PDF herunterladen
Horm Metab Res 2014; 46(09): 615-620
DOI: 10.1055/s-0034-1370967
Endocrine Research
© Georg Thieme Verlag KG Stuttgart · New York

Higher Insulin Sensitivity and Impaired Insulin Secretion in Cachetic Solid Ehrlich Tumour-Bearing Mice

N. M. Violato
1   Institute of Bioscience, São Paulo State University, Botucatu, SP, Brazil
,
A. Rafacho
2   Department of Physiological Sciences, Center of Biological Sciences, Federal University of Santa Catarina, Florianópolis, SC, Brazil
,
A. C. Boschero
3   Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas, SP, Brazil
,
J. R. Bosqueiro
4   Department of Physical Education, Faculty of Sciences, São Paulo State University, Bauru, SP, Brazil
› Institutsangaben
Weitere Informationen

Publikationsverlauf

received 19. September 2013

accepted 12. Februar 2014

Publikationsdatum:
18. März 2014 (online)

Auch verfügbar auf
    Lizenzen und Reprints

Abstract

Insulin secretion is mainly regulated by blood glucose concentration. On the other hand, changes in peripheral insulin sensitivity induce compensatory adaptations in pancreatic β-cells to maintain normoglycaemia. Tumour presence causes dramatic alterations in glucose homeostasis and insulin secretion because of the high glucose consumption by the tumour cells. Here, we investigated insulin secretion in solid Ehrlich tumour-bearing mice in association with cachexia. For that, male adult Swiss mice were subcutaneously inoculated with solid Ehrlich tumour cells and sacrificed at 14 days after tumour implantation (SET), while control mice received saline alone (CTL). Insulin secretion, following different stimuli, glucose tolerance, and insulin sensitivity as well as the expression of key proteins involved in insulin secretion was assessed. The SET group showed decreased glycaemia, insulinaemia, hepatic glycogen and body weight, and increased plasma free fatty acids and triglycerides, characteristics of cancer cachexia. A very interesting finding in this study was the development of higher glucose tolerance and insulin sensitivity in SET group. The dose-response curve of insulin secretion to increasing glucose concentrations (2.8–22.2 mM) showed an EC50 of 10 mM glucose for CTL mice and 13 mM glucose for SET mice. Insulin secretion was significantly reduced in SET islets at 30 mM KCl, 100 μM carbachol, 20 mM arginine, and 20 mM leucine. Moreover, AKT, PKA, PKC, and AchRM3 expressions were reduced by 17% to 24% in SET animals. These results, mainly the augmented insulin sensitivity, show that SET is an interesting model to study alterations in pancreatic function and carbohydrate metabolism in cancer cachexia.

Key words

cachexia - pancreatic β-cells - protein expression
 

  • References

  • 1 Henquin JC. Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes 2000; 49: 1751-1760
    CrossrefPubMedSuche in Google Scholar
  • 2 Henquin JC. The dual control of insulin secretion by glucose involves triggering and amplifying pathways in β-cells. Diabetes Res Clin Pract 2011; 93: 27-31
    CrossrefPubMedSuche in Google Scholar
  • 3 Ma J, Giovannuci E, Pollak M, Leavitt A, Tao Y, Gaziano JM, Stampfer MJ. A prospective study of plasma C-peptide and colorectal cancer risk in men. J Natl Cancer Inst 2004; 96: 546-553
    CrossrefPubMedSuche in Google Scholar
  • 4 Healy LA, Ryan AM, Carroll P, Ennis D, Crowley V, Boyle T, Kennedy MJ, Connolly E, Reynolds JV. Metabolic syndrome, central obesity and insulin resistance are associated with adverse pathological features in postmenopausal breast cancer. Clin Oncol 2010; 22: 281-288
    CrossrefPubMedSuche in Google Scholar
  • 5 Mu N, Zhu Y, Wang Y, Zhang H, Xue F. Insulin resistance: A significant risk factor of endometrial cancer. Gynecol Oncol 2012; 125: 751-757
    CrossrefPubMedSuche in Google Scholar
  • 6 Cui Y, Andersen DK. Diabetes and pancreatic cancer. Endocr Relat Cancer 2012; 19: F9-F26
    CrossrefPubMedSuche in Google Scholar
  • 7 Fernandes LC, Machado UF, Nogueira CR, Carpinelli AR, Curi R. Insulin secretion in Walker 256 tumour cachexia. Am J Physiology 1990; 258: 1033-1036
    PubMedSuche in Google Scholar
  • 8 Hursting SD, Berguer NA. Energy balance, host related factors and cancer progression. J Clin Oncol 2010; 28: 4058-4065
    CrossrefPubMedSuche in Google Scholar
  • 9 Tisdale MJ. Cancer Cachexia. Curr Opin Gastroenterol 2010; 26: 146-151
    CrossrefPubMedSuche in Google Scholar
  • 10 Asp ML, Tian M, Wendel AA, Belury MA. Evidence for the contribution of insulin resistance to the development of cachexia in tumor-bearing mice. Int J Cancer 2009; 126: 756-763
    PubMedSuche in Google Scholar
  • 11 Mathupala SP, Rempel A, Pedersen PL. Glucose catabolism in cancer cells. J Biol Chem 1995; 270: 16918-16925
    CrossrefPubMedSuche in Google Scholar
  • 12 Tigerina AJ. The biochemical basis of metabolism in cancer cachexia. Dimens Crit Care Nurs 2004; 23: 237-243
    CrossrefPubMedSuche in Google Scholar
  • 13 Rohdenburg GL, Bernhard A, Krehbiel O. Sugar tolerance in cancer. JAMA 1919; 72: 1528-1530
    CrossrefPubMedSuche in Google Scholar
  • 14 Tayek JA. A review of cancer cachexia and abnormal glucose in humans with cancer. J Am Coll Nutr 1992; 11: 445-456
    CrossrefPubMedSuche in Google Scholar
  • 15 Argilés JM, Alvarez B, López-soriano FJ. The metabolic basis of cancer cachexia. Med Res Rev 1997; 17: 477-498
    CrossrefPubMedSuche in Google Scholar
  • 16 Sugiura K. Tumor transplantation. In: GAY WI. Methods of Animal Experimentation. Academic Press; New York and London: 1965. 2. 171-222
    CrossrefSuche in Google Scholar
  • 17 Stewart LH. The cancer investigator. Cancer Res 1959; 19: 804-818
    PubMedSuche in Google Scholar
  • 18 Silva RJ, Silva MG, Vilela LC, Fecchio D. Cytokine profile of Ehrlich ascites tumor treated with Bothrops jararaca venom. Mediators Inflamm 2002; 11: 197-201
    CrossrefPubMedSuche in Google Scholar
  • 19 Rafacho A, Giozzet AGV, Boschero AC, Bosqueiro JR. Functional alterations in endocrine pancreas of rats with different degrees of dexamethasone-induced insulin resistance. Pancreas 2008; 36: 284-293
    CrossrefPubMedSuche in Google Scholar
  • 20 El Razi Neto S, Zorn TMT, Curi R, Carpinelli AR. Impairment of insulin secretion in pancreatic islets isolated from Walker 256 tumor-bearing rats. Am J Physiol Cell Physiol 1996; 271: C804-C809
    PubMedSuche in Google Scholar
  • 21 Rebeca R, Bracht L, Noleto GR, Martinez GR, Cadena SMSC, Carnieri EGS, Rocha MEM, de Oliveira MBM. Production of cachexia mediators by Walker 256 cells from ascitic tumors. Cell Biochem Funct 2008; 26: 731-736
    CrossrefPubMedSuche in Google Scholar
  • 22 Evans WJ, Morley JE, Argilés J, Bales C, Baracos V, Guttridge D, Jatoi A, Kalantar-Zadeh K, Lochs H, Mantovani G, Marks D, Mitch WE, Muscaritoli M, Najand A, Ponikowski P, Fanelli FR, Schambelan M, Schols A, Schuster M, Thomas D, Wolfe R, Anker SD. Cachexia: a new definition. Clin Nutr 2008; 27: 793-799
    CrossrefPubMedSuche in Google Scholar
  • 23 Argilés JM, López-Soriano FJ, Busquets S. Novel approaches to the treatment of cachexia. Drug Discov Today 2008; 13: 73-78
    CrossrefPubMedSuche in Google Scholar
  • 24 Tisdale MJ. Mechanisms of cancer cachexia. Physiol Rev 2009; 89: 381-410
    CrossrefPubMedSuche in Google Scholar
  • 25 Argilés JM, López-Soriano FJ, Busquets S. Mechanisms and treatment of cancer cachexia. Nutr Metab Cardiovasc Dis 2013; 23 (Suppl. 01) S19-S24
    CrossrefPubMedSuche in Google Scholar
  • 26 Arner P. Lipases in cachexia. Science 2011; 333: 163-164
    CrossrefPubMedSuche in Google Scholar
  • 27 Das SK. Adipose triglyceride lipase contributes to cancer-associated cachexia. Science 2011; 333: 233-238
    CrossrefPubMedSuche in Google Scholar
  • 28 Pinto JA, Folador A, Bonato SJ, Aikawa J, Yamazaki RK, Pizato N, Facin M, Grohs H, de Oliveira HHP, Naliwaiko K, Ferraz AC, Nishiyama A, Fernandez R, Curi R, Fernandes LC. Fish oil supplementation in F1 generation associated with naproxen, clenbuterol, and insulin administration reduce tumor growth and cachexia in Walker 256 tumor-bearing Rats. J Nutr Biochem 2004; 15: 358-365
    CrossrefPubMedSuche in Google Scholar
  • 29 Nune EA, Kuczera D, Brito GAP, Bonatto SJR, Yamazaki RK, Tanhoffer RA, Mund RC, Kryczyk M, Fernandes LC. β-Hydroxy-β-methylbutyrate supplementation reduces tumor growth and tumor cell proliferation ex vivo and prevents cachexia in Walker 256 tumor-bearing rats by modifying nuclear factor-κB expression. Nutr Res 2008; 28: 487-493
    CrossrefPubMedSuche in Google Scholar
  • 30 Hirai K, Ishiko O, Tisdale MJ. Mechanism of depletion of liver glycogen in cancer cachexia. Biochem Biophys Res Commun 1997; 241: 49-52
    CrossrefPubMedSuche in Google Scholar
  • 31 Korekane H, Nishikawa A, Iamamura K. Mechanisms mediating metabolic abnormalities in the livers of Ehrlich ascites tumor-bearing mice. Arch Biochem Biophys 2003; 412: 216-222
    CrossrefPubMedSuche in Google Scholar
  • 32 Lohsiriwat V, Lohsiriwat D, Boonnuch W, Chinswangwatanakul V, Akaraviputh T, Lert-akayamanee N. Pre-operative hypoalbuminemia is a major risk factor for postoperative complications following rectal cancer surgery. World J Gastroenterol 2008; 28: 1248-1251
    PubMedSuche in Google Scholar
  • 33 Kemik O, Sumer A, Kemik AS, Hasirci I, Purisa S, Dulger AC, Demiriz B, Tuzun S. The relationship among acute-phase response proteins, cytokines and hormones in cachectic patients with colon cancer. World J Surg Oncol 2010; 8: 85
    CrossrefPubMedSuche in Google Scholar
  • 34 Farrell G. Insulin resistance, obesity, and liver cancer. Clin Gastroentrol Hepatol 2014; 12: 117-119
    PubMedSuche in Google Scholar
  • 35 Westley RL, May FEB. A twenty-first century cancer epidemic caused by obesity: the involvement of insulin, diabetes, and insulin-like growth factors. Int J Endocrinol 2013; 2013: 632461
    PubMedSuche in Google Scholar
  • 36 Beck SA, Tisdale MJ. Effect of insulin on weight loss and tumour growth in a cachexia model. Br J Cancer 1989; 59: 677-681
    CrossrefPubMedSuche in Google Scholar
  • 37 Papa V, Pezzino V, Costantino A, Belfiore A, Giuffrida D, Frittitta L, Vanelli GB, Brand R, Goldfine ID, Vigneri R. Elevated insulin receptor content in human breast cancer. J Clin Invest 1990; 86: 1503-1510
    CrossrefPubMedSuche in Google Scholar
  • 38 Novosyadlyy R, Lann DE, Vijayakumar A, Rowzee A, Lazzarino DA, Fierz Y, Carboni JM, Gottardis MM, Pennisi PA, Molinolo AA, Kurshan N, Mejia W, Stefania S, Yakar S, Wood TL, LeRoith D. Insulin mediated acceleration of breast cancer development and progression in a non obese model of type 2 diabetes. Cancer Res 2010; 70: 741-751
    CrossrefPubMedSuche in Google Scholar
  • 39 Rydén M, Agustsson T, Laurencikiene J, Britton T, Sjolin E, Isaksson B, Permet J, Arner P. Lipolysis – not inflammation, cell death, or lipogenesis – is involved in adipose tissue loss in cancer cachexia. Cancer 2008; 113: 1695-1704
    CrossrefPubMedSuche in Google Scholar
  • 40 Bing C, Taylor S, Tisdale MJ, Williams G. Cachexia in MAC16 adenocarcinoma: suppression of hunger despite normal regulation of leptin, insulin and hypothalamic neuropeptide Y. J Neurochem 2001; 79: 1004-1012
    CrossrefPubMedSuche in Google Scholar
  • 41 Gromada J, Hughes TE. Ringing the dinner bell for insulin: Muscarinic M3 receptor activity in the control of pancreatic b cell function. Cell Metab 2006; 3: 390-392
    CrossrefPubMedSuche in Google Scholar
  • 42 de Azua IR, Gautam D, Guettier JM, Wess J. Novel insights into the function of β-cell M3 muscarinic acetylcholine receptors: therapeutic implications. Trends Endocrinol Metab 2011; 22: 74-80
    CrossrefPubMedSuche in Google Scholar
  • 43 Ishikawa T, Iwasaki E, Kanatani K, Sugino F, Kaneko O, Nakayama K. Involvement of novel protein kinase C isoforms in carbachol-stimulated insulin secretion from rat pancreatic islets. Life Sci 2005; 77: 462-469
    CrossrefPubMedSuche in Google Scholar
  • 44 Nesher R, Anteby E, Yedovizky M, Warwar N, Kaiser N, Cerasi E. Cell protein kinase and the dynamics of the insulin. Diabetes 2002; 51: s68-s73
    CrossrefPubMedSuche in Google Scholar