) and neuropeptide Y (NPY), and cytokines leptin and adiponectin in 94 patients with histologically confirmed PDAC. Thirty-nine patients with Type 2 diabetes without PDAC and 29 healthy individuals with no evidence of acute or chronic diseases were examined as controls. RESULTS Significantly lower plasma concentrations of GIP were found in PDAC patients with new-onset diabetes/prediabetes (n = 76), or in those with normal glucose regulation (n = 18), compared to patients with Type 2 diabetes without PDAC and controls (15.5 (3.7-64.5) or 6.5 (1.7-24.5) vs. 39.8 (15.1-104.7) and 28.8 (7.4-112.2) ng/L, p < 0.001); the same relationship was observed for PP (38.9 (10.2-147.9) or 28.1 (7.9-100.0) vs 89.1 (38.0-208.9) and 75.8 (30.1-190.6) ng/L, p < 0.01), respectively. The lowest levels of GIP and PP concentrations were found in PDAC patients with new-onset diabetes/prediabetes and weight loss > 2 kg (p < 0.001). CONCLUSIONS We conclude that GIP and PP plasma concentrations are lower in pancreatic cancer irrespective of the degree of glucose intolerance as compared to Type 2 diabetic patients and healthy controls. In new onset diabetes especially if associated with weight loss, these changes may represent a new clue for the diagnosis of PDAC.
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Dugnani E, Balzano G, Pasquale V, Scavini M, Aleotti F, Liberati D, Di Terlizzi G, Gandolfi A, Petrella G, Reni M, Doglioni C, Bosi E, Falconi M, Piemonti L. Insulin resistance is associated with the aggressiveness of pancreatic ductal carcinoma. Acta Diabetol 2016; 53:945-956. [PMID: 27552832 DOI: 10.1007/s00592-016-0893-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Accepted: 07/27/2016] [Indexed: 12/15/2022]
Abstract
AIMS To study whether insulin resistance accelerates the development and/or the progression of pancreatic adenocarcinoma (PDAC), we hypothesized that patients with insulin resistance, compared with those without insulin resistance, show: (1) a younger age and more advanced PDAC stage at diagnosis and (2) a shorter disease-free and overall survival after PDAC diagnosis. METHODS Prospective observational study of patients admitted to a referral center for pancreatic disease. Insulin resistance was defined as a HOMA-IR value greater than the 66th percentile value of the patients included in this study. Survival was estimated according to Kaplan-Meier and by Cox regression. RESULTS Of 296 patients with PDAC, 99 (33 %) met criteria for being classified as insulin resistant at diagnosis. Median follow-up time after diagnosis was 5.27 ± 0.23 years. Patients with insulin resistance received a diagnosis of PDAC at a similar age compared to patients without insulin resistance (67.1 ± 9 vs. 66.8 ± 10 years, p = 0.68), but were more likely to have a cancer stage ≥3 (23.2 vs. 14.2 %, p = 0.053) and a residual disease after surgery (R1 56.4 vs. 38 %; p = 0.007). The median overall survival was 1.3 ± 0.14 and 1.79 ± 0.11 years for the patients with and without insulin resistance, respectively (p = 0.016). Results did not change when patients with diabetes at PDAC diagnosis were excluded from the analysis. Multivariate analysis showed that insulin resistance was independently associated with overall survival. CONCLUSIONS Insulin resistance is associated with the aggressiveness of PDAC.
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Affiliation(s)
- Erica Dugnani
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy
| | - Gianpaolo Balzano
- Pancreatic Surgery Unit, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy
| | - Valentina Pasquale
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy
| | - Marina Scavini
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy
| | - Francesca Aleotti
- Pancreatic Surgery Unit, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy
| | - Daniela Liberati
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy
| | - Gaetano Di Terlizzi
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy
| | - Alessandra Gandolfi
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy
| | - Giovanna Petrella
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy
| | - Michele Reni
- Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy
| | - Claudio Doglioni
- Department of Pathology, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Emanuele Bosi
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy
| | - Massimo Falconi
- Pancreatic Surgery Unit, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | - Lorenzo Piemonti
- Diabetes Research Institute, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132, Milan, Italy.
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Hart PA, Bellin MD, Andersen DK, Bradley D, Cruz-Monserrate Z, Forsmark CE, Goodarzi MO, Habtezion A, Korc M, Kudva YC, Pandol SJ, Yadav D, Chari ST. Type 3c (pancreatogenic) diabetes mellitus secondary to chronic pancreatitis and pancreatic cancer. Lancet Gastroenterol Hepatol 2016; 1:226-237. [PMID: 28404095 DOI: 10.1016/s2468-1253(16)30106-6] [Citation(s) in RCA: 293] [Impact Index Per Article: 32.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 07/25/2016] [Accepted: 07/26/2016] [Indexed: 02/07/2023]
Abstract
Diabetes mellitus is a group of diseases defined by persistent hyperglycaemia. Type 2 diabetes, the most prevalent form, is characterised initially by impaired insulin sensitivity and subsequently by an inadequate compensatory insulin response. Diabetes can also develop as a direct consequence of other diseases, including diseases of the exocrine pancreas. Historically, diabetes due to diseases of the exocrine pancreas was described as pancreatogenic or pancreatogenous diabetes mellitus, but recent literature refers to it as type 3c diabetes. It is important to note that type 3c diabetes is not a single entity; it occurs because of a variety of exocrine pancreatic diseases with varying mechanisms of hyperglycaemia. The most commonly identified causes of type 3c diabetes are chronic pancreatitis, pancreatic ductal adenocarcinoma, haemochromatosis, cystic fibrosis, and previous pancreatic surgery. In this Review, we discuss the epidemiology, pathogenesis, and clinical relevance of type 3c diabetes secondary to chronic pancreatitis and pancreatic ductal adenocarcinoma, and highlight several important knowledge gaps.
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Affiliation(s)
- Phil A Hart
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
| | - Melena D Bellin
- Division of Pediatric Endocrinology and Schulze Diabetes Institute, University of Minnesota Medical Center, Minneapolis, MN, USA
| | - Dana K Andersen
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - David Bradley
- Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University, Wexner Medical Center, Columbus, OH, USA
| | - Zobeida Cruz-Monserrate
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Christopher E Forsmark
- Division of Gastroenterology, Hepatology, and Nutrition, University of Florida, Gainesville, FL, USA
| | - Mark O Goodarzi
- Division of Endocrinology, Diabetes, and Metabolism, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Aida Habtezion
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Murray Korc
- Departments of Medicine, Biochemistry, and Molecular Biology, Indiana University School of Medicine, Indiana University Simon Cancer Center, Indianapolis, IN, USA; Pancreatic Cancer Signature Center, Indiana University Simon Cancer Center, Indianapolis, IN, USA
| | - Yogish C Kudva
- Division of Endocrinology and Metabolism, Mayo Clinic, Rochester, MN, USA
| | - Stephen J Pandol
- Department of Veterans Affairs, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Dhiraj Yadav
- Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh and UPMC Medical Center, Pittsburgh, PA, USA; Department of Medicine, University of Pittsburgh and UPMC Medical Center, Pittsburgh, PA, USA
| | - Suresh T Chari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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Saisho Y. Pancreas Volume and Fat Deposition in Diabetes and Normal Physiology: Consideration of the Interplay Between Endocrine and Exocrine Pancreas. Rev Diabet Stud 2016; 13:132-147. [PMID: 28012279 DOI: 10.1900/rds.2016.13.132] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The pancreas is comprised of exocrine and endocrine components. Despite the fact that they are derived from a common origin in utero, these two compartments are often studied individually because of the different roles and functions of the exocrine and endocrine pancreas. Recent studies have shown that not only type 1 diabetes (T1D), but also type 2 diabetes (T2D), is characterized by a deficit in beta-cell mass, suggesting that pathological changes in the pancreas are critical events in the natural history of diabetes. In both patients with T1D and those with T2D, pancreas mass and exocrine function have been reported to be reduced. On the other hand, pancreas volume and pancreatic fat increase with obesity. Increased beta-cell mass with increasing obesity has also been observed in humans, and ectopic fat deposits in the pancreas have been reported to cause beta-cell dysfunction. Moreover, neogenesis and transdifferentiation from the exocrine to the endocrine compartment in the postnatal period are regarded as a source of newly formed beta-cells. These findings suggest that there is important interplay between the endocrine and exocrine pancreas throughout life. This review summarizes the current knowledge on physiological and pathological changes in the exocrine and endocrine pancreas (i.e., beta-cell mass), and discusses the potential mechanisms of the interplay between the two compartments in humans to understand the pathophysiology of diabetes better.
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Affiliation(s)
- Yoshifumi Saisho
- Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
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Early pancreatic carcinogenesis - risk factors, early symptoms, and the impact of antidiabetic drugs. Eur J Gastroenterol Hepatol 2016; 28:e19-25. [PMID: 27120389 DOI: 10.1097/meg.0000000000000646] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Risk factors (long-term diabetes, obesity) and early symptoms (new-onset diabetes, loss of weight, or persistent low body mass) are the initial symptoms of pancreatic carcinogenesis. They may be influenced by antidiabetic drugs and their correct evaluation is a prerequisite for early diagnosis of pancreatic cancer (PC). We review the risk factors, early symptoms, and the impact of antidiabetic drugs on early pancreatic carcinogenesis. The main source of data was the database Medline/PubMed and abstracts of international congresses (DDW, UEGW). The risk factors and early symptoms are integral components of the familial PC surveillance and sporadic PC screening. Preventive programs should always be include multistep and multidisciplinary procedures. The correct evaluation of antidiabetic drugs and their interactions with other components of pancreatic carcinogenesis may influence the early diagnosis of PC.
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Inaishi J, Saisho Y, Sato S, Kou K, Murakami R, Watanabe Y, Kitago M, Kitagawa Y, Yamada T, Itoh H. Effects of Obesity and Diabetes on α- and β-Cell Mass in Surgically Resected Human Pancreas. J Clin Endocrinol Metab 2016; 101:2874-82. [PMID: 27070277 PMCID: PMC4929842 DOI: 10.1210/jc.2016-1374] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2016] [Accepted: 04/07/2016] [Indexed: 12/16/2022]
Abstract
CONTEXT The ethnic difference in β-cell regenerative capacity in response to obesity may be attributable to different phenotypes of type 2 diabetes among ethnicities. OBJECTIVE This study aimed to clarify the effects of diabetes and obesity on β- (BCM) and α-cell mass (ACM) in the Japanese population. DESIGN, SETTING, AND PARTICIPANTS We obtained the pancreases of 99 individuals who underwent pancreatic surgery and whose resected pancreas sample contained adequate normal pancreas for histological analysis. Questionnaires on a family history of diabetes and history of obesity were conducted in 59 patients. Pancreatic sections were stained for insulin or glucagon, and fractional β- and α-cell area were measured. Islet size and density as well as β-cell turnover were also quantified. RESULTS In patients with diabetes, BCM was decreased by 46% compared with age- and body mass index-matched nondiabetic patients (1.48% ± 1.08% vs 0.80% ± 0.54%, P < .001), whereas there was no difference in ACM between the groups. There was no effect of obesity or history of obesity on BCM and ACM irrespective of the presence or absence of diabetes. There was a negative correlation between BCM, but not ACM, and glycated hemoglobin before and after pancreatic surgery. In addition, reduced BCM was observed in patients with pancreatic cancer compared with those with other pancreatic tumors. CONCLUSIONS These findings suggest that the increase in BCM in the face of insulin resistance is extremely limited in the Japanese, and BCM rather than ACM has a major role in regulating blood glucose level in humans.
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Affiliation(s)
- Jun Inaishi
- Departments of Internal Medicine (J.I., Y.S., S.S., K.K., R.M., Y.W., H.I.), Surgery (M.K., Y.K.), and Pathology (T.Y.), Keio University School of Medicine, Tokyo 160-8582, Japan; and Department of Pathology (T.Y.), Saitama Medical University, Saitama 350-0495, Japan
| | - Yoshifumi Saisho
- Departments of Internal Medicine (J.I., Y.S., S.S., K.K., R.M., Y.W., H.I.), Surgery (M.K., Y.K.), and Pathology (T.Y.), Keio University School of Medicine, Tokyo 160-8582, Japan; and Department of Pathology (T.Y.), Saitama Medical University, Saitama 350-0495, Japan
| | - Seiji Sato
- Departments of Internal Medicine (J.I., Y.S., S.S., K.K., R.M., Y.W., H.I.), Surgery (M.K., Y.K.), and Pathology (T.Y.), Keio University School of Medicine, Tokyo 160-8582, Japan; and Department of Pathology (T.Y.), Saitama Medical University, Saitama 350-0495, Japan
| | - Kinsei Kou
- Departments of Internal Medicine (J.I., Y.S., S.S., K.K., R.M., Y.W., H.I.), Surgery (M.K., Y.K.), and Pathology (T.Y.), Keio University School of Medicine, Tokyo 160-8582, Japan; and Department of Pathology (T.Y.), Saitama Medical University, Saitama 350-0495, Japan
| | - Rie Murakami
- Departments of Internal Medicine (J.I., Y.S., S.S., K.K., R.M., Y.W., H.I.), Surgery (M.K., Y.K.), and Pathology (T.Y.), Keio University School of Medicine, Tokyo 160-8582, Japan; and Department of Pathology (T.Y.), Saitama Medical University, Saitama 350-0495, Japan
| | - Yuusuke Watanabe
- Departments of Internal Medicine (J.I., Y.S., S.S., K.K., R.M., Y.W., H.I.), Surgery (M.K., Y.K.), and Pathology (T.Y.), Keio University School of Medicine, Tokyo 160-8582, Japan; and Department of Pathology (T.Y.), Saitama Medical University, Saitama 350-0495, Japan
| | - Minoru Kitago
- Departments of Internal Medicine (J.I., Y.S., S.S., K.K., R.M., Y.W., H.I.), Surgery (M.K., Y.K.), and Pathology (T.Y.), Keio University School of Medicine, Tokyo 160-8582, Japan; and Department of Pathology (T.Y.), Saitama Medical University, Saitama 350-0495, Japan
| | - Yuko Kitagawa
- Departments of Internal Medicine (J.I., Y.S., S.S., K.K., R.M., Y.W., H.I.), Surgery (M.K., Y.K.), and Pathology (T.Y.), Keio University School of Medicine, Tokyo 160-8582, Japan; and Department of Pathology (T.Y.), Saitama Medical University, Saitama 350-0495, Japan
| | - Taketo Yamada
- Departments of Internal Medicine (J.I., Y.S., S.S., K.K., R.M., Y.W., H.I.), Surgery (M.K., Y.K.), and Pathology (T.Y.), Keio University School of Medicine, Tokyo 160-8582, Japan; and Department of Pathology (T.Y.), Saitama Medical University, Saitama 350-0495, Japan
| | - Hiroshi Itoh
- Departments of Internal Medicine (J.I., Y.S., S.S., K.K., R.M., Y.W., H.I.), Surgery (M.K., Y.K.), and Pathology (T.Y.), Keio University School of Medicine, Tokyo 160-8582, Japan; and Department of Pathology (T.Y.), Saitama Medical University, Saitama 350-0495, Japan
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Lee W, Yoon YS, Han HS, Cho JY, Choi Y, Jang JY, Choi H. Prognostic relevance of preoperative diabetes mellitus and the degree of hyperglycemia on the outcomes of resected pancreatic ductal adenocarcinoma. J Surg Oncol 2016; 113:203-8. [DOI: 10.1002/jso.24133] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2015] [Accepted: 11/30/2015] [Indexed: 01/17/2023]
Affiliation(s)
- Woohyung Lee
- Department of Surgery; Seoul National University Bundang Hospital; Seoul National University College of Medicine; Republic of Korea
| | - Yoo-Seok Yoon
- Department of Surgery; Seoul National University Bundang Hospital; Seoul National University College of Medicine; Republic of Korea
| | - Ho-Seong Han
- Department of Surgery; Seoul National University Bundang Hospital; Seoul National University College of Medicine; Republic of Korea
| | - Jai Young Cho
- Department of Surgery; Seoul National University Bundang Hospital; Seoul National University College of Medicine; Republic of Korea
| | - YoungRok Choi
- Department of Surgery; Seoul National University Bundang Hospital; Seoul National University College of Medicine; Republic of Korea
| | - Jae Yool Jang
- Department of Surgery; Seoul National University Bundang Hospital; Seoul National University College of Medicine; Republic of Korea
| | - Hanlim Choi
- Department of Surgery; Seoul National University Bundang Hospital; Seoul National University College of Medicine; Republic of Korea
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Javeed N, Sagar G, Dutta SK, Smyrk TC, Lau JS, Bhattacharya S, Truty M, Petersen GM, Kaufman RJ, Chari ST, Mukhopadhyay D. Pancreatic Cancer-Derived Exosomes Cause Paraneoplastic β-cell Dysfunction. Clin Cancer Res 2015; 21:1722-33. [PMID: 25355928 PMCID: PMC4383684 DOI: 10.1158/1078-0432.ccr-14-2022] [Citation(s) in RCA: 139] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Accepted: 10/11/2014] [Indexed: 12/14/2022]
Abstract
PURPOSE Pancreatic cancer frequently causes diabetes. We recently proposed adrenomedullin as a candidate mediator of pancreatic β-cell dysfunction in pancreatic cancer. How pancreatic cancer-derived adrenomedullin reaches β cells remote from the cancer to induce β-cell dysfunction is unknown. We tested a novel hypothesis that pancreatic cancer sheds adrenomedullin-containing exosomes into circulation, which are transported to β cells and impair insulin secretion. EXPERIMENTAL METHODS We characterized exosomes from conditioned media of pancreatic cancer cell lines (n = 5) and portal/peripheral venous blood of patients with pancreatic cancer (n = 20). Western blot analysis showed the presence of adrenomedullin in pancreatic cancer-exosomes. We determined the effect of adrenomedullin-containing pancreatic cancer exosomes on insulin secretion from INS-1 β cells and human islets, and demonstrated the mechanism of exosome internalization into β cells. We studied the interaction between β-cell adrenomedullin receptors and adrenomedullin present in pancreatic cancer-exosomes. In addition, the effect of adrenomedullin on endoplasmic reticulum (ER) stress response genes and reactive oxygen/nitrogen species generation in β cells was shown. RESULTS Exosomes were found to be the predominant extracellular vesicles secreted by pancreatic cancer into culture media and patient plasma. Pancreatic cancer-exosomes contained adrenomedullin and CA19-9, readily entered β cells through caveolin-mediated endocytosis or macropinocytosis, and inhibited insulin secretion. Adrenomedullin in pancreatic cancer exosomes interacted with its receptor on β cells. Adrenomedullin receptor blockade abrogated the inhibitory effect of exosomes on insulin secretion. β cells exposed to adrenomedullin or pancreatic cancer exosomes showed upregulation of ER stress genes and increased reactive oxygen/nitrogen species. CONCLUSIONS Pancreatic cancer causes paraneoplastic β-cell dysfunction by shedding adrenomedullin(+)/CA19-9(+) exosomes into circulation that inhibit insulin secretion, likely through adrenomedullin-induced ER stress and failure of the unfolded protein response.
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Affiliation(s)
- Naureen Javeed
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
| | - Gunisha Sagar
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
| | - Shamit K Dutta
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
| | - Thomas C Smyrk
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Julie S Lau
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
| | - Santanu Bhattacharya
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
| | - Mark Truty
- Department of Surgery, Mayo Clinic, Rochester, Minnesota
| | - Gloria M Petersen
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Randal J Kaufman
- Degenerative Disease Research Program, Sanford Burnham Medical Research Institute, La Jolla, California
| | - Suresh T Chari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
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Zhang C, Yang G, Ling Y, Chen G, Zhou T. The early diagnosis of pancreatic cancer and diabetes: what's the relationship? J Gastrointest Oncol 2014; 5:481-8. [PMID: 25436129 DOI: 10.3978/j.issn.2078-6891.2014.055] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2014] [Accepted: 07/20/2014] [Indexed: 12/20/2022] Open
Abstract
Pancreatic cancer (PC) has a dismal prognosis as cancer-specific symptoms occur only at an advanced stage. If the cancer is to be discovered early, it will have to be done in asymptomatic individuals. Since the incidence of PC is low, screening for asymptomatic cancer in the general population will not be feasible. Screening will have to be restricted to subjects at high risk for PC. The proportion of PC patients who also have hyperglycemia or diabetes has previously been under appreciated; new data show that up to 80% are either hyperglycemic or diabetic and this can be evident in the pre-symptomatic phase. Diabetes improves following PC resection suggesting that diabetes is caused by the cancer. Conversely, older subjects with new-onset diabetes have an approximately eight fold higher risk of having PC compared to the general population. Recognition of new-onset diabetes as an early manifestation of PC could lead to diagnosis of asymptomatic, early stage PC. However, primary type 2 diabetes is common and PC is relatively uncommon in the general population and the two forms of diabetes are clinically indistinguishable. The success of the strategy to use new-onset hyperglycemia and diabetes as a screening tool to identify subjects with a high likelihood of having asymptomatic PC will depend largely on our ability to differentiate PC-associated diabetes from the more common type 2 diabetes using a (serologic) biomarker.
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Affiliation(s)
- Changsong Zhang
- 1 Clinical Oncology Laboratory, Changzhou Cancer Hospital of Soochow University, Changzhou 213002, China ; 2 The Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, China ; 3 The Hepatic Surgery Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China ; 4 The Hepatobiliary Surgery Centre, The Ningbo No. 2 Hospital, Ningbo 315010, China
| | - Guangshun Yang
- 1 Clinical Oncology Laboratory, Changzhou Cancer Hospital of Soochow University, Changzhou 213002, China ; 2 The Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, China ; 3 The Hepatic Surgery Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China ; 4 The Hepatobiliary Surgery Centre, The Ningbo No. 2 Hospital, Ningbo 315010, China
| | - Yang Ling
- 1 Clinical Oncology Laboratory, Changzhou Cancer Hospital of Soochow University, Changzhou 213002, China ; 2 The Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, China ; 3 The Hepatic Surgery Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China ; 4 The Hepatobiliary Surgery Centre, The Ningbo No. 2 Hospital, Ningbo 315010, China
| | - Guihua Chen
- 1 Clinical Oncology Laboratory, Changzhou Cancer Hospital of Soochow University, Changzhou 213002, China ; 2 The Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, China ; 3 The Hepatic Surgery Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China ; 4 The Hepatobiliary Surgery Centre, The Ningbo No. 2 Hospital, Ningbo 315010, China
| | - Tianbao Zhou
- 1 Clinical Oncology Laboratory, Changzhou Cancer Hospital of Soochow University, Changzhou 213002, China ; 2 The Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai 200433, China ; 3 The Hepatic Surgery Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China ; 4 The Hepatobiliary Surgery Centre, The Ningbo No. 2 Hospital, Ningbo 315010, China
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Javeed N, Sagar G, Dutta SK, Smyrk TC, Lau JS, Bhattacharya S, Truty M, Petersen GM, Kaufman RJ, Chari ST, Mukhopadhyay D. Pancreatic Cancer-Derived Exosomes Cause Paraneoplastic β-cell Dysfunction. Clin Cancer Res 2014. [PMID: 25355928 DOI: 10.1158/1078-0432.ccr-14-2022.pancreatic] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
PURPOSE Pancreatic cancer frequently causes diabetes. We recently proposed adrenomedullin as a candidate mediator of pancreatic β-cell dysfunction in pancreatic cancer. How pancreatic cancer-derived adrenomedullin reaches β cells remote from the cancer to induce β-cell dysfunction is unknown. We tested a novel hypothesis that pancreatic cancer sheds adrenomedullin-containing exosomes into circulation, which are transported to β cells and impair insulin secretion. EXPERIMENTAL METHODS We characterized exosomes from conditioned media of pancreatic cancer cell lines (n = 5) and portal/peripheral venous blood of patients with pancreatic cancer (n = 20). Western blot analysis showed the presence of adrenomedullin in pancreatic cancer-exosomes. We determined the effect of adrenomedullin-containing pancreatic cancer exosomes on insulin secretion from INS-1 β cells and human islets, and demonstrated the mechanism of exosome internalization into β cells. We studied the interaction between β-cell adrenomedullin receptors and adrenomedullin present in pancreatic cancer-exosomes. In addition, the effect of adrenomedullin on endoplasmic reticulum (ER) stress response genes and reactive oxygen/nitrogen species generation in β cells was shown. RESULTS Exosomes were found to be the predominant extracellular vesicles secreted by pancreatic cancer into culture media and patient plasma. Pancreatic cancer-exosomes contained adrenomedullin and CA19-9, readily entered β cells through caveolin-mediated endocytosis or macropinocytosis, and inhibited insulin secretion. Adrenomedullin in pancreatic cancer exosomes interacted with its receptor on β cells. Adrenomedullin receptor blockade abrogated the inhibitory effect of exosomes on insulin secretion. β cells exposed to adrenomedullin or pancreatic cancer exosomes showed upregulation of ER stress genes and increased reactive oxygen/nitrogen species. CONCLUSIONS Pancreatic cancer causes paraneoplastic β-cell dysfunction by shedding adrenomedullin(+)/CA19-9(+) exosomes into circulation that inhibit insulin secretion, likely through adrenomedullin-induced ER stress and failure of the unfolded protein response.
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Affiliation(s)
- Naureen Javeed
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
| | - Gunisha Sagar
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
| | - Shamit K Dutta
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
| | - Thomas C Smyrk
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Julie S Lau
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
| | - Santanu Bhattacharya
- Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
| | - Mark Truty
- Department of Surgery, Mayo Clinic, Rochester, Minnesota
| | - Gloria M Petersen
- Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Randal J Kaufman
- Degenerative Disease Research Program, Sanford Burnham Medical Research Institute, La Jolla, California
| | - Suresh T Chari
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
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Wolpin BM, Bao Y, Qian ZR, Wu C, Kraft P, Ogino S, Stampfer MJ, Sato K, Ma J, Buring JE, Sesso HD, Lee IM, Gaziano JM, McTiernan A, Phillips LS, Cochrane BB, Pollak MN, Manson JE, Giovannucci EL, Fuchs CS. Hyperglycemia, insulin resistance, impaired pancreatic β-cell function, and risk of pancreatic cancer. J Natl Cancer Inst 2013; 105:1027-35. [PMID: 23847240 DOI: 10.1093/jnci/djt123] [Citation(s) in RCA: 131] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Obesity and diabetes mellitus are associated with an increased risk of pancreatic cancer. These associations may be secondary to consequences of peripheral insulin resistance, pancreatic β-cell dysfunction, or hyperglycemia itself. Hemoglobin A1c (HbA1c) is a measure of hyperglycemia, whereas plasma insulin and proinsulin are markers of peripheral insulin resistance, and the proinsulin to insulin ratio marks pancreatic β-cell dysfunction. METHODS This was a prospective, nested case-control study of 449 case patients and 982 control subjects with prediagnostic blood samples and no diabetes history from five prospective US cohorts followed through 2008. Two or three control subjects were matched to each case patient by year of birth, cohort, smoking, and fasting status. Pancreatic cancer risk was assessed by prediagnostic HbA1c, insulin, proinsulin, and proinsulin to insulin ratio with multivariable-adjusted logistic regression. All P values were two-sided. RESULTS The highest vs lowest quintiles of HbA1c, insulin, and proinsulin were associated with with an increased risk for pancreatic cancer (odds ratio [OR] = 1.79; 95% confidence interval [CI] = 1.17 to 2.72, P trend = .04 for HbA1c; OR = 1.57; 95% CI = 1.08 to 2.30; Ptrend = .002 for insulin; and OR = 2.22; 95% CI = 1.50 to 3.29; P trend < .001 for proinsulin). Proinsulin to insulin ratio was not associated with pancreatic cancer risk. Results were similar across studies (all P heterogeneity > .29). In cancers developing 10 or more years after blood collection, the associations with insulin and proinsulin became stronger (highest vs lowest quintile, OR = 2.77; 95% CI = 1.28 to 5.99 for insulin and OR = 3.60; 95% CI = 1.68 to 7.72 for proinsulin). In mutually adjusted models including HbA1c, insulin, and proinsulin, only proinsulin remained statistically significant ( highest vs lowest quintile, OR = 2.55; 95% CI = 1.54 to 4.21; Ptrend < .001). CONCLUSIONS Among participants from five large prospective cohorts, circulating markers of peripheral insulin resistance, rather than hyperglycemia or pancreatic β-cell dysfunction, were independently associated with pancreatic cancer risk.
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Affiliation(s)
- Brian M Wolpin
- Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02215, USA.
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Abstract
Up to 85% of patients with pancreatic cancer have diabetes or hyperglycaemia, which frequently manifests as early as 2-3 years before a diagnosis of pancreatic cancer. Conversely, patients with new-onset diabetes have a 5-8-fold increased risk of being diagnosed with pancreatic cancer within 1-3 years of developing diabetes. Emerging evidence now indicates that pancreatic cancer causes diabetes. As in type 2 diabetes, β-cell dysfunction and peripheral insulin resistance are seen in pancreatic cancer-induced diabetes. However, unlike in patients with type 2 diabetes, glucose control worsens in patients with pancreatic cancer in the face of ongoing, often profound, weight loss. Diabetes and weight loss, which precede cachexia onset by several months, are paraneoplastic phenomena induced by pancreatic cancer. Although the pathogenesis of these pancreatic cancer-induced metabolic alterations is only beginning to be understood, these are likely mechanisms to promote the survival and growth of pancreatic cancer in a hostile and highly desmoplastic microenvironment. Interestingly, these metabolic changes could enable early diagnosis of pancreatic cancer, if they can be distinguished from the ones that occur in patients with type 2 diabetes. One such possible biomarker is adrenomedullin, which is a potential mediator of β-cell dysfunction in pancreatic cancer-induced diabetes.
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Muniraj T, Chari ST. Diabetes and pancreatic cancer. MINERVA GASTROENTERO 2013; 15:118-20. [PMID: 23207610 PMCID: PMC3932318 DOI: 10.6092/1590-8577/2286] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2014] [Accepted: 02/02/2014] [Indexed: 12/29/2022]
Abstract
The relationship between diabetes and pancreatic cancer is complex. Diabetes or impaired glucose tolerance is present in more than 2/3rd of pancreatic cancer patients. Epidemiological studies have consistently shown a modest increase in the risk of pancreatic cancer in type 2 diabetes, with an inverse relationship to duration of disease. Additionally, recent studies suggest that anti-diabetic medications may modulate the risk of pancreatic cancer in type 2 diabetes. Subjects >50 years of age with new onset diabetes are at higher risk of having pancreatic cancer. However, to screen new-onset diabetes for pancreatic cancer, additional markers are needed that can distinguish pancreatic cancer-associated diabetes from type 2 diabetes.
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Affiliation(s)
- T Muniraj
- Yale University School of Medicine, New Haven, CT, USA
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Abstract
Tumorigenesis of pancreatic cancer (PC) and the pathophysiology of type 2 diabetes mellitus (DM2) are emerging as intertwined pathways. As the operative morbidity and mortality of pancreatectomy has improved, incidence has increased and survival has remained mostly unchanged. The diagnosis of DM2 suggests pancreatic dysfunction and possible early carcinogenesis. DM2 is a significant comorbidity predicting worse outcomes in patients undergoing pancreatic resection as part of the treatment of PC. This article examines this phenomena and suggests possible approaches to screening and diagnosis.
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Affiliation(s)
- John C McAuliffe
- Department of Surgery, The Kirklin Clinic, UAB Medical Center, 1802 6th Avenue South, Birmingham, AL 35294, USA
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Correlation between blood activin levels and clinical parameters of type 2 diabetes. EXPERIMENTAL DIABETES RESEARCH 2012; 2012:410579. [PMID: 23304117 PMCID: PMC3533484 DOI: 10.1155/2012/410579] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/26/2012] [Accepted: 11/15/2012] [Indexed: 12/18/2022]
Abstract
Aims. Activins A and B, and their binding protein, follistatin, regulate glucose metabolism and inflammation. Consequently, their role in type 2 diabetes (T2D) was examined. Methods. Blood was taken from fasted participants (34 males; 58 females; 50–75 years) with diabetes or during an oral glucose tolerance test (OGTT). Clinical parameters were assessed, and blood assayed for activins, follistatin, and C-reactive protein. Results. Serum levels of activin A (93.3 ± 27.0 pg/mL, mean ± SD), B (81.8 ± 30.8 pg/mL), or follistatin (6.52 ± 3.15 ng/mL) were not different (P > 0.05) between subjects with normal OGTT (n = 39), impaired glucose tolerance and/or fasting glucose (n = 17), or T2D (n = 36). However, activin A and/or activin B were positively correlated with parameters of insulin resistance and T2D, including fasting glucose (P < 0.001), fasting insulin (P = 0.02), glycated hemoglobin (P = 0.003), and homeostasis model assessment of insulin resistance (HOMA-IR; P < 0.001). Follistatin was positively correlated with HOMA-IR alone (P = 0.01). Conclusions. These data indicate that serum measurements of activin A, B, or follistatin cannot discriminate risk for T2D in individual patients, but the activins display a positive relationship with clinical parameters of the disease.
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Aggarwal G, Ramachandran V, Javeed N, Arumugam T, Dutta S, Klee GG, Klee EW, Smyrk TC, Bamlet W, Han JJ, Rumie Vittar NB, De Andrade M, Mukhopadhyay D, Petersen GM, Fernandez-Zapico ME, Logsdon CD, Chari ST. Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in β cells and mice. Gastroenterology 2012; 143:1510-1517.e1. [PMID: 22960655 PMCID: PMC3787599 DOI: 10.1053/j.gastro.2012.08.044] [Citation(s) in RCA: 124] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2011] [Revised: 08/14/2012] [Accepted: 08/30/2012] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS New-onset diabetes in patients with pancreatic cancer is likely to be a paraneoplastic phenomenon caused by tumor-secreted products. We aimed to identify the diabetogenic secretory product(s) of pancreatic cancer. METHODS Using microarray analysis, we identified adrenomedullin as a potential mediator of diabetes in patients with pancreatic cancer. Adrenomedullin was up-regulated in pancreatic cancer cell lines, in which supernatants reduced insulin signaling in beta cell lines. We performed quantitative reverse-transcriptase polymerase chain reaction and immunohistochemistry on human pancreatic cancer and healthy pancreatic tissues (controls) to determine expression of adrenomedullin messenger RNA and protein, respectively. We studied the effects of adrenomedullin on insulin secretion by beta cell lines and whole islets from mice and on glucose tolerance in pancreatic xenografts in mice. We measured plasma levels of adrenomedullin in patients with pancreatic cancer, patients with type 2 diabetes mellitus, and individuals with normal fasting glucose levels (controls). RESULTS Levels of adrenomedullin messenger RNA and protein were increased in human pancreatic cancer samples compared with controls. Adrenomedullin and conditioned media from pancreatic cell lines inhibited glucose-stimulated insulin secretion from beta cell lines and islets isolated from mice; the effects of conditioned media from pancreatic cancer cells were reduced by small hairpin RNA-mediated knockdown of adrenomedullin. Conversely, overexpression of adrenomedullin in mice with pancreatic cancer led to glucose intolerance. Mean plasma levels of adrenomedullin (femtomoles per liter) were higher in patients with pancreatic cancer compared with patients with diabetes or controls. Levels of adrenomedullin were higher in patients with pancreatic cancer who developed diabetes compared those who did not. CONCLUSIONS Adrenomedullin is up-regulated in patients with pancreatic cancer and causes insulin resistance in β cells and mice.
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Affiliation(s)
- Gaurav Aggarwal
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota
| | | | - Naureen Javeed
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota
| | | | - Shamit Dutta
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - George G. Klee
- Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Eric W. Klee
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Thomas C. Smyrk
- Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - William Bamlet
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Jing Jing Han
- Schulze Center for Novel Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Natalia B. Rumie Vittar
- Schulze Center for Novel Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Mariza De Andrade
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Debabrata Mukhopadhyay
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Gloria M. Petersen
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Martin E. Fernandez-Zapico
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota
- Schulze Center for Novel Therapeutics, Mayo Clinic College of Medicine, Rochester, Minnesota
| | - Craig D. Logsdon
- Department of Cancer Biology, UT MD Anderson Cancer Center, Houston, Texas
| | - Suresh T. Chari
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, Minnesota
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Abstract
Epidemiological studies clearly indicate that the risk of pancreatic cancer (PC) is increased in diabetic patients, but most studies focus on overall diabetes or type 2 diabetes mellitus (T2DM), and there are few studies on the risks of type 1 and type 3c (secondary) diabetes. Possible mechanisms for increased cancer risk in diabetes include cellular proliferative effects of hyperglycemia, hyperinsulinemia, and abnormalities in insulin/IGF receptor pathways. Recently, insulin and insulin secretagogues have been observed to increase the PC risk, while metformin treatment reduces the cancer risk in diabetic subjects. In addition, anticancer drugs used to treat PC may either cause diabetes or worsen coexisting diabetes. T3cDM has emerged as a major subset of diabetes and may have the highest risk of pancreatic carcinoma especially in patients with chronic pancreatitis. T3cDM is also a consequence of PC in at least 30% of patients. Distinguishing T3cDM from the more prevalent T2DM among new-onset diabetic patients can be aided by an assessment of clinical features and confirmed by finding a deficiency in postprandial pancreatic polypeptide release. In conclusion, diabetes and PC have a complex relationship that requires more clinical attention. The risk of developing PC can be reduced by aggressive prevention and treatment of T2DM and obesity and the prompt diagnosis of T3cDM may allow detection of a tumor at a potentially curable stage.
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Affiliation(s)
- YunFeng Cui
- Department of Surgery, Johns Hopkins Bayview Medical Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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Li J, Cao G, Ma Q, Liu H, Li W, Han L. The bidirectional interation between pancreatic cancer and diabetes. World J Surg Oncol 2012; 10:171. [PMID: 22920886 PMCID: PMC3499274 DOI: 10.1186/1477-7819-10-171] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2012] [Accepted: 08/11/2012] [Indexed: 12/15/2022] Open
Abstract
The bidirectional interation between pancreatic cancer (PanCa) and diabetes has been confirmed by epidemiological studies, which provide evidence-based medical support for further research into the mechanisms involved in the interaction. We reviewed the literature regarding the role of diabetes in the generation and progression of PanCa and the mechanism by which PanCa induces diabetes for its malignant progression. The effect of antidiabetic drugs on the occurrence and prognosis of PanCa was also reviewed. Diabetes may directly promote the progression of PanCa by pancreatic duct enlargement and hypertension, as well as by enabling an increased tumor volume. Hyperinsulinemia, insulin resistance, cytokines, hyperglycemia and genotype change are also important factors in the progression of PanCa with diabetes. Hyperglycemia may be the first clinical manifestation and is helpful in the early diagnosis of PanCa. Furthermore, antidiabetic drugs can have different effects on the occurrence and prognosis of PanCa. The bidirectional interation between PanCa and diabetes is involved in the occurrence, proliferation, invasion, metastasis and prognosis of PanCa with diabetes. The discovery of biomarkers for the early diagnosis of PanCa, as well as the novel usage of metformin for its antitumor effects and determining the potential mechanisms of these effects, may be the next direction for PanCa research and treatment.
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Affiliation(s)
- Junhui Li
- Department of General Surgery, Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, 157 West 5th Road, Xi'an 710004, People's Republic of China
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Early diagnosis of pancreatic adenocarcinoma: role of stroma, surface proteases, and glucose-homeostatic agents. Pancreas 2012; 41:663-70. [PMID: 22695086 DOI: 10.1097/mpa.0b013e31823b5827] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES New-onset diabetes in pancreatic adenocarcinoma is due to a combination of insulin resistance and decreased β-cell function. Its differentiation from the common type 2 diabetes is the prerequisite for early diagnosis of pancreatic adenocarcinoma. Little attention has been paid to pancreatic stroma and surface proteases. METHODS The activated fibroblasts selectively express fibroblast activation protein α, a structural homolog of the ubiquitously expressed dipeptidyl peptidase 4. Their role in pancreatic carcinogenesis is reviewed. RESULTS Homodimers and heterodimers of both enzymes display high specificity for peptides and proteins with penultimate proline or alanine. Most glucose-homeostatic agents are candidate substrates of these enzymes. The biological activity of truncated substrates is decreased or absent. CONCLUSIONS The interactions of surface proteases with glucose-homeostatic agents may adequately explain the evolution of diabetes associated with pancreatic adenocarcinoma and differentiate it from the common type 2 diabetes.
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Basso D, Greco E, Padoan A, Fogar P, Scorzeto M, Fadi E, Bozzato D, Moz S, Navaglia F, Zambon CF, Seraglia R, De Carlo E, Valerio A, Reggiani C, Pedrazzoli S, Plebani M. Altered intracellular calcium fluxes in pancreatic cancer induced diabetes mellitus: Relevance of the S100A8 N-terminal peptide (NT-S100A8). J Cell Physiol 2010; 226:456-68. [DOI: 10.1002/jcp.22355] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Gong Z, Holly EA, Wang F, Chan JM, Bracci PM. Intake of fatty acids and antioxidants and pancreatic cancer in a large population-based case-control study in the San Francisco Bay Area. Int J Cancer 2010; 127:1893-904. [PMID: 20104522 PMCID: PMC2930138 DOI: 10.1002/ijc.25208] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
There are no well-established modifiable risk factors for pancreatic cancer except smoking. Some dietary factors have been associated with pancreatic cancer risk and require further study. We examined the associations among intake of specific fatty acids and antioxidants and risk of pancreatic cancer in a large population-based case-control study in the San Francisco Bay Area. Unconditional logistic regression models were used to compute odds ratios (ORs) and 95% confidence intervals (CI) as estimates of relative risk. Positive associations were observed for high levels of the 8 individual saturated fatty acids (4th vs. 1st quartile: ORs ranged from 1.6 to 2.6; all p(trend) < 0.01), monounsaturated palmitoleic and oleic fatty acids [OR = 1.6 (95% CI: 1.2-2.1) and 1.4 (95% CI: 1.1-1.9); both p(trend) < 0.01], and polyunsaturated linolenic acid [OR = 1.5 (95% CI: 1.1-2.0); p(trend) = 0.02]. Inverse associations were observed for high levels of gadolic acid [4th vs. 1st quartile: OR = 0.68 (95% CI: 0.50-0.92); p(trend) = 0.007] and omega-3 fatty acids [>or=0.85 g/day vs. 1st quartile: OR = 0.47 (95% CI: 0.25-0.90)]. An inverse association was also observed for high total intake of vitamin C [4th vs. 1st quartile: OR = 0.69 (95% CI: 0.51-0.94); p(trend) = 0.004] and of vitamin E [OR = 0.67 (95% CI: 0.49-0.92); p(trend) = 0.01]. Although similar decreased risks were also observed for high supplemental intake of these 2 vitamins (both p(trend) < 0.01), no association was observed for intake from food alone. These results support the hypotheses that a high intake of saturated and certain monounsaturated fatty acids may increase the risk of pancreatic cancer, whereas greater intake of omega-3 fatty acids, vitamins C and E may reduce the risk.
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Affiliation(s)
- Zhihong Gong
- Department of Epidemiology and Biostatistics, School of Medicine, University of California San Francisco, San Francisco, CA
| | - Elizabeth A. Holly
- Department of Epidemiology and Biostatistics, School of Medicine, University of California San Francisco, San Francisco, CA
- Department of Health Research and Policy, School of Medicine, Stanford University, Stanford, CA
| | - Furong Wang
- Department of Epidemiology and Biostatistics, School of Medicine, University of California San Francisco, San Francisco, CA
| | - June M. Chan
- Department of Epidemiology and Biostatistics, School of Medicine, University of California San Francisco, San Francisco, CA
- Department of Urology, School of Medicine, University of California San Francisco, San Francisco, CA
| | - Paige M. Bracci
- Department of Epidemiology and Biostatistics, School of Medicine, University of California San Francisco, San Francisco, CA
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