Skip to main content
Erschienen in: Acta Diabetologica 6/2016

23.08.2016 | Original Article

Insulin resistance is associated with the aggressiveness of pancreatic ductal carcinoma

verfasst von: Erica Dugnani, Gianpaolo Balzano, Valentina Pasquale, Marina Scavini, Francesca Aleotti, Daniela Liberati, Gaetano Di Terlizzi, Alessandra Gandolfi, Giovanna Petrella, Michele Reni, Claudio Doglioni, Emanuele Bosi, Massimo Falconi, Lorenzo Piemonti

Erschienen in: Acta Diabetologica | Ausgabe 6/2016

Einloggen, um Zugang zu erhalten

Abstract

Aims

To study whether insulin resistance accelerates the development and/or the progression of pancreatic adenocarcinoma (PDAC), we hypothesized that patients with insulin resistance, compared with those without insulin resistance, show: (1) a younger age and more advanced PDAC stage at diagnosis and (2) a shorter disease-free and overall survival after PDAC diagnosis.

Methods

Prospective observational study of patients admitted to a referral center for pancreatic disease. Insulin resistance was defined as a HOMA-IR value greater than the 66th percentile value of the patients included in this study. Survival was estimated according to Kaplan–Meier and by Cox regression.

Results

Of 296 patients with PDAC, 99 (33 %) met criteria for being classified as insulin resistant at diagnosis. Median follow-up time after diagnosis was 5.27 ± 0.23 years. Patients with insulin resistance received a diagnosis of PDAC at a similar age compared to patients without insulin resistance (67.1 ± 9 vs. 66.8 ± 10 years, p = 0.68), but were more likely to have a cancer stage ≥3 (23.2 vs. 14.2 %, p = 0.053) and a residual disease after surgery (R1 56.4 vs. 38 %; p = 0.007). The median overall survival was 1.3 ± 0.14 and 1.79 ± 0.11 years for the patients with and without insulin resistance, respectively (p = 0.016). Results did not change when patients with diabetes at PDAC diagnosis were excluded from the analysis. Multivariate analysis showed that insulin resistance was independently associated with overall survival.

Conclusions

Insulin resistance is associated with the aggressiveness of PDAC.
Literatur
1.
Zurück zum Zitat Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R (2009) Diabetes and cancer. Endocr Relat Cancer 16:1103–1123CrossRefPubMed Vigneri P, Frasca F, Sciacca L, Pandini G, Vigneri R (2009) Diabetes and cancer. Endocr Relat Cancer 16:1103–1123CrossRefPubMed
2.
Zurück zum Zitat Tsilidis KK, Kasimis JC, Lopez DS, Ntzani EE, Ioannidis JP (2015) Type 2 diabetes and cancer: umbrella review of meta-analyses of observational studies. BMJ 350:g7607CrossRefPubMed Tsilidis KK, Kasimis JC, Lopez DS, Ntzani EE, Ioannidis JP (2015) Type 2 diabetes and cancer: umbrella review of meta-analyses of observational studies. BMJ 350:g7607CrossRefPubMed
3.
Zurück zum Zitat Carstensen B, Read SH, Friis S et al (2016) Cancer incidence in persons with type 1 diabetes: a five-country study of 9000 cancers in type 1 diabetic individuals. Diabetologia 59:980–988CrossRefPubMedPubMedCentral Carstensen B, Read SH, Friis S et al (2016) Cancer incidence in persons with type 1 diabetes: a five-country study of 9000 cancers in type 1 diabetic individuals. Diabetologia 59:980–988CrossRefPubMedPubMedCentral
4.
Zurück zum Zitat Pannala R, Basu A, Petersen GM, Chari ST (2009) New-onset diabetes: a potential clue to the early diagnosis of pancreatic cancer. Lancet Oncol 10:88–95CrossRefPubMedPubMedCentral Pannala R, Basu A, Petersen GM, Chari ST (2009) New-onset diabetes: a potential clue to the early diagnosis of pancreatic cancer. Lancet Oncol 10:88–95CrossRefPubMedPubMedCentral
5.
Zurück zum Zitat Sah RP, Nagpal SJ, Mukhopadhyay D, Chari ST (2013) New insights into pancreatic cancer-induced paraneoplastic diabetes. Nat Rev Gastroenterol Hepatol 10:423–433CrossRefPubMedPubMedCentral Sah RP, Nagpal SJ, Mukhopadhyay D, Chari ST (2013) New insights into pancreatic cancer-induced paraneoplastic diabetes. Nat Rev Gastroenterol Hepatol 10:423–433CrossRefPubMedPubMedCentral
6.
Zurück zum Zitat Illes D, Terzin V, Holzinger G et al (2016) New-onset type 2 diabetes mellitus—a high-risk group suitable for the screening of pancreatic cancer? Pancreatology 16:266–271CrossRefPubMed Illes D, Terzin V, Holzinger G et al (2016) New-onset type 2 diabetes mellitus—a high-risk group suitable for the screening of pancreatic cancer? Pancreatology 16:266–271CrossRefPubMed
8.
Zurück zum Zitat Hart PA, Chari ST (2013) Diabetes mellitus and pancreatic cancer: why the association matters? Pancreas 42:1207–1209CrossRefPubMed Hart PA, Chari ST (2013) Diabetes mellitus and pancreatic cancer: why the association matters? Pancreas 42:1207–1209CrossRefPubMed
9.
Zurück zum Zitat Elena JW, Steplowski E, Yu K et al (2013) Diabetes and risk of pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium. Cancer Causes Control 24:13–25CrossRefPubMed Elena JW, Steplowski E, Yu K et al (2013) Diabetes and risk of pancreatic cancer: a pooled analysis from the pancreatic cancer cohort consortium. Cancer Causes Control 24:13–25CrossRefPubMed
10.
Zurück zum Zitat Huxley R, Ansary-Moghaddam A, Berrington de Gonzalez A, Barzi F, Woodward M (2005) Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies. Br J Cancer 92:2076–2083CrossRefPubMedPubMedCentral Huxley R, Ansary-Moghaddam A, Berrington de Gonzalez A, Barzi F, Woodward M (2005) Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies. Br J Cancer 92:2076–2083CrossRefPubMedPubMedCentral
11.
Zurück zum Zitat Song S, Wang B, Zhang X et al (2015) Long-term diabetes mellitus is associated with an increased risk of pancreatic cancer: a meta-analysis. PLoS One 10:e0134321CrossRefPubMedPubMedCentral Song S, Wang B, Zhang X et al (2015) Long-term diabetes mellitus is associated with an increased risk of pancreatic cancer: a meta-analysis. PLoS One 10:e0134321CrossRefPubMedPubMedCentral
12.
Zurück zum Zitat Ben Q, Xu M, Ning X et al (2011) Diabetes mellitus and risk of pancreatic cancer: a meta-analysis of cohort studies. Eur J Cancer 47:1928–1937CrossRefPubMed Ben Q, Xu M, Ning X et al (2011) Diabetes mellitus and risk of pancreatic cancer: a meta-analysis of cohort studies. Eur J Cancer 47:1928–1937CrossRefPubMed
13.
Zurück zum Zitat Jee SH, Ohrr H, Sull JW, Yun JE, Ji M, Samet JM (2005) Fasting serum glucose level and cancer risk in Korean men and women. JAMA 293:194–202CrossRefPubMed Jee SH, Ohrr H, Sull JW, Yun JE, Ji M, Samet JM (2005) Fasting serum glucose level and cancer risk in Korean men and women. JAMA 293:194–202CrossRefPubMed
14.
Zurück zum Zitat Gapstur SM, Gann PH, Lowe W, Liu K, Colangelo L, Dyer A (2000) Abnormal glucose metabolism and pancreatic cancer mortality. JAMA 283:2552–2558CrossRefPubMed Gapstur SM, Gann PH, Lowe W, Liu K, Colangelo L, Dyer A (2000) Abnormal glucose metabolism and pancreatic cancer mortality. JAMA 283:2552–2558CrossRefPubMed
15.
Zurück zum Zitat Stolzenberg-Solomon RZ, Graubard BI, Chari S et al (2005) Insulin, glucose, insulin resistance, and pancreatic cancer in male smokers. JAMA 294:2872–2878CrossRefPubMed Stolzenberg-Solomon RZ, Graubard BI, Chari S et al (2005) Insulin, glucose, insulin resistance, and pancreatic cancer in male smokers. JAMA 294:2872–2878CrossRefPubMed
16.
Zurück zum Zitat Bosetti C, Rosato V, Li D et al (2014) Diabetes, antidiabetic medications, and pancreatic cancer risk: an analysis from the International pancreatic cancer case–control consortium. Ann Oncol 25:2065–2072CrossRefPubMedPubMedCentral Bosetti C, Rosato V, Li D et al (2014) Diabetes, antidiabetic medications, and pancreatic cancer risk: an analysis from the International pancreatic cancer case–control consortium. Ann Oncol 25:2065–2072CrossRefPubMedPubMedCentral
17.
Zurück zum Zitat Chari ST, Leibson CL, Rabe KG et al (2008) Pancreatic cancer-associated diabetes mellitus: prevalence and temporal association with diagnosis of cancer. Gastroenterology 134:95–101CrossRefPubMed Chari ST, Leibson CL, Rabe KG et al (2008) Pancreatic cancer-associated diabetes mellitus: prevalence and temporal association with diagnosis of cancer. Gastroenterology 134:95–101CrossRefPubMed
18.
Zurück zum Zitat Pannala R, Leibson CL, Rabe KG et al (2009) Temporal association of changes in fasting blood glucose and body mass index with diagnosis of pancreatic cancer. Am J Gastroenterol 104:2318–2325CrossRefPubMedPubMedCentral Pannala R, Leibson CL, Rabe KG et al (2009) Temporal association of changes in fasting blood glucose and body mass index with diagnosis of pancreatic cancer. Am J Gastroenterol 104:2318–2325CrossRefPubMedPubMedCentral
19.
Zurück zum Zitat Andersen DK, Andren-Sandberg A, Duell EJ et al (2013) Pancreatitis-diabetes-pancreatic cancer: summary of an NIDDK-NCI workshop. Pancreas 42:1227–1237CrossRefPubMed Andersen DK, Andren-Sandberg A, Duell EJ et al (2013) Pancreatitis-diabetes-pancreatic cancer: summary of an NIDDK-NCI workshop. Pancreas 42:1227–1237CrossRefPubMed
22.
Zurück zum Zitat Trajkovic-Arsic M, Kalideris E, Siveke JT (2013) The role of insulin and IGF system in pancreatic cancer. J Mol Endocrinol 50:R67–R74CrossRefPubMed Trajkovic-Arsic M, Kalideris E, Siveke JT (2013) The role of insulin and IGF system in pancreatic cancer. J Mol Endocrinol 50:R67–R74CrossRefPubMed
23.
Zurück zum Zitat Valsecchi ME, McDonald M, Brody JR et al (2012) Epidermal growth factor receptor and insulinlike growth factor 1 receptor expression predict poor survival in pancreatic ductal adenocarcinoma. Cancer 118:3484–3493CrossRefPubMed Valsecchi ME, McDonald M, Brody JR et al (2012) Epidermal growth factor receptor and insulinlike growth factor 1 receptor expression predict poor survival in pancreatic ductal adenocarcinoma. Cancer 118:3484–3493CrossRefPubMed
24.
Zurück zum Zitat Fisher WE, Boros LG, Schirmer WJ (1996) Insulin promotes pancreatic cancer: evidence for endocrine influence on exocrine pancreatic tumors. J Surg Res 63:310–313CrossRefPubMed Fisher WE, Boros LG, Schirmer WJ (1996) Insulin promotes pancreatic cancer: evidence for endocrine influence on exocrine pancreatic tumors. J Surg Res 63:310–313CrossRefPubMed
25.
Zurück zum Zitat Arcidiacono B, Iiritano S, Nocera A et al (2012) Insulin resistance and cancer risk: an overview of the pathogenetic mechanisms. Exp Diabetes Res 2012:789174CrossRefPubMedPubMedCentral Arcidiacono B, Iiritano S, Nocera A et al (2012) Insulin resistance and cancer risk: an overview of the pathogenetic mechanisms. Exp Diabetes Res 2012:789174CrossRefPubMedPubMedCentral
27.
Zurück zum Zitat Cohen DH, LeRoith D (2012) Obesity, type 2 diabetes, and cancer: the insulin and IGF connection. Endocr Relat Cancer 19:F27–F45CrossRefPubMed Cohen DH, LeRoith D (2012) Obesity, type 2 diabetes, and cancer: the insulin and IGF connection. Endocr Relat Cancer 19:F27–F45CrossRefPubMed
28.
Zurück zum Zitat Kaklamani VG, Linos A, Kaklamani E, Markaki I, Koumantaki Y, Mantzoros CS (1999) Dietary fat and carbohydrates are independently associated with circulating insulin-like growth factor 1 and insulin-like growth factor-binding protein 3 concentrations in healthy adults. J Clin Oncol 17:3291–3298PubMed Kaklamani VG, Linos A, Kaklamani E, Markaki I, Koumantaki Y, Mantzoros CS (1999) Dietary fat and carbohydrates are independently associated with circulating insulin-like growth factor 1 and insulin-like growth factor-binding protein 3 concentrations in healthy adults. J Clin Oncol 17:3291–3298PubMed
29.
Zurück zum Zitat Kaklamani VG, Linos A, Kaklamani E, Markaki I, Mantzoros C (1999) Age, sex, and smoking are predictors of circulating insulin-like growth factor 1 and insulin-like growth factor-binding protein 3. J Clin Oncol 17:813–817PubMed Kaklamani VG, Linos A, Kaklamani E, Markaki I, Mantzoros C (1999) Age, sex, and smoking are predictors of circulating insulin-like growth factor 1 and insulin-like growth factor-binding protein 3. J Clin Oncol 17:813–817PubMed
30.
Zurück zum Zitat Balzano G, Dugnani E, Pasquale V et al (2014) Clinical signature and pathogenetic factors of diabetes associated with pancreas disease (T3cDM): a prospective observational study in surgical patients. Acta Diabetol 51:801–811CrossRefPubMed Balzano G, Dugnani E, Pasquale V et al (2014) Clinical signature and pathogenetic factors of diabetes associated with pancreas disease (T3cDM): a prospective observational study in surgical patients. Acta Diabetol 51:801–811CrossRefPubMed
31.
Zurück zum Zitat Wallace TM, Levy JC, Matthews DR (2004) Use and abuse of HOMA modeling. Diabetes Care 27:1487–1495CrossRefPubMed Wallace TM, Levy JC, Matthews DR (2004) Use and abuse of HOMA modeling. Diabetes Care 27:1487–1495CrossRefPubMed
32.
Zurück zum Zitat Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D (1999) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of diet in renal disease study group. Ann Intern Med 130:461–470CrossRefPubMed Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D (1999) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of diet in renal disease study group. Ann Intern Med 130:461–470CrossRefPubMed
33.
Zurück zum Zitat Templeton AJ, McNamara MG, Seruga B et al (2014) Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J Natl Cancer Inst 106:dju124CrossRefPubMed Templeton AJ, McNamara MG, Seruga B et al (2014) Prognostic role of neutrophil-to-lymphocyte ratio in solid tumors: a systematic review and meta-analysis. J Natl Cancer Inst 106:dju124CrossRefPubMed
34.
Zurück zum Zitat Ni XJ, Zhang XL, Ou-Yang QW et al (2014) An elevated peripheral blood lymphocyte-to-monocyte ratio predicts favorable response and prognosis in locally advanced breast cancer following neoadjuvant chemotherapy. PLoS One 9:e111886CrossRefPubMedPubMedCentral Ni XJ, Zhang XL, Ou-Yang QW et al (2014) An elevated peripheral blood lymphocyte-to-monocyte ratio predicts favorable response and prognosis in locally advanced breast cancer following neoadjuvant chemotherapy. PLoS One 9:e111886CrossRefPubMedPubMedCentral
35.
Zurück zum Zitat Kanda M, Fujii T, Kodera Y, Nagai S, Takeda S, Nakao A (2011) Nutritional predictors of postoperative outcome in pancreatic cancer. Br J Surg 98:268–274CrossRefPubMed Kanda M, Fujii T, Kodera Y, Nagai S, Takeda S, Nakao A (2011) Nutritional predictors of postoperative outcome in pancreatic cancer. Br J Surg 98:268–274CrossRefPubMed
36.
Zurück zum Zitat Cereda E, Pedrolli C (2009) The Geriatric Nutritional Risk Index. Curr Opin Clin Nutr Metab care 12:1–7CrossRefPubMed Cereda E, Pedrolli C (2009) The Geriatric Nutritional Risk Index. Curr Opin Clin Nutr Metab care 12:1–7CrossRefPubMed
37.
Zurück zum Zitat Grote VA, Rohrmann S, Nieters A et al (2011) Diabetes mellitus, glycated haemoglobin and C-peptide levels in relation to pancreatic cancer risk: a study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Diabetologia 54:3037–3046CrossRefPubMed Grote VA, Rohrmann S, Nieters A et al (2011) Diabetes mellitus, glycated haemoglobin and C-peptide levels in relation to pancreatic cancer risk: a study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Diabetologia 54:3037–3046CrossRefPubMed
38.
Zurück zum Zitat Chari ST, Zapiach M, Yadav D, Rizza RA (2005) Beta-cell function and insulin resistance evaluated by HOMA in pancreatic cancer subjects with varying degrees of glucose intolerance. Pancreatology 5:229–233CrossRefPubMed Chari ST, Zapiach M, Yadav D, Rizza RA (2005) Beta-cell function and insulin resistance evaluated by HOMA in pancreatic cancer subjects with varying degrees of glucose intolerance. Pancreatology 5:229–233CrossRefPubMed
39.
Zurück zum Zitat Jiao L, Weinstein SJ, Albanes D et al (2011) Evidence that serum levels of the soluble receptor for advanced glycation end products are inversely associated with pancreatic cancer risk: a prospective study. Cancer Res 71:3582–3589CrossRefPubMedPubMedCentral Jiao L, Weinstein SJ, Albanes D et al (2011) Evidence that serum levels of the soluble receptor for advanced glycation end products are inversely associated with pancreatic cancer risk: a prospective study. Cancer Res 71:3582–3589CrossRefPubMedPubMedCentral
40.
Zurück zum Zitat Michaud DS, Wolpin B, Giovannucci E et al (2007) Prediagnostic plasma C-peptide and pancreatic cancer risk in men and women. Cancer Epidemiol Biomark Prev 16:2101–2109CrossRef Michaud DS, Wolpin B, Giovannucci E et al (2007) Prediagnostic plasma C-peptide and pancreatic cancer risk in men and women. Cancer Epidemiol Biomark Prev 16:2101–2109CrossRef
41.
Zurück zum Zitat Wolpin BM, Bao Y, Qian ZR et al (2013) Hyperglycemia, insulin resistance, impaired pancreatic beta-cell function, and risk of pancreatic cancer. J Natl Cancer Inst 105:1027–1035CrossRefPubMedPubMedCentral Wolpin BM, Bao Y, Qian ZR et al (2013) Hyperglycemia, insulin resistance, impaired pancreatic beta-cell function, and risk of pancreatic cancer. J Natl Cancer Inst 105:1027–1035CrossRefPubMedPubMedCentral
42.
Zurück zum Zitat van de Poll-Franse LV, Houterman S, Janssen-Heijnen ML, Dercksen MW, Coebergh JW, Haak HR (2007) Less aggressive treatment and worse overall survival in cancer patients with diabetes: a large population based analysis. Int J Cancer 120:1986–1992CrossRefPubMed van de Poll-Franse LV, Houterman S, Janssen-Heijnen ML, Dercksen MW, Coebergh JW, Haak HR (2007) Less aggressive treatment and worse overall survival in cancer patients with diabetes: a large population based analysis. Int J Cancer 120:1986–1992CrossRefPubMed
43.
Zurück zum Zitat Alberti KG, Zimmet PZ (1998) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 15:539–553CrossRefPubMed Alberti KG, Zimmet PZ (1998) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 15:539–553CrossRefPubMed
44.
Zurück zum Zitat Tang Q, Li X, Song P, Xu L (2016) Optimal cut-off values for the homeostasis model assessment of insulin resistance (HOMA-IR) and pre-diabetes screening: developments in research and prospects for the future. Drug Discov Ther 9:380–385CrossRef Tang Q, Li X, Song P, Xu L (2016) Optimal cut-off values for the homeostasis model assessment of insulin resistance (HOMA-IR) and pre-diabetes screening: developments in research and prospects for the future. Drug Discov Ther 9:380–385CrossRef
45.
Zurück zum Zitat Perseghin G, Calori G, Lattuada G et al (2012) Insulin resistance/hyperinsulinemia and cancer mortality: the Cremona study at the 15th year of follow-up. Acta Diabetol 49:421–428CrossRefPubMed Perseghin G, Calori G, Lattuada G et al (2012) Insulin resistance/hyperinsulinemia and cancer mortality: the Cremona study at the 15th year of follow-up. Acta Diabetol 49:421–428CrossRefPubMed
Metadaten
Titel
Insulin resistance is associated with the aggressiveness of pancreatic ductal carcinoma
verfasst von
Erica Dugnani
Gianpaolo Balzano
Valentina Pasquale
Marina Scavini
Francesca Aleotti
Daniela Liberati
Gaetano Di Terlizzi
Alessandra Gandolfi
Giovanna Petrella
Michele Reni
Claudio Doglioni
Emanuele Bosi
Massimo Falconi
Lorenzo Piemonti
Publikationsdatum
23.08.2016
Verlag
Springer Milan
Erschienen in
Acta Diabetologica / Ausgabe 6/2016
Print ISSN: 0940-5429
Elektronische ISSN: 1432-5233
DOI
https://doi.org/10.1007/s00592-016-0893-6

Weitere Artikel der Ausgabe 6/2016

Acta Diabetologica 6/2016 Zur Ausgabe

Leitlinien kompakt für die Innere Medizin

Mit medbee Pocketcards sicher entscheiden.

Seit 2022 gehört die medbee GmbH zum Springer Medizin Verlag

Update Innere Medizin

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.