|
1
|
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.
Collapse
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
| |
Collapse
|
|
2
|
Meziani J, de Jong JGY, Fuhler GM, Koopmann BDM, Levink IJM, Fockens P, Vleggaar FP, Bruno MJ, Cahen DL. Assessment of Glucose and HbA1c Monitoring in a Pancreatic Cancer Surveillance Program for High-Risk Individuals. Clin Transl Gastroenterol 2024; 15:e00777. [PMID: 39413349 DOI: 10.14309/ctg.0000000000000777] [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] [Received: 04/11/2024] [Accepted: 10/01/2024] [Indexed: 10/18/2024] Open
Abstract
INTRODUCTION Several studies suggest that new-onset diabetes mellitus is an early manifestation of pancreatic ductal adenocarcinoma (PDAC). Therefore, the International Cancer of the Pancreas Screening Consortium recommends glucose and hemoglobin A1c (HbA1c) monitoring in high-risk individuals (HRIs) undergoing surveillance. However, evidence that such monitoring improves PDAC detection is lacking. Our aim was to investigate the association between serum glucose and HbA1c values and the development of PDAC in HRIs undergoing surveillance. METHODS Participants were recruited from the familial pancreatic cancer surveillance cohort, which follows hereditary predisposed HRIs yearly by magnetic resonance imaging and/or endoscopic ultrasound and blood sampling. Those who underwent fasting glucose and/or HbA1c monitoring at least once were eligible candidates. RESULTS Four hundred four HRIs met the inclusion criteria. During a median follow-up of 41 months (range 14-120), 9 individuals developed PDAC and 4 (without PDAC) were diagnosed with new-onset diabetes mellitus. Glucose levels ranged from 3.4 to 10.7 mmol/L (mean 5.6 ± 0.7) and HbA1c levels from 25 to 68 mmol/mol (mean 37.7 ± 4.1). The mean values did not differ significantly between PDAC cases and controls. The percentage of individuals with at least one elevated value were comparable between PDAC cases and controls for glucose (33% and 27%, P = 0.707) and HbA1c (22% and 14%, P = 0.623). No consistent glucose or HbA1c trends over time suggested a correlation with PDAC development. DISCUSSION In this HRI surveillance cohort, measuring glucose and HbA1c values did not contribute to PDAC detection. Larger and longer-term studies are needed to determine the final role of glucose and HbA1c monitoring in PDAC surveillance.
Collapse
Affiliation(s)
- Jihane Meziani
- Department of Gastroenterology & Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Jedidja G Y de Jong
- Department of Gastroenterology & Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Gwenny M Fuhler
- Department of Gastroenterology & Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Brechtje D M Koopmann
- Department of Gastroenterology & Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Iris J M Levink
- Department of Gastroenterology & Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Paul Fockens
- Department of Gastroenterology & Hepatology, Amsterdam University Medical Center, Amsterdam, the Netherlands
| | - Frank P Vleggaar
- Department of Gastroenterology & Hepatology, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Marco J Bruno
- Department of Gastroenterology & Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Djuna L Cahen
- Department of Gastroenterology & Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| |
Collapse
|
|
3
|
Gong J, Li X, Feng Z, Lou J, Pu K, Sun Y, Hu S, Zhou Y, Song T, Shangguan M, Zhang K, Lu W, Dong X, Wu J, Zhu H, He Q, Xu H, Wu Y. Sorcin can trigger pancreatic cancer-associated new-onset diabetes through the secretion of inflammatory cytokines such as serpin E1 and CCL5. Exp Mol Med 2024; 56:2535-2547. [PMID: 39516378 PMCID: PMC11612510 DOI: 10.1038/s12276-024-01346-4] [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: 11/18/2023] [Revised: 07/28/2024] [Accepted: 08/19/2024] [Indexed: 11/16/2024] Open
Abstract
A rise in blood glucose is an early warning sign of underlying pancreatic cancer (PC) and may be an indicator of genetic events in PC progression. However, there is still a lack of mechanistic research on pancreatic cancer-associated new-onset diabetes (PCAND). In the present study, we identified a gene SRI, which possesses a SNP with the potential to distinguish PCAND and Type 2 diabetes mellitus (T2DM), by machine learning on the basis of the UK Biobank database. In vitro and in vivo, sorcin overexpression induced pancreatic β-cell dysfunction. Sorcin can form a positive feedback loop with STAT3 to increase the transcription of serpin E1 and CCL5, which may directly induce β-cell dysfunction. In 88 biopsies, the expression of sorcin was elevated in PC tissues, especially in PCAND samples. Furthermore, plasma serpin E1 levels are higher in peripheral blood samples from PCAND patients than in those from T2DM patients. In conclusion, sorcin may be the key driver in PCAND, and further study on the sorcin-STAT3-serpin E1/CCL5 signaling axis may help us better understand the pathogenesis of PCAND and identify potential biomarkers.
Collapse
Affiliation(s)
- Jiali Gong
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
- Department of Surgery, Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China
| | - Xiawei Li
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
- Harvard T.H. Chan School of Public Health, Harvard University, Boston, MA, USA
| | - Zengyu Feng
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jianyao Lou
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Kaiyue Pu
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Yongji Sun
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
- Department of Surgery, Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China
| | - Sien Hu
- Department of Surgery, Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China
| | - Yizhao Zhou
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Tianyu Song
- Department of Surgery, Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China
| | - Meihua Shangguan
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Kai Zhang
- School of Public Health and Eye Center The Second Affiliated Hospital, Zhejiang University, Hangzhou, China
| | - Wenjie Lu
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Xin Dong
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China
| | - Jian Wu
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- School of Public Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Institute of Wenzhou, Zhejiang University, Wenzhou, Zhejiang, China
| | - Hong Zhu
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China
- Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou, Zhejiang, China
| | - Qiaojun He
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China.
- Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou, Zhejiang, China.
| | - Hongxia Xu
- Innovation Institute for Artificial Intelligence in Medicine and Liangzhu Laboratory, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
| | - Yulian Wu
- Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
- Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
- Cancer Center, Zhejiang University, Hangzhou, Zhejiang, China.
- Department of Surgery, Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, Zhejiang, China.
| |
Collapse
|
|
4
|
Ren P, Yu X, Tang Q, Huan Y, Xu J, Wang Y, Xue C. Astaxanthin Supplementation Assists Sorafenib in Slowing Skeletal Muscle Atrophy in H22 Tumor-Bearing Mice via Reversing Abnormal Glucose Metabolism. Mol Nutr Food Res 2023; 67:e2300076. [PMID: 37177891 DOI: 10.1002/mnfr.202300076] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 04/05/2023] [Indexed: 05/15/2023]
Abstract
SCOPE Cachexia, which is often marked by skeletal muscular atrophy, is one of the leading causes of death in cancer patients. Astaxanthin, a carotenoid obtained from marine organisms that can aid in the prevention and treatment of a variety of disorders. In this study, to assess whether astaxanthin ameliorates weight loss and skeletal muscle atrophy in sorafenib-treated hepatocellular carcinoma mice is aimed. METHODS AND RESULTS H22 mice are treated with 30 mg kg-1 day-1 of sorafenib and 60 mg kg-1 day-1 of astaxanthin by gavage lasted for 18 days. Sorafenib does not delay skeletal muscle atrophy and weight loss, although it does not reduce tumor burden. Astaxanthin dramatically delays weight loss and skeletal muscle atrophy in sorafenib-treating mice, without affecting the food intake. Astaxanthin inhibits the tumor glycolysis, slows down gluconeogenesis, and improves insulin resistance in tumor-bearing mice. Astaxanthin increases glucose competition in skeletal muscle by targeting the PI3K/Akt/GLUT4 signaling pathway, and enhances glucose utilization efficiency in skeletal muscle, thereby slowing skeletal muscle atrophy. CONCLUSION The findings show the significant potential of astaxanthin as nutritional supplements for cancer patients, as well as the notion that nutritional interventions should be implemented at the initiation of cancer treatment, as instead of waiting until cachexia sets in.
Collapse
Affiliation(s)
- Pengfei Ren
- Laboratory of Food Science and Human Health, College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong, 266003, China
| | - Xinyue Yu
- Laboratory of Food Science and Human Health, College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong, 266003, China
| | - Qingjuan Tang
- Laboratory of Food Science and Human Health, College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong, 266003, China
| | - Yuchen Huan
- Laboratory of Food Science and Human Health, College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong, 266003, China
| | - Jie Xu
- Laboratory of Food Science and Human Health, College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong, 266003, China
| | - Yuming Wang
- Laboratory of Food Science and Human Health, College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong, 266003, China
- Laboratory of Marine Drugs and Biological Products, Pilot National Laboratory for Marine Science and Technology, Qingdao, Shandong, 266235, China
| | - Changhu Xue
- Laboratory of Food Science and Human Health, College of Food Science and Engineering, Ocean University of China, Qingdao, Shandong, 266003, China
- Laboratory of Marine Drugs and Biological Products, Pilot National Laboratory for Marine Science and Technology, Qingdao, Shandong, 266235, China
| |
Collapse
|
|
5
|
Balaban DV, Coman L, Balaban M, Zoican A, Pușcașu DA, Ayatollahi S, Mihălțeanu E, Costache RS, Ioniță-Radu F, Jinga M. Glycemic Abnormalities in Pancreatic Cystic Lesions—A Single-Center Retrospective Analysis. GASTROENTEROLOGY INSIGHTS 2023; 14:191-203. [DOI: doi.org/10.3390/gastroent14020015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/02/2023] Open
Abstract
Background and Objectives: Glucose metabolism alterations are very common in solid pancreatic lesions, particularly in pancreatic cancer. Similarly, diabetes and especially new-onset diabetes (NOD) have been associated with the malignant transformation of pancreatic cysts. We aimed to assess the prevalence and relevant associations of glycemic abnormalities in pancreatic cystic lesions (PCLs) in a retrospective analysis. Materials and Methods: We retrospectively recruited all patients who underwent endoscopic ultrasound for a PCL over a period of 36 months (January 2018 to December 2021). Final diagnosis was set by means of tissue acquisition, surgery, follow-up, or board decision. Demographic and clinical data, laboratory workup, and imaging features were extracted from the patients’ charts according to a predefined protocol. We considered fasting blood glucose (FBG) and HbA1c values and stratified the patients as nondiabetic (FBG ≤ 99 mg/dL, HbA1c ≤ 5.6%, no history of glycemic abnormalities), prediabetic (FBG 100–125 mg/dL, HbA1c 5.7–6.4%), or diabetic (long-lasting diabetes or NOD). Results: Altogether, 81 patients were included, with a median age of 66 years, and 54.3% of them were male. The overall prevalence of fasting hyperglycemia was 54.3%, comprising 34.6% prediabetes and 22.2% diabetes, of which 16.7% had NOD. The mean FBG and HbA1c levels were higher in malignant and premalignant PCLs (intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm (MCN), cystadenocarcinoma, and cystic neuroendocrine tumor) compared to the benign lesions (pseudocysts, walled-off necrosis, and serous cystadenoma): 117.0 mg/dL vs. 108.3 mg/dL and 6.1% vs. 5.5%, respectively. Conclusions: Hyperglycemia and diabetes are common in PCLs, with a high prevalence in premalignant and malignant cysts. Screening and follow-up for glycemic abnormalities should be routinely conducted for PCLs, as they can contribute to a tailored risk assessment of cysts.
Collapse
Affiliation(s)
- Daniel Vasile Balaban
- Internal Medicine and Gastroenterology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Gastroenterology Department, Central Military Emergency University Hospital, 010825 Bucharest, Romania
| | - Laura Coman
- Internal Medicine and Gastroenterology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Gastroenterology Department, Central Military Emergency University Hospital, 010825 Bucharest, Romania
| | - Marina Balaban
- Internal Medicine and Gastroenterology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Gastroenterology Department, Central Military Emergency University Hospital, 010825 Bucharest, Romania
| | - Andreea Zoican
- Internal Medicine and Gastroenterology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Gastroenterology Department, Central Military Emergency University Hospital, 010825 Bucharest, Romania
| | - Danusia Adriana Pușcașu
- Internal Medicine and Gastroenterology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Simin Ayatollahi
- Internal Medicine and Gastroenterology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Emanuela Mihălțeanu
- Internal Medicine and Gastroenterology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Raluca Simona Costache
- Internal Medicine and Gastroenterology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Gastroenterology Department, Central Military Emergency University Hospital, 010825 Bucharest, Romania
| | - Florentina Ioniță-Radu
- Internal Medicine and Gastroenterology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Gastroenterology Department, Central Military Emergency University Hospital, 010825 Bucharest, Romania
| | - Mariana Jinga
- Internal Medicine and Gastroenterology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Gastroenterology Department, Central Military Emergency University Hospital, 010825 Bucharest, Romania
| |
Collapse
|
|
6
|
Balaban DV, Coman L, Balaban M, Zoican A, Pușcașu DA, Ayatollahi S, Mihălțeanu E, Costache RS, Ioniță-Radu F, Jinga M. Glycemic Abnormalities in Pancreatic Cystic Lesions—A Single-Center Retrospective Analysis. GASTROENTEROLOGY INSIGHTS 2023; 14:191-203. [DOI: 10.3390/gastroent14020015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Background and Objectives: Glucose metabolism alterations are very common in solid pancreatic lesions, particularly in pancreatic cancer. Similarly, diabetes and especially new-onset diabetes (NOD) have been associated with the malignant transformation of pancreatic cysts. We aimed to assess the prevalence and relevant associations of glycemic abnormalities in pancreatic cystic lesions (PCLs) in a retrospective analysis. Materials and Methods: We retrospectively recruited all patients who underwent endoscopic ultrasound for a PCL over a period of 36 months (January 2018 to December 2021). Final diagnosis was set by means of tissue acquisition, surgery, follow-up, or board decision. Demographic and clinical data, laboratory workup, and imaging features were extracted from the patients’ charts according to a predefined protocol. We considered fasting blood glucose (FBG) and HbA1c values and stratified the patients as nondiabetic (FBG ≤ 99 mg/dL, HbA1c ≤ 5.6%, no history of glycemic abnormalities), prediabetic (FBG 100–125 mg/dL, HbA1c 5.7–6.4%), or diabetic (long-lasting diabetes or NOD). Results: Altogether, 81 patients were included, with a median age of 66 years, and 54.3% of them were male. The overall prevalence of fasting hyperglycemia was 54.3%, comprising 34.6% prediabetes and 22.2% diabetes, of which 16.7% had NOD. The mean FBG and HbA1c levels were higher in malignant and premalignant PCLs (intraductal papillary mucinous neoplasm (IPMN), mucinous cystic neoplasm (MCN), cystadenocarcinoma, and cystic neuroendocrine tumor) compared to the benign lesions (pseudocysts, walled-off necrosis, and serous cystadenoma): 117.0 mg/dL vs. 108.3 mg/dL and 6.1% vs. 5.5%, respectively. Conclusions: Hyperglycemia and diabetes are common in PCLs, with a high prevalence in premalignant and malignant cysts. Screening and follow-up for glycemic abnormalities should be routinely conducted for PCLs, as they can contribute to a tailored risk assessment of cysts.
Collapse
Affiliation(s)
- Daniel Vasile Balaban
- Internal Medicine and Gastroenterology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Gastroenterology Department, Central Military Emergency University Hospital, 010825 Bucharest, Romania
| | - Laura Coman
- Internal Medicine and Gastroenterology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Gastroenterology Department, Central Military Emergency University Hospital, 010825 Bucharest, Romania
| | - Marina Balaban
- Internal Medicine and Gastroenterology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Gastroenterology Department, Central Military Emergency University Hospital, 010825 Bucharest, Romania
| | - Andreea Zoican
- Internal Medicine and Gastroenterology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Gastroenterology Department, Central Military Emergency University Hospital, 010825 Bucharest, Romania
| | - Danusia Adriana Pușcașu
- Internal Medicine and Gastroenterology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Simin Ayatollahi
- Internal Medicine and Gastroenterology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Emanuela Mihălțeanu
- Internal Medicine and Gastroenterology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Raluca Simona Costache
- Internal Medicine and Gastroenterology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Gastroenterology Department, Central Military Emergency University Hospital, 010825 Bucharest, Romania
| | - Florentina Ioniță-Radu
- Internal Medicine and Gastroenterology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Gastroenterology Department, Central Military Emergency University Hospital, 010825 Bucharest, Romania
| | - Mariana Jinga
- Internal Medicine and Gastroenterology Department, Carol Davila University of Medicine and Pharmacy, 020021 Bucharest, Romania
- Gastroenterology Department, Central Military Emergency University Hospital, 010825 Bucharest, Romania
| |
Collapse
|
|
7
|
Yang J, Tan C, Zheng Z, Wang X, Liu X, Chen Y. Elevated Bile Acid Is Associated with Worsened Impaired Glucose Homeostasis in Pancreatic Ductal Adenocarcinoma Patients with Extrahepatic Cholestasis through Increased Hepatic Insulin Clearance. J Clin Med 2023; 12:2352. [PMID: 36983352 PMCID: PMC10052524 DOI: 10.3390/jcm12062352] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 03/02/2023] [Accepted: 03/06/2023] [Indexed: 03/22/2023] Open
Abstract
BACKGROUND Patients after pancreaticoduodenectomy (PD) showed improved glucose tolerance. Evidence for the effect of extrahepatic cholestasis on impaired glucose homeostasis secondary to ductal adenocarcinoma of the pancreatic head is limited. METHODS In this prospective cross-sectional study, 50 patients with ductal adenocarcinoma of the pancreatic head were included to assess the effect of extrahepatic cholestasis on glucose tolerance status based on the oral glucose tolerance test (OGTT) before pancreatic surgery. RESULTS Patients with extrahepatic cholestasis more frequently suffered from worsened impaired glucose homeostasis (prediabetes and new-onset diabetes, 95.2% vs. 58.6%, p = 0.004). Elevated bile acid level was recognized as an independent risk factor for impaired glucose homeostasis (p = 0.024, OR = 6.85). Hepatic insulin clearance (HIC) was significantly higher in patients with elevated bile acid levels (p = 0.001). A strong positive correlation was found between bile acid levels and HIC (r = 0.45, p = 0.001). CONCLUSIONS This study suggested a connection between elevated bile acid levels and worsened impaired glucose homeostasis through increased insulin clearance function in ductal adenocarcinoma of pancreatic head patients.
Collapse
Affiliation(s)
| | | | | | | | | | - Yonghua Chen
- Division of Pancreatic Surgery, Department of General Surgery, West China Hospital of Sichuan University, Chengdu 610041, China
| |
Collapse
|
|
8
|
Shichijo H, Hosaka T, Takewaki F, Sumitani Y, Ishida H, Yasuda K. Post-meal endogenous insulin secretion was significantly lower in head than in body/tail cancer of the pancreas. THE JOURNAL OF MEDICAL INVESTIGATION 2023; 70:350-354. [PMID: 37940518 DOI: 10.2152/jmi.70.350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2023]
Abstract
THE AIM Pancreatic cancer, a rapidly progressive malignancy, is often diagnosed in patients with diabetes. The incidence of pancreatic cancer has risen dramatically over recent decades. Early diagnosis of this malignancy is generally difficult because the symptoms do not become apparent until the disease has progressed, generally leading to a poor outcome. To achieve earlier diagnosis, we analyzed the clinical characteristics of pancreatic cancer patients showing deterioration of plasma glucose levels while hospitalized. METHOD Thirty-six cases were divided into 2 groups;those diagnosed with diabetes more than a year prior to identification of pancreatic cancer and diabetes secondary to pancreatic cancer. These 2 groups were further subdivided according to the tumor site (head or body/tail), allowing analysis of 4 subgroups. Anthropometric measurements, laboratory values were determined. RESULTS Both groups with diabetes lost at least 4 kg and showed HbA1c deterioration of at least 1% within 5 months of the pancreatic cancer diagnosis. The post-meal elevation of serum C-peptide immunoreactivity (CPR) was significantly decreased in the group with cancer of the pancreatic head, and this was unrelated to tumor size. CONCLUSION Characteristically, pancreatic head cancer was associated with decreased endogenous insulin secretion as compared to body/tail cancer. J. Med. Invest. 70 : 350-354, August, 2023.
Collapse
Affiliation(s)
- Hirotaka Shichijo
- Department of Diabetes, Endocrinology and Metabolism, Kyorin University School of Medicine, Tokyo, Japan
| | - Toshio Hosaka
- Laboratory of Clinical Nutrition, School of Food and Nutritional Sciences, University of Shizuoka, Shizuoka, Japan
| | - Fumie Takewaki
- Department of Diabetes, Endocrinology and Metabolism, Kyorin University School of Medicine, Tokyo, Japan
| | - Yoshikazu Sumitani
- Department of Diabetes, Endocrinology and Metabolism, Kyorin University School of Medicine, Tokyo, Japan
| | - Hitoshi Ishida
- Department of Diabetes, Endocrinology and Metabolism, Kyorin University School of Medicine, Tokyo, Japan
| | - Kazuki Yasuda
- Department of Diabetes, Endocrinology and Metabolism, Kyorin University School of Medicine, Tokyo, Japan
| |
Collapse
|
|
9
|
Infante M, Ricordi C. The unique pathophysiological features of diabetes mellitus secondary to total pancreatectomy: proposal for a new classification distinct from diabetes of the exocrine pancreas. Expert Rev Endocrinol Metab 2023; 18:19-32. [PMID: 36692892 DOI: 10.1080/17446651.2023.2168645] [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: 09/07/2022] [Accepted: 01/11/2023] [Indexed: 01/21/2023]
Abstract
INTRODUCTION Diabetes of the exocrine pancreas (DEP; a.k.a. pancreatic diabetes or pancreatogenic diabetes or type 3c diabetes mellitus or T3cDM) refers to different diabetes types resulting from disorders of the exocrine pancreas. DEP is characterized by the structural and functional loss of glucose-normalizing insulin secretion in the context of exocrine pancreatic dysfunction. Among these forms, new-onset diabetes mellitus secondary to total pancreatectomy (TP) has unique pathophysiological and clinical features, for which we propose a new nomenclature such as post-total pancreatectomy diabetes mellitus (PTPDM). AREAS COVERED TP results in the complete loss of pancreatic parenchyma, with subsequent absolute insulinopenia and lifelong need for exogenous insulin therapy. Patients with PTPDM also exhibit deficiency of glucagon, amylin and pancreatic polypeptide. These endocrine abnormalities, coupled with increased peripheral insulin sensitivity, deficiency of pancreatic enzymes and TP-related modifications of gastrointestinal anatomy, can lead to marked glucose variability and increased risk of iatrogenic (insulin-induced) severe hypoglycemic episodes ('brittle diabetes'). EXPERT OPINION We believe that diabetes mellitus secondary to TP should not be included in the DEP spectrum in light of its peculiar pathophysiological and clinical features. Therefore, we propose a new classification for this entity, that would likely provide more accurate prognosis and treatment strategies.
Collapse
Affiliation(s)
- Marco Infante
- Cell Transplant Center, Diabetes Research Institute (DRI), University of Miami Miller School of Medicine, Miami, FL, USA
- Section of Diabetes and Metabolic Disorders, UniCamillus, Saint Camillus International University of Health Sciences, Rome, Italy
- Diabetes Research Institute Federation (DRIF), Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Rome, Italy
| | - Camillo Ricordi
- Cell Transplant Center, Diabetes Research Institute (DRI), University of Miami Miller School of Medicine, Miami, FL, USA
| |
Collapse
|
|
10
|
Kiritani S, Ono Y, Takamatsu M, Oba A, Sato T, Ito H, Inoue Y, Takahashi Y. Diabetogenic liver metastasis from pancreatic cancer: a case report. Surg Case Rep 2022; 8:224. [PMID: 36576596 PMCID: PMC9797629 DOI: 10.1186/s40792-022-01582-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 12/23/2022] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Although new-onset diabetes has been described in up to 20% of patients with newly diagnosed pancreatic cancer, reports regarding new-onset diabetes associated with newly developed liver metastasis from pancreatic cancer are limited. CASE PRESENTATION A 60-year-old man was diagnosed with pancreatic tail cancer without impaired glycemic control. A curative-intent distal pancreatectomy with adjuvant S-1 chemotherapy was performed. Two years after surgery, a high HbA1c concentration and solitary liver metastasis were identified on follow-up examination. Two major chemotherapy regimens, gemcitabine/nab-paclitaxel and modified FOLFIRINOX, were sequentially administered to the patient; however, his carbohydrate 19-9 concentration continued to increase. Because the patient's glycemic control rapidly worsened in synchrony with the tumor growth, insulin therapy was initiated. Although the liver metastasis was refractory to chemotherapy, curative-intent left hepatectomy was performed because only one tumor remained. His impaired glycemic control improved immediately after surgery, and insulin therapy was terminated. When writing this report (2 years after hepatectomy), the patient was alive and recurrence-free. CONCLUSIONS New-onset diabetes appeared with the progression of metachronous liver metastasis from pancreatic cancer, without recurrence at any other site. The patient's diabetic state was improved by resection of the liver tumor, and liver metastasis itself was proven to have caused the glucometabolic disorder by increasing insulin resistance.
Collapse
Affiliation(s)
- Sho Kiritani
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital of the Japanese Foundation for Clinical Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Yoshihiro Ono
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital of the Japanese Foundation for Clinical Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan.
| | - Manabu Takamatsu
- Department of Pathology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Atsushi Oba
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital of the Japanese Foundation for Clinical Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Takafumi Sato
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital of the Japanese Foundation for Clinical Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Hiromichi Ito
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital of the Japanese Foundation for Clinical Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Yosuke Inoue
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital of the Japanese Foundation for Clinical Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| | - Yu Takahashi
- Division of Hepatobiliary and Pancreatic Surgery, Cancer Institute Hospital of the Japanese Foundation for Clinical Research, 3-8-31 Ariake, Koto-Ku, Tokyo, 135-8550, Japan
| |
Collapse
|
|
11
|
Lee HS, Chae W, Sung MJ, Keum J, Jo JH, Chung MJ, Park JY, Park SW, Song SY, Park EC, Nam CM, Jang SI, Bang S. Difference of risk of pancreatic cancer in new-onset diabetes and long-standing diabetes: population-based cohort study. J Clin Endocrinol Metab 2022; 108:1338-1347. [PMID: 36548964 DOI: 10.1210/clinem/dgac728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Revised: 12/09/2022] [Accepted: 12/12/2022] [Indexed: 12/24/2022]
Abstract
CONTEXT Considering the absence of methods to find pancreatic cancer early, surveillance of high-risk groups is needed for early diagnosis. OBJECTIVE The study aimed to investigate the effect in the incidence of pancreatic cancer and the differences between new-onset DM (NODM) and long-standing DM (LSDM) since NODM group is a representative high-risk group. METHODS The Korean National Health Insurance Service-National Sample Cohort between 2002 and 2013 data was used. Regarding 88,396 people with DM (case group), we conducted a 1:1 propensity score matching to select a matched non-DM population (control group). To investigate the interaction between DM and the time variable distinguishing NODM and LSDM, we performed a multi-variable time-dependent Cox regression analysis. RESULTS The incidence of pancreatic cancer was higher in the DM group compared to the non-DM group (0.52% vs. 0.16%, P < 0.001). The DM group had shown different risk of pancreatic cancer development according to the duration since the DM diagnosis (NODM hazard ratio (HR): 3.81, 95% confidence interval (CI): 2.97-4.88, P < 0.001; LSDM HR: 1.53, 95% CI: 1.11-2.11, P < 0.001). When the NODM and the LSDM groups were compared, the risk of pancreatic cancer was higher in the NODM group than LSDM group (HR: 1.55, P = 0.020). In subgroup analysis, NODM group showed that men (HR = 4.42 95% CI: 3.15-6.19, P < 0.001) and patients who were in their 50 s (HR = 7.54, 95% CI: 3.24-17.56, P < 0.001) were at a higher risk of developing pancreatic cancer than matched same sex or age control group (non-DM population), respectively. CONCLUSION The risk of pancreatic cancer was greater in people with DM than non-DM population. Among people with DM, NODM showed a higher risk of pancreatic cancer than long standing DM.
Collapse
Affiliation(s)
- Hee Seung Lee
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Wonjeong Chae
- Department of Health Policy and Management, Yonsei University Graduate School of Public Health, Seoul, Republic of Korea
- Institute of Health Services Research, Yonsei University, Seoul, Republic of Korea
| | - Min Je Sung
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jiyoung Keum
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jung Hyun Jo
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Moon Jae Chung
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Jeong Youp Park
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Seung Woo Park
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Si Young Song
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Eun-Cheol Park
- Institute of Health Services Research, Yonsei University, Seoul, Republic of Korea
- Department of Preventive Medicine, College of Medicine, Yonsei University, Seoul, Republic of Korea
| | - Chung Mo Nam
- Department of Preventive Medicine, College of Medicine, Yonsei University, Seoul, Republic of Korea
- Department of Biostatics, College of Medicine, Yonsei University, Seoul, Republic of Korea
| | - Sung-In Jang
- Institute of Health Services Research, Yonsei University, Seoul, Republic of Korea
- Department of Preventive Medicine, College of Medicine, Yonsei University, Seoul, Republic of Korea
| | - Seungmin Bang
- Division of Gastroenterology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
| |
Collapse
|
|
12
|
Ali S, Na R, Tuesley K, Spilsbury K, Stewart LM, Coory M, Webb PM, Donovan P, Pearson SA, Jordan SJ, Neale RE. The association between diabetes mellitus of different durations and risk of pancreatic cancer: an Australian national data-linkage study in women. Cancer Epidemiol 2022; 81:102266. [PMID: 36240705 DOI: 10.1016/j.canep.2022.102266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 08/29/2022] [Accepted: 09/19/2022] [Indexed: 11/02/2022]
Abstract
AIMS The bidirectional association between diabetes mellitus (DM) and pancreatic cancer (PC) is established; however, the strength of association between duration of DM and risk of PC needs further investigation. METHODS We conducted a case-control study nested within a population-based cohort of Australian women established using record linkage. Women diagnosed with PC from July 2007 to December 2013, were matched to five controls based on age and state of residence. DM was defined according to prescription of anti-diabetic medication from administrative prescription data. We used conditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI), adjusted for area-level socioeconomic status, rurality of residence, weighted comorbidity score, and predicted probability of obesity. RESULTS The analyses included 7,267 cases and 35,978 controls. The mean age at the time of DM diagnosis was 71 years whereas the mean age at the time of diagnosis of PC was 76 years. A history of DM of any duration was associated with a 2-fold increase in risk of PC (OR=2.12; 95%CI:1.96-2.29) compared to having no history of DM. The risk decreased with increasing duration of DM. The highest risk was in those who had recent-onset DM (OR=8.08; 95%CI:6.88-9.50 for <12 months of DM), but the risk remained elevated with ≥5 years of DM (OR=1.40; 95%CI:1.27-1.55). CONCLUSION The markedly increased risk of PC in those with recent-onset DM emphasises the need for further research to distinguish patients for whom new-onset DM is a manifestation of PC from those with type-2 DM. The elevated risk associated with long-standing DM suggests that preventing DM may contribute to a reduction in the incidence of PC.
Collapse
Affiliation(s)
- Sitwat Ali
- Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; School of Public Health, University of Queensland, Brisbane, Queensland, Australia
| | - Renhua Na
- Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
| | - Karen Tuesley
- Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; School of Public Health, University of Queensland, Brisbane, Queensland, Australia
| | - Katrina Spilsbury
- Centre for Health Research, University of Notre Dame Australia, Fremantle, Western Australia, Australia
| | - Louise M Stewart
- School of Population and Global Health, The University of Western Australia, Crawley, Western Australia, Australia
| | - Michael Coory
- Centre of Research Excellence in Stillbirth, Mater Research Institute, The University of Queensland, Brisbane, Queensland, Australia
| | - Penelope M Webb
- Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; School of Public Health, University of Queensland, Brisbane, Queensland, Australia
| | - Peter Donovan
- Royal Brisbane and Women's Hospital, Australia; Faculty of Medicine, The University of Queensland, Australia
| | - Sallie-Anne Pearson
- Centre for Big Data Research in Health, University of New South Wales UNSW, Sydney, New South Wales, Australia
| | - Susan J Jordan
- Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; School of Public Health, University of Queensland, Brisbane, Queensland, Australia
| | - Rachel E Neale
- Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; School of Public Health, University of Queensland, Brisbane, Queensland, Australia.
| |
Collapse
|
|
13
|
Usefulness of Practitioner-Led Pancreatic Cancer Screening. Diagnostics (Basel) 2022; 12:diagnostics12092257. [PMID: 36140658 PMCID: PMC9498137 DOI: 10.3390/diagnostics12092257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 09/11/2022] [Accepted: 09/14/2022] [Indexed: 11/17/2022] Open
Abstract
The 5-year survival rate for pancreatic cancer has improved (10%) but remains worse than that for other cancers. Early pancreatic cancer diagnosis is challenging, and delayed diagnosis can delay treatment, which impairs survival. Practitioners do not promptly refer cases to a general hospital, causing delayed discovery. Herein, we aimed to examine the usefulness of the Pancreatic Cancer Project in Matsue, whose objective is to detect pancreatic cancer in patients presenting at any medical institution in Matsue City. Clinical data were extracted from medical records, and abdominal ultrasonography and tumor marker blood level assessments were performed (n = 234; median age, 71 [range, 41–94] years; 51% male). Cases with abnormal abdominal ultrasonography or blood test findings were referred for specialist imaging and followed up. The pancreatic cancer detection rate was 6.0% (n = 14); all cases were referred to a general hospital by practitioners within 1 month. Patients had stage IA (n = 1), IIA (n = 6), IIB (n = 2), III (n = 1), and IV (n = 4) disease. Overall, pancreatic cancer could be detected at an earlier stage (I–II), but referral to a general hospital by visiting practitioners should be prompt. The Pancreatic Cancer Project in Matsue may help improve the detection and prognosis of pancreatic cancer.
Collapse
|
|
14
|
The Impact of the Association between Cancer and Diabetes Mellitus on Mortality. J Pers Med 2022; 12:jpm12071099. [PMID: 35887596 PMCID: PMC9322980 DOI: 10.3390/jpm12071099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Revised: 06/29/2022] [Accepted: 06/30/2022] [Indexed: 11/17/2022] Open
Abstract
The prevalence of cancer, diabetes mellitus (DM), and hypertension is increasing in ageing populations. We analyzed the association of DM with cancer and its effects on cancer mortality. The data of 2009–2018 from the Korea National Hospital Discharge In-depth Injury Survey were used; 169,959 adults with cancer as the main diagnosis were identified. The association rule for unsupervised machine learning was used. Association rule mining was used to analyze the association between the diseases. Logistic regression was performed to determine the effects of DM on cancer mortality. DM prevalence was 12.9%. Cancers with high DM prevalence were pancreatic (29.9%), bile duct (22.7%), liver (21.4%), gallbladder (15.5%), and lung cancers (15.4%). Cancers with high hypertension prevalence were bile duct (31.4%), ureter (30.5%), kidney (29.5%), pancreatic (28.1%), and bladder cancers (27.5%). The bidirectional association between DM and hypertension in cancer was the strongest (lift = 2.629, interest support [IS] scale = 0.426), followed by that between lung cancer and hypertension (lift = 1.280, IS scale = 0.204), liver cancer and DM (lift = 1.658, IS scale = 0.204), hypertension and liver cancer and DM (lift = 3.363, IS scale = 0.197), colorectal cancer and hypertension (lift = 1.133, IS scale = 0.180), and gastric cancer and hypertension (lift = 1.072, IS scale = 0.175). DM increased liver cancer mortality (p = 0.000), while hypertension significantly increased the mortality rate of stomach, colorectal, liver, and lung cancers. Our study confirmed the association between cancer and DM. Consequently, a patient management strategy with presumptive diagnostic ability for DM and hypertension is required to decrease cancer mortality rates.
Collapse
|
|
15
|
Shah I, Sawhney MS. Reply. Gastroenterology 2022; 162:1779-1780. [PMID: 35032501 DOI: 10.1053/j.gastro.2022.01.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 01/12/2022] [Indexed: 12/02/2022]
Affiliation(s)
- Ishani Shah
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
| | - Mandeep S Sawhney
- Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts
| |
Collapse
|
|
16
|
Kim K, Gaddam S, Liu Q. Pathogenesis, Epidemiology, and Prognosis of Pancreatic Adenocarcinomas. HEPATO-PANCREATO-BILIARY MALIGNANCIES 2022:461-481. [DOI: 10.1007/978-3-030-41683-6_28] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
17
|
Chae K, Perlman J, Fransman RB, Wolfgang CL, De Jesus-Acosta A, Mathioudakis N. A Rare Case of Subcutaneous Insulin Resistance Presumed to be due to Paraneoplastic Process in Pancreatic Adenocarcinoma. AACE Clin Case Rep 2021; 7:379-382. [PMID: 34765736 PMCID: PMC8573285 DOI: 10.1016/j.aace.2021.06.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/31/2021] [Accepted: 06/02/2021] [Indexed: 11/12/2022] Open
Abstract
Objective We describe a rare case of profound subcutaneous insulin resistance (SIR) presumed due to a paraneoplastic process caused by pancreatic adenocarcinoma that improved with intravenous insulin and tumor resection. Methods An 80-year-old man with previously well-controlled type 2 diabetes mellitus had worsening glycemic control (hemoglobin A1C increase of 6.5% to 8.6% over 4 months) following a recent diagnosis of pancreatic adenocarcinoma. His blood glucose was uncontrolled at 600 mg/dL despite rapid up-titration of a subcutaneous basal-bolus insulin regimen totaling 1000 units/d. Extensive evaluation of insulin resistance including insulin antibodies and anti-insulin receptor antibodies was negative. Due to clinical deterioration, the patient underwent pancreaticoduodenectomy before the completion of neoadjuvant chemotherapy. The patient received intravenous insulin before surgery, which resulted in rapid improvement in glycemic control. The patient’s blood glucose normalized, and he was maintained on metformin monotherapy following pancreaticoduodenectomy. Results This patient had evidence of SIR in the setting of pancreatic adenocarcinoma. SIR was likely a paraneoplastic process as glycemic control improved after tumor resection. Interestingly, the patient did not have hyperinsulinemia but rather evidence of β-cell dysfunction, which highlights the possibility of exogenous insulin resistance. Conclusion Paraneoplastic processes due to pancreatic adenocarcinoma can cause SIR, marked by profound hyperglycemia and deteriorating functional status. It is, therefore important to recognize this rare syndrome and appropriately escalate to a higher level of care and consider proceeding with tumor resection.
Collapse
Affiliation(s)
- Kacey Chae
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Jordan Perlman
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Ryan B Fransman
- Deparment of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | | | - Ana De Jesus-Acosta
- Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Nestoras Mathioudakis
- Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
| |
Collapse
|
|
18
|
Kim K, Kim IJ, Pak K, Kang T, Seol YM, Choi YJ, Kim H. Prognostic value of metabolic activity of the psoas muscle evaluated by preoperative 18F-FDG PET-CT in breast cancer: a retrospective cross-sectional study. BMC Cancer 2021; 21:1151. [PMID: 34706697 PMCID: PMC8555075 DOI: 10.1186/s12885-021-08886-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 10/14/2021] [Indexed: 11/10/2022] Open
Abstract
Background This study aimed to evaluate the potential of metabolic activity of the psoas muscle measured by 18F-fluorodeoxyglucose positron emission tomography-computed tomography to predict treatment outcomes in patients with resectable breast cancer. Methods The medical records of 288 patients who had undergone surgical resection for stages I–III invasive ductal carcinoma of the breast between January 2014 and December 2014 in Pusan National University Hospital were reviewed. The standardized uptake values (SUVs) of the bilateral psoas muscle were normalized using the mean SUV of the liver. SUVRmax was calculated as the ratio of the maximum SUV of the average bilateral psoas muscle to the mean SUV of the liver. SUVRmean was calculated as the ratio of the mean SUV of the bilateral psoas muscle to the mean SUV of the liver. Results Univariate analyses identified a higher T stage, higher N stage, estrogen receptor negativity, progesterone receptor negativity, human epidermal growth factor receptor 2 positivity, triple-negative breast cancer, mastectomy (rather than breast-conserving surgery), SUVRmean > 0.464, and SUVRmax > 0.565 as significant adverse factors for disease-free survival (DFS). Multivariate Cox regression analysis revealed that N3 stage (hazard ratio [HR] = 5.347, P = 0.031) was an independent factor for recurrence. An SUVRmax > 0.565 (HR = 4.987, P = 0.050) seemed to have a correlation with shorter DFS. Conclusions A higher SUVRmax of the psoas muscle, which could be a surrogate marker of insulin resistance, showed strong potential as an independent prognostic factor for recurrence in patients with resectable breast cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08886-2.
Collapse
Affiliation(s)
- Keunyoung Kim
- Department of Nuclear Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan, South Korea
| | - In-Joo Kim
- Department of Nuclear Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan, South Korea
| | - Kyoungjune Pak
- Department of Nuclear Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan, South Korea
| | - Taewoo Kang
- Department of Surgery, Busan Cancer Center, Pusan National University Hospital and Biomedical Research Institute, Pusan National University Hospital, Busan, South Korea
| | - Young Mi Seol
- Department of Hematology-Oncology, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Hospital, 179 Gudeok-ro, Seo-gu, Busan, 49241, South Korea
| | - Young Jin Choi
- Department of Hematology-Oncology, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Hospital, 179 Gudeok-ro, Seo-gu, Busan, 49241, South Korea
| | - Hyojeong Kim
- Department of Hematology-Oncology, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Hospital, 179 Gudeok-ro, Seo-gu, Busan, 49241, South Korea.
| |
Collapse
|
|
19
|
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:cancers13205224. [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] [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.
Collapse
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
- Correspondence: ; Tel.: +61-2-87389029
| |
Collapse
|
|
20
|
Sasaki H, Saisho Y, Inaishi J, Itoh H. Revisiting Regulators of Human β-cell Mass to Achieve β-cell-centric Approach Toward Type 2 Diabetes. J Endocr Soc 2021; 5:bvab128. [PMID: 34405128 PMCID: PMC8361804 DOI: 10.1210/jendso/bvab128] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Indexed: 02/07/2023] Open
Abstract
Type 2 diabetes (T2DM) is characterized by insulin resistance and β-cell dysfunction. Because patients with T2DM have inadequate β-cell mass (BCM) and β-cell dysfunction worsens glycemic control and makes treatment difficult, therapeutic strategies to preserve and restore BCM are needed. In rodent models, obesity increases BCM about 3-fold, but the increase in BCM in humans is limited. Besides, obesity-induced changes in BCM may show racial differences between East Asians and Caucasians. Recently, the developmental origins of health and disease hypothesis, which states that the risk of developing noncommunicable diseases including T2DM is influenced by the fetal environment, has been proposed. It is known in rodents that animals with low birthweight have reduced BCM through epigenetic modifications, making them more susceptible to diabetes in the future. Similarly, in humans, we revealed that individuals born with low birthweight have lower BCM in adulthood. Because β-cell replication is more frequently observed in the 5 years after birth, and β cells are found to be more plastic in that period, a history of childhood obesity increases BCM. BCM in patients with T2DM is reduced by 20% to 65% compared with that in individuals without T2DM. However, since BCM starts to decrease from the stage of borderline diabetes, early intervention is essential for β-cell protection. In this review, we summarize the current knowledge on regulatory factors of human BCM in health and diabetes and propose the β-cell–centric concept of diabetes to enhance a more pathophysiology-based treatment approach for T2DM.
Collapse
Affiliation(s)
- Hironobu Sasaki
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.,Center for Preventive Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Yoshifumi Saisho
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Jun Inaishi
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.,Center for Preventive Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Hiroshi Itoh
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| |
Collapse
|
|
21
|
Abstract
Surgical oncology is cancer care that focuses on using surgery to diagnose, stage, and treat cancer and is one of the main treatments for malignancy. Patients older than 65 years are generally considered geriatric. The incidence of cancer in geriatric patients is increasing annually. Candidacy for surgical intervention depends on factors such as cancer type, size, location, grade and stage of the tumor, and the patient's overall health status and age. Despite increasing agreement that age should not limit treatment options, geriatric patients tend to be undertreated. Cancer in geriatric patients has different features than in younger patients. As such, treatment options may be dissimilar in these 2 cohorts. Here, care of the geriatric patient undergoing surgical oncology interventions is discussed.
Collapse
Affiliation(s)
- Dalton Skipper
- Dalton Skipper is Manager of Education, Emory Healthcare, 1459 Montreal Rd MOB, Suite 210, Tucker, GA 30084
| |
Collapse
|
|
22
|
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.
Collapse
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
| |
Collapse
|
|
23
|
Khan S, Safarudin RF, Kupec JT. Validation of the ENDPAC model: Identifying new-onset diabetics at risk of pancreatic cancer. Pancreatology 2021; 21:550-555. [PMID: 33583686 PMCID: PMC8393564 DOI: 10.1016/j.pan.2021.02.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Revised: 01/20/2021] [Accepted: 02/02/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Patients with new-onset diabetes are known to be at a higher risk of developing pancreatic cancer. The Enriching New-Onset Diabetes for Pancreatic Cancer (ENDPAC) model was recently developed to identify new-onset diabetics with this higher risk. Further validation is needed before the ENDPAC model is implemented as part of a screening program to identify pancreatic cancer. METHODS A retrospective case-control study was performed; a cohort of patients with new-onset diabetes was identified using hemoglobin A1c. Patients were scored by the ENDPAC model and then divided based on whether pancreatic cancer was diagnosed after the diagnosis of diabetes. The performance of the model was assessed globally and at different cutoffs. RESULTS There were 6254 controls and 48 cases of pancreatic cancer. Bivariate analysis showed that patients with pancreatic cancer lost weight before diagnosis while controls gained weight (-0.93 kg/m2 vs. 0.45 kg/m2, p < 0.00∗). Cases had a more significant increase in their HbA1C from one year before (1.3% vs. 0.82%, p = 0.02). Smoking and pancreatitis rates were higher in cases compared to controls (p < 0.00∗). The area under the curve (AUC) of the ENDPAC model was 0.72. A score >1 was the optimal cutoff. At this cutoff, the sensitivity was 56%, specificity was 75%, and pancreatic cancer prevalence increased from 0.78% at baseline to 1.7%. CONCLUSION The ENDPAC model was validated in an independent cohort of patients with new-onset diabetes.
Collapse
Affiliation(s)
- Salman Khan
- Department of Medicine, School of Medicine, West Virginia University, USA,Corresponding author. (S. Khan)
| | - Rudi Fnu Safarudin
- Department of Pharmaceutical Systems and Policy, West Virginia University School of Pharmacy, USA,School of Mathematics and Natural Sciences, Tadulako University, Indonesia
| | - Justin T. Kupec
- Section of Gastroenterology & Hepatology, West Virginia University, Morgantown, West Virginia, USA
| |
Collapse
|
|
24
|
Menini S, Iacobini C, Vitale M, Pesce C, Pugliese G. Diabetes and Pancreatic Cancer-A Dangerous Liaison Relying on Carbonyl Stress. Cancers (Basel) 2021; 13:313. [PMID: 33467038 PMCID: PMC7830544 DOI: 10.3390/cancers13020313] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 01/09/2021] [Accepted: 01/14/2021] [Indexed: 02/06/2023] Open
Abstract
Both type 2 (T2DM) and type 1 (T1DM) diabetes mellitus confer an increased risk of pancreatic cancer in humans. The magnitude and temporal trajectory of the risk conferred by the two forms of diabetes are similar, suggesting a common mechanism. Carbonyl stress is a hallmark of hyperglycemia and dyslipidemia, which accompanies T2DM, prediabetes, and obesity. Accumulating evidence demonstrates that diabetes promotes pancreatic ductal adenocarcinoma (PDAC) in experimental models of T2DM, a finding recently confirmed in a T1DM model. The carbonyl stress markers advanced glycation end-products (AGEs), the levels of which are increased in diabetes, were shown to markedly accelerate tumor development in a mouse model of Kras-driven PDAC. Consistently, inhibition of AGE formation by trapping their carbonyl precursors (i.e., reactive carbonyl species, RCS) prevented the PDAC-promoting effect of diabetes. Considering the growing attention on carbonyl stress in the onset and progression of several cancers, including breast, lung and colorectal cancer, this review discusses the mechanisms by which glucose and lipid imbalances induce a status of carbonyl stress, the oncogenic pathways activated by AGEs and their precursors RCS, and the potential use of carbonyl-scavenging agents and AGE inhibitors in PDAC prevention and treatment, particularly in high-risk diabetic individuals.
Collapse
Affiliation(s)
- Stefano Menini
- Department of Clinical and Molecular Medicine, “La Sapienza” University, 00189 Rome, Italy; (S.M.); (C.I.); (M.V.)
| | - Carla Iacobini
- Department of Clinical and Molecular Medicine, “La Sapienza” University, 00189 Rome, Italy; (S.M.); (C.I.); (M.V.)
| | - Martina Vitale
- Department of Clinical and Molecular Medicine, “La Sapienza” University, 00189 Rome, Italy; (S.M.); (C.I.); (M.V.)
| | - Carlo Pesce
- Department of Neurosciences, Rehabilitation, Ophtalmology, Genetic and Maternal Infantile Sciences (DINOGMI), Department of Excellence of MIUR, University of Genoa Medical School, 16132 Genoa, Italy;
| | - Giuseppe Pugliese
- Department of Clinical and Molecular Medicine, “La Sapienza” University, 00189 Rome, Italy; (S.M.); (C.I.); (M.V.)
| |
Collapse
|
|
25
|
Goess R, Mutgan AC, Çalışan U, Erdoğan YC, Ren L, Jäger C, Safak O, Stupakov P, Istvanffy R, Friess H, Ceyhan GO, Demir IE. Patterns and Relevance of Langerhans Islet Invasion in Pancreatic Cancer. Cancers (Basel) 2021; 13:cancers13020249. [PMID: 33440856 PMCID: PMC7826785 DOI: 10.3390/cancers13020249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 01/06/2021] [Indexed: 11/16/2022] Open
Abstract
Background: Pancreatic cancer-associated diabetes mellitus (PC-DM) is present in most patients with pancreatic cancer, but its pathogenesis remains poorly understood. Therefore, we aimed to characterize tumor infiltration in Langerhans islets in pancreatic cancer and determine its clinical relevance. METHODS Langerhans islet invasion was systematically analyzed in 68 patientswith pancreatic ductal adenocarcinoma (PDAC) using histopathological examination and 3D in vitro migration assays were performed to assess chemoattraction of pancreatic cancer cells to isletcells. RESULTS Langerhans islet invasion was present in all patients. We found four different patterns of islet invasion: (Type I) peri-insular invasion with tumor cells directly touching the boundary, but not penetrating the islet; (Type II) endo-insular invasion with tumor cells inside the round islet; (Type III) distorted islet structure with complete loss of the round islet morphology; and (Type IV)adjacent cancer and islet cells with solitary islet cells encountered adjacent to cancer cells. Pancreatic cancer cells did not exhibit any chemoattraction to islet cells in 3D assays in vitro. Further, there was no clinical correlation of islet invasion using the novel Islet Invasion Severity Score (IISS), which includes all invasion patterns with the occurrence of diabetes mellitus. However, Type IV islet invasion was related to worsened overall survival in our cohort. CONCLUSIONS We systematically analyzed, for the first time, islet invasion in human pancreatic cancer. Four different main patterns of islet invasion were identified. Diabetes mellitus was not related to islet invasion. However, moreresearch on this prevailing feature of pancreatic cancer is needed to better understand underlying principles.
Collapse
Affiliation(s)
- Ruediger Goess
- Department of Surgery, Klinikum Rechts der Isar, Technical University of Munich, Ismaninger Str. 22, D-81675 Munich, Germany; (R.G.); (A.C.M.); (U.Ç.); (Y.C.E.); (L.R.); (C.J.); (O.S.); (P.S.); (R.I.); (H.F.); (G.O.C.)
| | - Ayse Ceren Mutgan
- Department of Surgery, Klinikum Rechts der Isar, Technical University of Munich, Ismaninger Str. 22, D-81675 Munich, Germany; (R.G.); (A.C.M.); (U.Ç.); (Y.C.E.); (L.R.); (C.J.); (O.S.); (P.S.); (R.I.); (H.F.); (G.O.C.)
| | - Umut Çalışan
- Department of Surgery, Klinikum Rechts der Isar, Technical University of Munich, Ismaninger Str. 22, D-81675 Munich, Germany; (R.G.); (A.C.M.); (U.Ç.); (Y.C.E.); (L.R.); (C.J.); (O.S.); (P.S.); (R.I.); (H.F.); (G.O.C.)
| | - Yusuf Ceyhun Erdoğan
- Department of Surgery, Klinikum Rechts der Isar, Technical University of Munich, Ismaninger Str. 22, D-81675 Munich, Germany; (R.G.); (A.C.M.); (U.Ç.); (Y.C.E.); (L.R.); (C.J.); (O.S.); (P.S.); (R.I.); (H.F.); (G.O.C.)
| | - Lei Ren
- Department of Surgery, Klinikum Rechts der Isar, Technical University of Munich, Ismaninger Str. 22, D-81675 Munich, Germany; (R.G.); (A.C.M.); (U.Ç.); (Y.C.E.); (L.R.); (C.J.); (O.S.); (P.S.); (R.I.); (H.F.); (G.O.C.)
- Department of General Surgery (Gastrointestinal Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou 646000, China
| | - Carsten Jäger
- Department of Surgery, Klinikum Rechts der Isar, Technical University of Munich, Ismaninger Str. 22, D-81675 Munich, Germany; (R.G.); (A.C.M.); (U.Ç.); (Y.C.E.); (L.R.); (C.J.); (O.S.); (P.S.); (R.I.); (H.F.); (G.O.C.)
| | - Okan Safak
- Department of Surgery, Klinikum Rechts der Isar, Technical University of Munich, Ismaninger Str. 22, D-81675 Munich, Germany; (R.G.); (A.C.M.); (U.Ç.); (Y.C.E.); (L.R.); (C.J.); (O.S.); (P.S.); (R.I.); (H.F.); (G.O.C.)
| | - Pavel Stupakov
- Department of Surgery, Klinikum Rechts der Isar, Technical University of Munich, Ismaninger Str. 22, D-81675 Munich, Germany; (R.G.); (A.C.M.); (U.Ç.); (Y.C.E.); (L.R.); (C.J.); (O.S.); (P.S.); (R.I.); (H.F.); (G.O.C.)
| | - Rouzanna Istvanffy
- Department of Surgery, Klinikum Rechts der Isar, Technical University of Munich, Ismaninger Str. 22, D-81675 Munich, Germany; (R.G.); (A.C.M.); (U.Ç.); (Y.C.E.); (L.R.); (C.J.); (O.S.); (P.S.); (R.I.); (H.F.); (G.O.C.)
| | - Helmut Friess
- Department of Surgery, Klinikum Rechts der Isar, Technical University of Munich, Ismaninger Str. 22, D-81675 Munich, Germany; (R.G.); (A.C.M.); (U.Ç.); (Y.C.E.); (L.R.); (C.J.); (O.S.); (P.S.); (R.I.); (H.F.); (G.O.C.)
| | - Güralp O. Ceyhan
- Department of Surgery, Klinikum Rechts der Isar, Technical University of Munich, Ismaninger Str. 22, D-81675 Munich, Germany; (R.G.); (A.C.M.); (U.Ç.); (Y.C.E.); (L.R.); (C.J.); (O.S.); (P.S.); (R.I.); (H.F.); (G.O.C.)
- Department of General Surgery, HPB-Unit, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul 34684, Turkey
| | - Ihsan Ekin Demir
- Department of Surgery, Klinikum Rechts der Isar, Technical University of Munich, Ismaninger Str. 22, D-81675 Munich, Germany; (R.G.); (A.C.M.); (U.Ç.); (Y.C.E.); (L.R.); (C.J.); (O.S.); (P.S.); (R.I.); (H.F.); (G.O.C.)
- Department of General Surgery, HPB-Unit, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul 34684, Turkey
- German Cancer Consortium (DKTK), Partner Site Munich, D-81675 Munich, Germany
- CRC 1321 Modelling and Targeting Pancreatic Cancer, D-81675 Munich, Germany
- Correspondence: ; Tel.: +49-89-4140-5868
| |
Collapse
|
|
26
|
Brown ML, Schneyer A. A Decade Later: Revisiting the TGFβ Family's Role in Diabetes. Trends Endocrinol Metab 2021; 32:36-47. [PMID: 33261990 DOI: 10.1016/j.tem.2020.11.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 11/02/2020] [Accepted: 11/03/2020] [Indexed: 12/16/2022]
Abstract
In 2010, we published a review summarizing the role of the transforming growth factor-beta (TGFβ) family of proteins in diabetes. At that time there were still many outstanding questions that needed to be answered. In this updated review, we revisit the topic and provide new evidence that supports findings from previous studies included in the 2010 review and adds to the knowledge base with new findings and information. The most substantial contributions in the past 10 years have been in the areas of human data, the investigation of TGFβ family members other than activin [e.g., bone morphogenetic proteins (BMPs), growth and differentiation factor 11 (GDF11), nodal], and the expansion of β-cell number through various mechanisms including transdifferentiation, which was previously believed to not be possible.
Collapse
Affiliation(s)
| | - Alan Schneyer
- Fairbanks Pharmaceuticals, Inc., Springfield, MA 01199, USA
| |
Collapse
|
|
27
|
Wyart E, Bindels LB, Mina E, Menga A, Stanga S, Porporato PE. Cachexia, a Systemic Disease beyond Muscle Atrophy. Int J Mol Sci 2020; 21:E8592. [PMID: 33202621 PMCID: PMC7696729 DOI: 10.3390/ijms21228592] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2020] [Revised: 11/06/2020] [Accepted: 11/12/2020] [Indexed: 02/06/2023] Open
Abstract
Cachexia is a complication of dismal prognosis, which often represents the last step of several chronic diseases. For this reason, the comprehension of the molecular drivers of such a condition is crucial for the development of management approaches. Importantly, cachexia is a syndrome affecting various organs, which often results in systemic complications. To date, the majority of the research on cachexia has been focused on skeletal muscle, muscle atrophy being a pivotal cause of weight loss and the major feature associated with the steep reduction in quality of life. Nevertheless, defining the impact of cachexia on other organs is essential to properly comprehend the complexity of such a condition and potentially develop novel therapeutic approaches.
Collapse
Affiliation(s)
- Elisabeth Wyart
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, 10126 Turin, Italy; (E.W.); (E.M.); (A.M.)
| | - Laure B. Bindels
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université Catholique de Louvain, 1200 Brussels, Belgium;
| | - Erica Mina
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, 10126 Turin, Italy; (E.W.); (E.M.); (A.M.)
| | - Alessio Menga
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, 10126 Turin, Italy; (E.W.); (E.M.); (A.M.)
| | - Serena Stanga
- Neuroscience Institute Cavalieri Ottolenghi, 10043 Orbassano (TO), Department of Neuroscience Rita Levi Montalcini, University of Turin, 10126 Turin, Italy;
| | - Paolo E. Porporato
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, 10126 Turin, Italy; (E.W.); (E.M.); (A.M.)
| |
Collapse
|
|
28
|
Gheorghe G, Bungau S, Ilie M, Behl T, Vesa CM, Brisc C, Bacalbasa N, Turi V, Costache RS, Diaconu CC. Early Diagnosis of Pancreatic Cancer: The Key for Survival. Diagnostics (Basel) 2020; 10:869. [PMID: 33114412 PMCID: PMC7694042 DOI: 10.3390/diagnostics10110869] [Citation(s) in RCA: 52] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2020] [Revised: 10/16/2020] [Accepted: 10/23/2020] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer (PC) is one of the most aggressive forms of cancer. Negative prognosis is mainly due to the late diagnosis in advanced stages, when the disease is already therapeutically overcome. Studies in recent years have focused on identifying biomarkers that could play a role in early diagnosis, leading to the improvement of morbidity and mortality. Currently, the only biomarker widely used in the diagnosis of PC is carbohydrate antigen 19-9 (CA19.9), which has, however, more of a prognostic role in the follow-up of postoperative recurrence than a diagnostic role. Other biomarkers, recently identified as the methylation status of ADAMTS1 (A disintegrin and metalloproteinase with thrombospondin motifs 1) and BNC1 (zinc finger protein basonuclin-1) in cell-free deoxyribonucleic acid (DNA), may play a role in the early detection of PC. This review focuses on the diagnosis of PC in its early stages.
Collapse
Affiliation(s)
- Gina Gheorghe
- Department 5, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (G.G.); (M.I.); (R.S.C.)
- Department of Internal Medicine, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania
| | - Madalina Ilie
- Department 5, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (G.G.); (M.I.); (R.S.C.)
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
| | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab 140401, India;
| | - Cosmin Mihai Vesa
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410041 Oradea, Romania;
| | - Ciprian Brisc
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410041 Oradea, Romania;
| | - Nicolae Bacalbasa
- Department of Surgery, “Ion Cantacuzino” Clinical Hospital, 030167 Bucharest, Romania;
- Department 13, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Vladiana Turi
- Department of Cardiology, “Victor Babeş” University of Medicine and Pharmacy, 300041 Timisoara, Romania;
| | - Raluca Simona Costache
- Department 5, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (G.G.); (M.I.); (R.S.C.)
- Department of Gastroenterology, “Carol Davila” University Emergency Central Military Hospital, 010825 Bucharest, Romania
| | - Camelia Cristina Diaconu
- Department 5, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania; (G.G.); (M.I.); (R.S.C.)
- Department of Internal Medicine, Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania
| |
Collapse
|
|
29
|
Bitterman DS, Winter KA, Hong TS, Fuchs CS, Regine WF, Abrams RA, Safran H, Hoffman JP, Benson AB, Kasunic T, Mulcahy M, Strauss JF, DiPetrillo T, Stella PJ, Chen Y, Plastaras JP, Crane CH. Impact of Diabetes and Insulin Use on Prognosis in Patients With Resected Pancreatic Cancer: An Ancillary Analysis of NRG Oncology RTOG 9704. Int J Radiat Oncol Biol Phys 2020; 109:201-211. [PMID: 32858111 DOI: 10.1016/j.ijrobp.2020.08.042] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 07/31/2020] [Accepted: 08/14/2020] [Indexed: 12/14/2022]
Abstract
PURPOSE Diabetes mellitus (DM) has been proposed to be tumorigenic; however, prior studies of the association between DM and survival are conflicting. The goal of this ancillary analysis of RTOG 9704, a randomized controlled trial of adjuvant chemotherapy in pancreatic cancer, was to determine the prognostic effects of DM and insulin use on survival. METHODS AND MATERIALS Eligible patients from RTOG 9704 with available data on DM and insulin use were included. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method, and variable levels were compared using log-rank test. Cox proportional hazards models were created to assess the associations among DM, insulin use, and body mass index phenotypes on outcomes. RESULTS Of 538 patients enrolled from 1998 to 2002, 238 patients were eligible with analyzable DM and insulin use data. Overall 34% of patients had DM and 66% did not. Of patients with DM, 64% had insulin-dependent DM, and 36% had non-insulin-dependent DM. On univariable analysis, neither DM nor insulin dependence were associated with OS or DFS (P > .05 for all). On multivariable analysis, neither DM, insulin use, nor body mass index were independently associated with OS or DFS. Nonwhite race (hazard ratio [HR], 2.18; 95% confidence interval [CI], 1.35-3.50; P = .0014), nodal involvement (HR, 1.74; 95% CI, 1.24-2.45; P = .0015), and carbohydrate antigen 19-9 (CA19-9) ≥90 U/mL (HR, 3.61; 95% CI, 2.32-5.63; P < .001) were associated with decreased OS. Nonwhite race (HR, 1.67; 95% CI, 1.05-2.63; P = .029) and CA19-9 ≥90 U/mL (HR, 2.86; 95% CI, 1.85-4.40; P < .001) were associated with decreased DFS. CONCLUSIONS DM and insulin use were not associated with OS or DFS in patients with pancreatic cancer in this study. Race, nodal involvement, and increased CA19-9 were significant predictors of outcomes. These data might apply to the more modern use of neoadjuvant therapies for potentially resectable pancreatic cancer.
Collapse
Affiliation(s)
| | - Kathryn A Winter
- NRG Oncology Statistics and Data Management Center, Philadelphia, Pennsylvania
| | - Theodore S Hong
- Massachusetts General Hospital Cancer Center, Boston, Massachusetts
| | | | - William F Regine
- University of Maryland/Greenebaum Cancer Center, Baltimore, Maryland
| | | | | | | | | | | | | | - James F Strauss
- Texas Health Resources Presbyterian Hospital Dallas (accrual under University of Texas/Presbyterian Hospital), Dallas, Texas
| | | | - Philip J Stella
- St. Joseph Mercy Hospital (accrual under Michigan Cancer Research Consortium CCOP), Ypsilanti, Michigan
| | | | - John P Plastaras
- University of Pennsylvania/Abramson Cancer Center, Philadelphia, Pennsylvania
| | | |
Collapse
|
|
30
|
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.
Collapse
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.
| |
Collapse
|
|
31
|
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.
Collapse
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
| |
Collapse
|
|
32
|
Affiliation(s)
- Murray Korc
- From the Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| |
Collapse
|
|
33
|
Xu R, You J, Li F, Yan B. Postoperative Fasting Blood Glucose Predicts Prognosis in Stage I-III Colorectal Cancer Patients Undergoing Resection. Gastroenterol Res Pract 2020; 2020:2482409. [PMID: 32382263 PMCID: PMC7199537 DOI: 10.1155/2020/2482409] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2019] [Revised: 12/25/2019] [Accepted: 12/28/2019] [Indexed: 12/12/2022] Open
Abstract
PURPOSE The relationship between high blood glucose and colorectal cancer (CRC) has been studied, but the role of postoperative fasting blood glucose (FBG) in patients with a prior normal FBG has never been addressed. METHODS A total of 120 CRC patients staged I-III were enrolled, and the prognostic value of postoperative FBG for disease-free survival (DFS) was determined by Kaplan-Meier analysis. Univariate and multivariate analyses were conducted to test other clinicopathological parameters, including preoperative hemoglobin (HGB) and the neutrophil-lymphocyte ratio (NLR). RESULTS By a cut-off point of 5.11 mmol/L, 51 and 69 patients were divided into low postoperative FBG (<5.11 mmol/L) and high postoperative FBG (≥5.11 mmol/L) groups, respectively. A high postoperative FBG was more common in older age (P = 0.01), left-located tumor (P = 0.02), smaller tumor diameter (P = 0.01), node negative involvement (P = 0.01), lesser positive lymph nodes (P = 0.02), and high preoperative HGB (P = 0.01). Further, high postoperative FBG patients displayed a significantly better DFS than low postoperative FBG patients (48.80 ± 22.12 months vs. 40.06 ± 24.36 months, P = 0.04), but it was less likely to be an independent prognostic factor. CONCLUSIONS Postoperative FBG plays a temporal prognostic role for patients with stage I-III CRC with a prior normal FBG, but it is not an independent prognostic factor.
Collapse
Affiliation(s)
- Rui Xu
- Department of Oncology, Hainan Hospital of PLA General Hospital, Sanya city, Hainan province 572000, China
| | - Junhao You
- Department of Oncology, Hainan Hospital of PLA General Hospital, Sanya city, Hainan province 572000, China
| | - Fang Li
- Department of Oncology, Hainan Hospital of PLA General Hospital, Sanya city, Hainan province 572000, China
| | - Bing Yan
- Department of Oncology, Hainan Hospital of PLA General Hospital, Sanya city, Hainan province 572000, China
| |
Collapse
|
|
34
|
Dev R, Bruera E, Dalal S. Insulin resistance and body composition in cancer patients. Ann Oncol 2019; 29 Suppl 2:ii18-ii26. [PMID: 29506229 DOI: 10.1093/annonc/mdx815] [Citation(s) in RCA: 88] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Cancer cachexia, weight loss with altered body composition, is a multifactorial syndrome propagated by symptoms that impair caloric intake, tumor byproducts, chronic inflammation, altered metabolism, and hormonal abnormalities. Cachexia is associated with reduced performance status, decreased tolerance to chemotherapy, and increased mortality in cancer patients. Insulin resistance as a consequence of tumor byproducts, chronic inflammation, and endocrine dysfunction has been associated with weight loss in cancer patients. Insulin resistance in cancer patients is characterized by increased hepatic glucose production and gluconeogenesis, and unlike type 2 diabetes, normal fasting glucose with high, normal or low levels of insulin. Cancer cachexia results in altered body composition with the loss of lean muscle mass with or without the loss of adipose tissue. Alteration in visceral adiposity, accumulation of intramuscular adipose tissue, and secretion of adipocytokines from adipose cells may play a role in promoting the metabolic derangements associated with cachexia including a proinflammatory environment and insulin resistance. Increased production of ghrelin, testosterone deficiency, and low vitamin D levels may also contribute to altered metabolism of glucose. Cancer cachexia cannot be easily reversed by standard nutritional interventions and identifying and treating cachexia at the earliest stage of development is advocated. Experts advocate for multimodal therapy to address symptoms that impact caloric intake, reduce chronic inflammation, and treat metabolic and endocrine derangements, which propagate the loss of weight. Treatment of insulin resistance may be a critical component of multimodal therapy for cancer cachexia and more research is needed.
Collapse
Affiliation(s)
- R Dev
- Department of Symptom Control & Palliative Medicine, University of Texas MD Anderson Cancer Center, Houston, USA
| | - E Bruera
- Department of Symptom Control & Palliative Medicine, University of Texas MD Anderson Cancer Center, Houston, USA
| | - S Dalal
- Department of Symptom Control & Palliative Medicine, University of Texas MD Anderson Cancer Center, Houston, USA
| |
Collapse
|
|
35
|
Gastric Emptying and Distal Gastrectomy Independently Enhance Postprandial Glucagon-Like Peptide-1 Release After a Mixed Meal and Improve Glycemic Control in Subjects Having Undergone Pancreaticoduodenectomy. Pancreas 2019; 48:953-957. [PMID: 31268979 DOI: 10.1097/mpa.0000000000001361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
OBJECTIVES New-onset diabetes frequently resolves after pancreaticoduodenectomy (PD). Glucagon-like peptide-1 (GLP-1) conceivably is involved as its release is enhanced by rapid gastric emptying and distal bowel exposure to nutrients. We aimed at studying factors associated with GLP-1 release after PD. METHODS Fifteen PD subjects with distal gastrectomy (Whipple) and 15 with pylorus preservation were evaluated. A test meal containing 1 g paracetamol to measure gastric emptying was ingested. Blood for the measurement of paracetamol, glucose, insulin, and GLP-1 was drawn at baseline and 10, 20, 30, 60, 90, 120, 150, and 180 minutes thereafter. The Matsuda index of insulin sensitivity was calculated. RESULTS In univariate analysis, gastric emptying correlated with GLP-1. Glucagon-like peptide-1 responses to the modes of operation did not differ. Multiple regression analysis confirmed gastric emptying and Whipple versus pylorus-preserving pancreaticoduodenectomy as independent predictors of GLP-1 release. The Matsuda index of insulin sensitivity correlated with GLP-1 concentrations and inversely with body mass index. Patients after Whipple procedure revealed lower glycated hemoglobin as compared with pylorus-preserving pancreaticoduodenectomy. CONCLUSIONS Following PD, the postprandial GLP-1 release seems to be enhanced by rapid gastric emptying and to improve insulin sensitivity. Partial gastrectomy versus pylorus preservation enhanced the release of GLP-1, conceivably because of greater distal bowel exposure to undigested nutrients.
Collapse
|
|
36
|
Pizzato M, Turati F, Rosato V, La Vecchia C. Exploring the link between diabetes and pancreatic cancer. Expert Rev Anticancer Ther 2019; 19:681-687. [PMID: 31287962 DOI: 10.1080/14737140.2019.1642109] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Introduction: Epidemiological studies indicate an association between type 2 diabetes and pancreatic cancer but the complex and multidirectional relationship between them remains unclear. Areas covered: We summarized epidemiological evidence on diabetes and pancreatic cancer exploring the time-risk relationship. We described mechanisms linking long-standing diabetes to pancreatic cancer. We discussed pancreatic cancer-associated diabetes and its implication in the early detection of pancreatic cancer. Expert opinion: The markedly increased risk of pancreatic cancer in patients with new-onset diabetes compared with long-standing diabetes observed in several epidemiological studies indicates a complex and bidirectional connection, with long-standing diabetes being a predisposing factor for pancreatic cancer (increasing the risk of the malignancy 1.5- to 2-fold) and new-onset diabetes an early manifestation of the tumor. Identifying clinical features and biomarkers to distinguish pancreatic cancer-associated diabetes from type 2 diabetes is an important goal to improve management and survival of this cancer. Imaging (MRI) for middle-age patients with new-onset diabetes may be considered.
Collapse
Affiliation(s)
- Margherita Pizzato
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano , Milan , Italy
| | - Federica Turati
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano , Milan , Italy
| | - Valentina Rosato
- Unit of Medical Statistics and Biometry, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano , Milano , Italy
| | - Carlo La Vecchia
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano , Milan , Italy
| |
Collapse
|
|
37
|
Miguel Martín Guerra J, Martín Asenjo M, Tellería Gómez P, Iglesias Pérez C. Cetoacidosis diabética como guía diagnóstica: Caso clínico. REVISTA MÉDICA CLÍNICA LAS CONDES 2019. [DOI: 10.1016/j.rmclc.2019.06.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
|
|
38
|
Hart PA, Andersen DK, Mather KJ, Castonguay AC, Bajaj M, Bellin MD, Bradley D, Contreras N, Habtezion A, Korc M, Kudva Y, Petrov MS, Whitcomb DC, Yadav D, Yuan Y, Rinaudo JA, Srivastava S, Serrano J. Evaluation of a Mixed Meal Test for Diagnosis and Characterization of PancrEaTogEniC DiabeTes Secondary to Pancreatic Cancer and Chronic Pancreatitis: Rationale and Methodology for the DETECT Study From the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer. Pancreas 2019; 47:1239-1243. [PMID: 30325863 PMCID: PMC6195331 DOI: 10.1097/mpa.0000000000001168] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [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
Pancreatogenic diabetes mellitus is most commonly the result of chronic pancreatitis but can also occur secondary to pancreatic cancer. The early identification of pancreatogenic diabetes and distinction from the more prevalent type 2 diabetes are clinically significant; however, currently, there is no validated method to differentiate these diabetes subtypes. We describe a study, "Evaluation of a Mixed Meal Test for Diagnosis and Characterization of PancrEaTogEniC DiabeTes Secondary to Pancreatic Cancer and Chronic Pancreatitis: the DETECT study," that seeks to address this knowledge gap. The DETECT study is a multicenter study that will examine differences in hormone and glucose excursions after a mixed meal test. The study will also create a biorepository that will be used to evaluate novel diagnostic biomarkers for differentiating these diabetes subtypes.
Collapse
Affiliation(s)
- Phil A. Hart
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Dana K. Andersen
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Kieren J. Mather
- Division of Endocrinology & Metabolism, Indiana University School of Medicine, Indianapolis IN
| | - Alicia C. Castonguay
- Department of Neurology, University of Toledo, College of Medicine, Toledo, OH
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Mandeep Bajaj
- Section of Endocrinology, Diabetes and Metabolism, Baylor College of Medicine, Houston, TX
| | - Melena D. Bellin
- Departments of Pediatrics and Surgery, University of Minnesota Medical School, Minneapolis, MN
| | - David Bradley
- Diabetes and Metabolism Research Center, Division of Endocrinology, Diabetes & Metabolism, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Noemy Contreras
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Aida Habtezion
- Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA
| | - Murray Korc
- Departments of Medicine, and Biochemistry and Molecular Biology, Indiana University School of Medicine, the Melvin and Bren Simon Cancer Center, and the Pancreatic Cancer Signature Center, Indianapolis, IN
| | - Yogish Kudva
- Division of Endocrinology, Mayo Clinic College of Medicine, Rochester, MN
| | - Maxim S. Petrov
- Department of Surgery, University of Auckland, Auckland, New Zealand
| | - David C. Whitcomb
- Departments of Medicine, Cell Biology & Molecular Physiology, and Department of Human Genetics, University of Pittsburgh, and UPMC, Pittsburgh, PA
| | - Dhiraj Yadav
- Division of Gastroenterology & Hepatology, University of Pittsburgh Medical Center, Pittsburgh, PA
| | - Ying Yuan
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Jo Ann Rinaudo
- Cancer Biomarker Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Rockville, MD
| | - Sudhir Srivastava
- Cancer Biomarker Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Rockville, MD
| | - Jose Serrano
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | | |
Collapse
|
|
39
|
Rawla P, Sunkara T, Gaduputi V. Epidemiology of Pancreatic Cancer: Global Trends, Etiology and Risk Factors. World J Oncol 2019; 10:10-27. [PMID: 30834048 PMCID: PMC6396775 DOI: 10.14740/wjon1166] [Citation(s) in RCA: 1462] [Impact Index Per Article: 243.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2018] [Accepted: 11/14/2018] [Indexed: 12/24/2022] Open
Abstract
Pancreatic cancer is the seventh leading cause of cancer-related deaths worldwide. However, its toll is higher in more developed countries. Reasons for vast differences in mortality rates of pancreatic cancer are not completely clear yet, but it may be due to lack of appropriate diagnosis, treatment and cataloging of cancer cases. Because patients seldom exhibit symptoms until an advanced stage of the disease, pancreatic cancer remains one of the most lethal malignant neoplasms that caused 432,242 new deaths in 2018 (GLOBOCAN 2018 estimates). Globally, 458,918 new cases of pancreatic cancer have been reported in 2018, and 355,317 new cases are estimated to occur until 2040. Despite advancements in the detection and management of pancreatic cancer, the 5-year survival rate still stands at 9% only. To date, the causes of pancreatic carcinoma are still insufficiently known, although certain risk factors have been identified, such as tobacco smoking, diabetes mellitus, obesity, dietary factors, alcohol abuse, age, ethnicity, family history and genetic factors, Helicobacter pylori infection, non-O blood group and chronic pancreatitis. In general population, screening of large groups is not considered useful to detect the disease at its early stage, although newer techniques and the screening of tightly targeted groups (especially of those with family history), are being evaluated. Primary prevention is considered of utmost importance. Up-to-date statistics on pancreatic cancer occurrence and outcome along with a better understanding of the etiology and identifying the causative risk factors are essential for the primary prevention of this disease.
Collapse
Affiliation(s)
- Prashanth Rawla
- Department of Internal Medicine, SOVAH Health, Martinsville, VA 24112, USA
| | - Tagore Sunkara
- Department of Gastroenterology and Hepatology, Mercy Medical Center, Des Moines, IA 50314, USA
| | - Vinaya Gaduputi
- Division of Gastroenterology, SBH Health System, Bronx, NY, USA
| |
Collapse
|
|
40
|
Setiawan VW, Stram DO, Porcel J, Chari ST, Maskarinec G, Le Marchand L, Wilkens LR, Haiman CA, Pandol SJ, Monroe KR. Pancreatic Cancer Following Incident Diabetes in African Americans and Latinos: The Multiethnic Cohort. J Natl Cancer Inst 2019; 111:27-33. [PMID: 29917105 PMCID: PMC6335114 DOI: 10.1093/jnci/djy090] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2018] [Revised: 03/08/2018] [Accepted: 04/17/2018] [Indexed: 12/18/2022] Open
Abstract
Background Diabetes has been proposed to be a risk factor for and a consequence of pancreatic cancer (PC). The relationship between recent-onset diabetes and PC is not well understood, and data in minorities are sparse. We examined the relationships between recent-onset diabetes and PC incidence in African Americans and Latinos in the Multiethnic Cohort. Methods A total of 48 995 African Americans and Latinos without prior diabetes and cancer at baseline (1993-1996) were included in the study. Questionnaires, Medicare data, and California hospital discharge files were used to identify new diabetes diagnoses. Cox regressions were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer associated with diabetes and with diabetes duration. Results A total of 15 833 (32.3%) participants developed diabetes between baseline and 2013. A total of 408 incident PC cases were identified during follow-up. Diabetes was associated with PC (HRage75 = 2.39, 95% CI = 1.91 to 2.98). Individuals with recent-onset diabetes (within three or fewer years of PC diagnosis) had a greater risk compared with those with long-term diabetes across all ages. The HRage75 for recent-onset diabetes was 4.08 (95% CI = 2.76 to 6.03) in Latinos and 3.38 (95% CI = 2.30 to 4.98) in African Americans. Conclusions Diabetes was associated with a more than twofold higher risk of PC in African Americans and Latinos, but recent-onset diabetes was associated with a 2.3-fold greater increase in risk of PC than long-standing diabetes. Our findings support the hypothesis that recent-onset diabetes is a manifestation of PC and that long-standing diabetes is a risk factor for this malignancy.
Collapse
Affiliation(s)
- Veronica Wendy Setiawan
- Department of Preventive Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA
- Norris Comprehensive Cancer Center, Keck School of Medicine of University of Southern California, Los Angeles, CA
| | - Daniel O Stram
- Department of Preventive Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA
| | - Jacqueline Porcel
- Norris Comprehensive Cancer Center, Keck School of Medicine of University of Southern California, Los Angeles, CA
| | - Suresh T Chari
- Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN
| | | | - Loïc Le Marchand
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI
| | - Lynne R Wilkens
- Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI
| | - Christopher A Haiman
- Department of Preventive Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA
- Norris Comprehensive Cancer Center, Keck School of Medicine of University of Southern California, Los Angeles, CA
| | - Stephen J Pandol
- Division of Gastroenterology, Departments of Medicine, Cedars-Sinai Medical Center and Department of Veterans Affairs, Los Angeles, CA
| | - Kristine R Monroe
- Department of Preventive Medicine, Keck School of Medicine of University of Southern California, Los Angeles, CA
| |
Collapse
|
|
41
|
Chhoda A, Lu L, Clerkin BM, Risch H, Farrell JJ. Current Approaches to Pancreatic Cancer Screening. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:22-35. [PMID: 30558719 DOI: 10.1016/j.ajpath.2018.09.013] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 08/29/2018] [Accepted: 09/26/2018] [Indexed: 12/19/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of only 8% and is estimated to be the second leading cause of cancer-related deaths by 2021. Prior convention held that screening for PDAC would not be beneficial; however, a deeper understanding of the carcinogenesis pathway supports a potential window of opportunity among the target population. Screening for PDAC is not a standard practice among the general population because of its low incidence. However, screening may be beneficial for individuals with familial history, chronic diseases with genetic predispositions, or inherited cancer syndromes, such as hereditary breast ovarian cancer syndrome, hereditary pancreatitis, Peutz-Jeghers syndrome, familial atypical multiple mole melanoma, Lynch syndrome (hereditary nonpolyposis colorectal cancer), ataxia telangiectasia, and Li-Fraumeni syndrome, all of which have been associated with an increased risk of developing PDAC. The screening strategies among these high-risk individuals are targeted to identify precursor lesions and PDAC at an early resectable stage. This review describes the risk factors for pancreatic cancer, especially the genetic risk factors in high-risk individuals and current screening strategies available for PDAC.
Collapse
Affiliation(s)
- Ankit Chhoda
- Yale Waterbury Internal Medicine Program, Yale School of Medicine, New Haven, Connecticut
| | - Lingeng Lu
- Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut
| | - Barbara M Clerkin
- Pancreatic Disease Program, Yale School of Medicine, New Haven, Connecticut
| | - Harvey Risch
- Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut
| | - James J Farrell
- Yale Center for Pancreatic Diseases, Yale School of Medicine, New Haven, Connecticut; Yale Center for Pancreatic Diseases, Department of Digestive Diseases, Yale School of Public Health, New Haven, Connecticut.
| |
Collapse
|
|
42
|
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.
Collapse
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
| |
Collapse
|
|
43
|
Zhang Z, Qin W, Sun Y. Contribution of biomarkers for pancreatic cancer-associated new-onset diabetes to pancreatic cancer screening. Pathol Res Pract 2018; 214:1923-1928. [PMID: 30477640 DOI: 10.1016/j.prp.2018.10.003] [Citation(s) in RCA: 4] [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: 07/11/2018] [Revised: 09/09/2018] [Accepted: 10/17/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Pancreatic cancer (PaC) is one of the deadliest types of tumor, and it is regarded as a fatal disease, with a 5-year survival rate less than 10%. Most clinical diagnoses for PaC are made at an advanced stage because of the insidious onset of the disease, which leads to an extremely poor prognosis. RECENT FINDINGS The relationship between diabetes mellitus (DM) and PaC has been established by several decades of research, and the prevalence of DM in patients with PaC has been reported to be 40%, with half of the patients having developed new-onset DM within 2 years or less. Increasing evidence suggests that new-onset DM is associated with a high prevalence of PaC, and PaC resection ameliorates DM. Therefore, screening for PaC may be needed in patients with newly developed DM. PURPOSE The objective of this review was to present our current understanding of biomarkers for PaC-associated new-onset DM (PCAND), to offer a perspective on the prospects and problems of using this strategy for early screening to differentiate PCAND from new-onset type 2 DM not associated with PaC and to suggest candidate biomarkers to use for PaC screening in patients with new-onset DM. Finding sensitive and specific biomarkers to manage these patients constitutes a challenge for the research community and for public health policies.
Collapse
Affiliation(s)
- Zhenjun Zhang
- Institute of Hepatobiliary and Pancreatic Diseases, School of Medicine, Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, China
| | - Wenjie Qin
- Institute of Hepatobiliary and Pancreatic Diseases, School of Medicine, Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, China
| | - Yuling Sun
- Institute of Hepatobiliary and Pancreatic Diseases, School of Medicine, Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, China.
| |
Collapse
|
|
44
|
The Role of Insulin-like Growth Factor (IGF) Axis in Early Diagnosis of Pancreatic Adenocarcinoma (PDAC). J Clin Gastroenterol 2018; 52:569-572. [PMID: 29912760 DOI: 10.1097/mcg.0000000000001073] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
New-onset diabetes mellitus (DM) is one of the first symptoms of pancreatic adenocarcinoma (PDAC). The frequency of endocrine disorders is estimated between 40% and 80% in patients with pancreatic cancer. DM is a risk factor for cancer development but it may also be a consequence of the tumor growth. Data confirming the existence of a relationship between long standing type 2 DM and an increased risk of PDAC comes from numerous clinical studies. Insulin resistance phenomenon and hyperinsulinemia may result in the increased proliferation of pancreatic islets which in turn may cause a predisposition to cancer development. In contrast, it is proved that new-onset DM among patients over 50 years old significantly increases the risk of PDAC recognition. Insulin-like growth factor 1 (IGF-1) and their complex proteins, IGF binding proteins, which comprise the IGF axis play a crucial role in carbohydrate metabolism disorders and, studies have shown that they may contribute to PDAC growth. Some studies confirm that IGF-1 is connected with early carcinogenesis in animals and humans. Assessing the levels of these proteins may thus be helpful in early recognition of PDAC in patients with recently detected endocrine disorders, especially pancreatic DM.
Collapse
|
|
45
|
Lee S, Hwang HK, Kang CM, Lee WJ. Adverse Oncologic Impact of New-Onset Diabetes Mellitus on Recurrence in Resected Pancreatic Ductal Adenocarcinoma: A Comparison With Long-standing and Non-Diabetes Mellitus Patients. Pancreas 2018; 47:816-822. [PMID: 29975349 DOI: 10.1097/mpa.0000000000001099] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVES Diabetes mellitus (DM) is prevalent with pancreatic ductal adenocarcinoma (PDAC). Importantly, new-onset DM is characteristic of the disease and could be an early sign of PDAC. The clinical outcome of PDAC with new-onset DM may differ from that in patients without DM or long-standing DM. METHODS We retrospectively reviewed medical records of PDAC patients who underwent curative resection between 2006 and 2014. New-onset DM was defined as a diagnosis of DM within 24 months before the diagnosis of PDAC. Survival analysis and Cox regression were performed to evaluate oncologic outcomes. RESULTS No significant differences in clinical characteristics were found in 3 groups. Overall survival of patients with new-onset DM was worse than non-DM (22 vs 33 months, P = 0.039). New-onset DM was highly associated with early recurrence (hazard ratio, 1.451; 95% confidence interval, 1.054-1.999; P = 0.022). Poor oncologic outcome of new-onset DM was more pronounced in low T stage patients (overall survival in low vs high T stage, 33 vs 18 months; P = 0.129). CONCLUSIONS Pancreatic ductal adenocarcinoma with new-onset DM has worse oncologic outcomes than non-DM or long-standing DM. These results suggest that new-onset DM represents aggressive tumor biology, especially in the early stage of PDAC.
Collapse
|
|
46
|
Thuesen ACB, Vaag A. Perspectives on diabetes mortality as the result of residual confounding and reverse causality by common disease. Diabetes Obes Metab 2018; 20:1342-1349. [PMID: 29381250 DOI: 10.1111/dom.13238] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 01/16/2018] [Accepted: 01/24/2018] [Indexed: 12/17/2022]
Abstract
Type 2 diabetes (T2D) is associated with major global health burdens, including 2 to 4 times increased rates of morbidity and mortality from cardiovascular disease. However, T2D remains an exclusion diagnosis in individuals with arbitrarily elevated blood-glucose levels. While it is well-established that diabetes is associated with an elevated risk of cardiovascular disease and cancer, it has recently been shown that heart failure and cancer may precede, and even contribute to, the development of T2D. In the present review, we have summarized these findings and discuss their potential implications for our understanding of the T2D disease entity, including its treatment and associated increased mortality. We suggest that the existence of a hitherto unrecognized distinct T2D subtype, secondary to heart failure and/or cancer, may substantially contribute to the excess mortality reported in T2D patients with mild disease. Treatment and clinical care of this subtype needs to be defined separately from the general T2D phenotype.
Collapse
Affiliation(s)
| | - Allan Vaag
- Cardiovascular and Metabolic Disease (CVMD) Translational Medicine Unit, Early Clinical Development, IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden
| |
Collapse
|
|
47
|
Desai D, Rao D, Sukrithan V, Weinstein E, Goyal A, Schubart U. Pancreatic Cancer Heralded by Worsening Glycemic Control: A Report of Two Cases. J Investig Med High Impact Case Rep 2017. [PMID: 28634594 PMCID: PMC5468763 DOI: 10.1177/2324709617714286] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Pancreatic ductal adenocarcinoma is the third leading cause of cancer-related death in the United States. Since it is usually diagnosed at an advanced stage, its prognosis remains poor. The initial presentation varies according to the tumor location. The most common presenting signs are weight loss, jaundice, and pain. Several epidemiological, clinical, and experimental studies over the past 2 decades have shown that long-standing diabetes is a modest risk factor for pancreatic cancer. However, new-onset diabetes has also been observed to be an early manifestation of pancreatic cancer. We report 2 cases where worsening glycemic control led to the diagnosis of pancreatic cancer.
Collapse
Affiliation(s)
| | - Devika Rao
- Montefiore Hospital and Medical Center, Bronx, NY, USA
| | | | | | | | | |
Collapse
|
|
48
|
Andersen DK, Korc M, Petersen GM, Eibl G, Li D, Rickels MR, Chari ST, Abbruzzese JL. Diabetes, Pancreatogenic Diabetes, and Pancreatic Cancer. Diabetes 2017; 66:1103-1110. [PMID: 28507210 PMCID: PMC5399609 DOI: 10.2337/db16-1477] [Citation(s) in RCA: 298] [Impact Index Per Article: 37.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 01/25/2017] [Indexed: 12/16/2022]
Abstract
The relationships between diabetes and pancreatic ductal adenocarcinoma (PDAC) are complex. Longstanding type 2 diabetes (T2DM) is a risk factor for pancreatic cancer, but increasing epidemiological data point to PDAC as also a cause of diabetes due to unknown mechanisms. New-onset diabetes is of particular interest to the oncology community as the differentiation of new-onset diabetes caused by PDAC as distinct from T2DM may allow for earlier diagnosis of PDAC. To address these relationships and raise awareness of the relationships between PDAC and diabetes, a symposium entitled Diabetes, Pancreatogenic Diabetes, and Pancreatic Cancer was held at the American Diabetes Association's 76th Scientific Sessions in June 2016. This article summarizes the data presented at that symposium, describing the current understanding of the interrelationships between diabetes, diabetes management, and pancreatic cancer, and identifies areas where additional research is needed.
Collapse
MESH Headings
- Blood Glucose/metabolism
- Carcinoma, Pancreatic Ductal/epidemiology
- Carcinoma, Pancreatic Ductal/genetics
- Carcinoma, Pancreatic Ductal/immunology
- Causality
- Diabetes Mellitus/classification
- Diabetes Mellitus/drug therapy
- Diabetes Mellitus/epidemiology
- Diabetes Mellitus/etiology
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/epidemiology
- Diabetes Mellitus, Type 2/genetics
- Diabetes Mellitus, Type 2/metabolism
- Genetic Predisposition to Disease
- Humans
- Hypoglycemic Agents/therapeutic use
- Inflammation
- Obesity/epidemiology
- Obesity/immunology
- Pancreatic Neoplasms/epidemiology
- Pancreatic Neoplasms/genetics
- Pancreatic Neoplasms/immunology
- Pancreatitis, Chronic/complications
- Pancreatitis, Chronic/epidemiology
- Pancreatitis, Chronic/genetics
- Pancreatitis, Chronic/immunology
- Risk Factors
Collapse
Affiliation(s)
- Dana K Andersen
- Division of Digestive Diseases and Nutrition, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
| | - Murray Korc
- Division of Endocrinology, Department of Medicine, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, and Indiana University Melvin and Bren Simon Cancer Center and Pancreatic Cancer Signature Center, Indianapolis, IN
| | | | - Guido Eibl
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA
| | - Donghui Li
- Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX
| | - Michael R Rickels
- Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Suresh T Chari
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN
| | - James L Abbruzzese
- Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, NC
| |
Collapse
|
|
49
|
Ben Q, Zhong J, Fei J, Chen H, Yv L, Tan J, Yuan Y. Risk Factors for Sporadic Pancreatic Neuroendocrine Tumors: A Case-Control Study. Sci Rep 2016; 6:36073. [PMID: 27782199 PMCID: PMC5080551 DOI: 10.1038/srep36073] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Accepted: 10/11/2016] [Indexed: 02/06/2023] Open
Abstract
The current study examined risk factors for sporadic pancreatic neuroendocrine tumors (PNETs), including smoking, alcohol use, first-degree family history of any cancer (FHC), and diabetes in the Han Chinese ethnic group. In this clinic-based case-control analysis on 385 patients with sporadic PNETs and 614 age- and sex-matched controls, we interviewed subjects using a specific questionnaire on demographics and potential risk factors. An unconditional multivariable logistic regression analysis was used to estimate adjusted odds ratios (AORs). No significant differences were found between patients and controls in terms of demographic variables. Most of the patients with PNETs had well-differentiated PNETs (G1, 62.9%) and non-advanced European Neuroendocrine Tumor Society (ENETS) stage (stage I or II, 83.9%). Ever/heavy smoking, a history of diabetes and a first-degree FHC were independent risk factors for non-functional PNETs. Only heavy drinking was found to be an independent risk factor for functional PNETs (AOR = 1.87; 95% confidence interval [CI], 1.01–3.51). Ever/heavy smoking was also associated with advanced ENETS staging (stage III or IV) at the time of diagnosis. This study identified first-degree FHC, ever/heavy smoking, and diabetes as risk factors for non-functional PNETs, while heavy drinking as a risk factor for functional PNETs.
Collapse
Affiliation(s)
- Qiwen Ben
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University, Shanghai, 200025, China
| | - Jie Zhong
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University, Shanghai, 200025, China
| | - Jian Fei
- Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University, Shanghai, 200025, China
| | - Haitao Chen
- Department of Geriatrics, Changhai Hospital of Second Military Medical University, Shanghai, China
| | - Lifen Yv
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University, Shanghai, 200025, China
| | - Jihong Tan
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University, Shanghai, 200025, China
| | - Yaozong Yuan
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiaotong University, Shanghai, 200025, China
| |
Collapse
|
|
50
|
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.
Collapse
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
| |
Collapse
|