An Investigation of Insulin Resistance and Cachexia Relation in Patients with Metastatic Gastrointestinal Malignancies
-
Ebrahim Farashi
,
Ahmad Mahmoodpour
,
Aliakbar Movassaghpour Akbari
,
Zohreh Sanaat
,
Parvin Sarbakhsh
,
Seyed Hadi Chavoshi
,
Mortaza Raeisi
,
Parya Valizadeh
,
Saba Ghaffary
Abstract
Background: Insulin resistance has been suggested as one of the known metabolic disorders during cachexia. This study hypothesized that cachexia in cancer patients might be related to insulin resistance as early as cachexia development.
Methods: This study was performed on 46 patients with metastatic gastrointestinal cancer. Anthropometric characteristics and biochemical markers were assessed at baseline, second and third month. Insulin resistance was assessed using the homeostasis model assessment-estimated insulin resistance (HOMA IR) method. SFQ-36 questions were used to assess the patients' quality of life at baseline, second and third months.
Results: Anthropometric characteristic was significantly associated between pre-cachectic and non-pre-cachectic patients in third month. Cholesterol (P-value = 0.93), albumin (P-value: 0.82), and serum creatinine (P-value = 0.88) in pre-cachectic patients decreased over three months. There was an increasing trend of insulin resistance between pre-cachectic and non-pre-cachectic patients in third month. Cholesterol had an upward trend with a significant relation in cachectic patients [(P-value = 0.00), (P-value = 0.03), (P-value = 0.01)]. We detected a decreasing trend of insulin resistance between cachectic and non-cachectic patients from second to third month (P-value = 0.04). SFQ evaluation had no significant relation with cachectic status.
Conclusion: Previous studies showed that the use of NSAIDs, progesterone’s, corticosteroids, COX-2 inhibitors, anabolic agents and drugs targeting inflammatory cytokines may be beneficial for improving of symptoms of cachexia. Significant relation between anthropometric variables with pre-cachexia and cachectic conditions was concluded. Patients' outcome and its relation with insulin resistance demonstrated a significant relation between the cachectic and non-cachectic patients in the third month. We also detected the increased serum cholesterol level in cachectic patients, moreover, higher cholesterol levels in expired cachectic patients than in the living.
1. Fearon K, Strasser F, Anker SD, et al. Definition and classification of cancer cachexia: an international consensus. lancet Oncol. 2011;12(5):489-95.
2. Porporato P. Understanding cachexia as a cancer metabolism syndrome. Oncogenesis. 2016;5(2):e200.
3. 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. 2010;126(3):756-63.
4. Honors MA, Kinzig KP. The role of insulin resistance in the development of muscle wasting during cancer cachexia. J Cachexia Sarcopenia Muscle. 2012;3(1):5-11.
5. Zilbermint MF, Dobs AS. Nonsteroidal selective androgen receptor modulator Ostarine™ in cancer cachexia. Future Oncol. 2009;5(8):1211-20.
6. Stephens NA, Skipworth RJ, Fearon KC. Cachexia, survival and the acute phase response. Curr Opin Support Palliat Care. 2008;2(4):267-74.
7. Dąbrowski M, Szymańska-Garbacz E, Miszczyszyn Z, Dereziński T, Czupryniak L. Risk factors for cancer development in type 2 diabetes: a retrospective case-control study. BMC Cancer. 2016;16(1):1-9.
8. Jasani B, Donaldson L, Ratcliffe J, Sokhi G. Mechanism of impaired glucose tolerance in patients with neoplasia. Brit J Cancer. 1978;38(2):287-92.
9. Jaworski K, Sarkadi-Nagy E, Duncan RE, Ahmadian M, Sul HS. Regulation of triglyceride metabolism. IV. Hormonal regulation of lipolysis in adipose tissue. Am J Physiol Gastrointest Liver Physiol. 2007;293(1):G1-G4.
10. Argilés JM, López‐Soriano FJ. The role of cytokines in cancer cachexia. Med Res Rev. 1999;19(3):223-48.
11. Costelli P, Reffo P, Penna F, Autelli R, Bonelli G, Baccino FM. Ca2+-dependent proteolysis in muscle wasting. Int J Biochem Cell Biol. 2005;37(10):2134-46.
12. Lecker SH, Goldberg AL, Mitch WE. Protein degradation by the ubiquitin–proteasome pathway in normal and disease states. J Am Soc Nephrol. 2006;17(7):1807-19.
13. Maltoni M, Nanni O, Scarpi E, Rossi D, Serra P, Amadori D. High-dose progestins for the treatment of cancer anorexia–cachexia syndrome: a systematic review of randomised clinical trials. Ann Oncol. 2001;12(3):289-300.
14. Roubenoff R. Sarcopenic obesity: the confluence of two epidemics. Obesity. 2004;12(6):887.
15. Cahill G, Aoki T, Brennan M, Müller W. Insulin and muscle amino acid balance. Proc Nutr Soc. 1972;31(2):233-8.
16. Dev R, Bruera E, Dalal S. Insulin resistance and body composition in cancer patients. Ann Oncol. 2018;29:ii18-ii26.
17. Zhang X, Shao H, Zheng X. Amino acids at the intersection of nutrition and insulin sensitivity. Drug Discov Today. 2019;24(4):1038-43.
18. Stahl EP, Dhindsa DS, Lee SK, Sandesara PB, Chalasani NP, Sperling LS. Nonalcoholic Fatty Liver Disease and the Heart: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019;73(8):948-63.
19. Novotny GW, Lundh M, Backe MB, et al. Transcriptional and translational regulation of cytokine signaling in inflammatory β-cell dysfunction and apoptosis. Arch Biochem Biophys. 2012;528(2):171-84.
20. Patel HJ, Patel BM. TNF-α and cancer cachexia: Molecular insights and clinical implications. Life Sci. 2017;170:56-63.
21. Holroyde CP, Gabuzda TG, Putnam RC, Paul P, Reichard GA. Altered glucose metabolism in metastatic carcinoma. Cancer Rese. 1975;35(12):3710-4.
22. Dewey A, Baughan C, Dean TP, Higgins B, Johnson I. Eicosapentaenoic acid (EPA, an omega‐3 fatty acid from fish oils) for the treatment of cancer cachexia. Cochrane Database Syst Rev. 2007;2007(1):CD004597.
23. Berenstein G, Ortiz Z. Megestrol acetate for treatment of anorexia‐cachexia syndrome. Cochrane Database Syst Rev. 2013;2013(3):CD004310.
24. McMillan D, Leen E, Smith J, et al. Effect of extended ibuprofen administration on the acute phase protein response in colorectal cancer patients. Eur J Surg Oncol. 1995;21(5):531-4.
25. Preston T, Fearon K, McMillan D, et al. Effect of ibuprofen on the acute-phase response and protein metabolism in patients with cancer and weight loss. J Brit Surg. 1995;82(2):229-34.
26. Kaasa S, Loge JH, Fayers P, et al. Symptom assessment in palliative care: a need for international collaboration. J Clin Oncol. 2008;26(23):3867-73.
27. Blum D, Stene G, Solheim T, et al. Validation of the Consensus-Definition for Cancer Cachexia and evaluation of a classification model-a study based on data from an international multicentre project (EPCRC-CSA). Ann Oncol. 2014;25(8):1635-42.
28. Matthews DR, Hosker J, Rudenski A, Naylor B, Treacher D, Turner R. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412-9.
29. Jenkinson C. The SF-36 Physical and Mental Health Summary Measures: An Example of How to Interpret Scores. J Health Serv Res Policy. 1998;3(2):92-6.
30. Murphy SL, Xu J, Kochanek KD, Arias E, Tejada-Vera B. Deaths: final Data for 2018. Natl Vital Stat Rep. 2021;69(13):1-83.
31. Fearon KC, Glass DJ, Guttridge DC. Cancer cachexia: mediators, signaling, and metabolic pathways. Cell Metab. 2012;16(2):153-66.
32. Dunne RF, Mustian KM, Garcia JM, et al. Research Priorities in Cancer Cachexia: The University of Rochester Cancer Center NCI Community Oncology Research Program (NCORP) Research Base Symposium on Cancer Cachexia and Sarcopenia. Curr Opin Support Palliat Care.2017;11(4):278.
33. Millar C, Reid J, Porter S. Providing care for palliative cancer patients who have cachexia: are we meeting the challenge. Cancer Nursing Practice. 2009;8(4):24-7.
34. Mantovani G, Madeddu C, Macciò A. Drugs in development for treatment of patients with cancer-related anorexia and cachexia syndrome. Drug Des Devel Ther. 2013;7:645-56.
35. Dewys WD, Begg C, Lavin PT, et al . Prognostic effect of weiglet loss prior to chemotherapy in cancer patients. Am J Med. 1980; 69(4):91-497.
36. Kim HL, Belldegrun AS, Freitas DG, et al. Paraneoplastic signs and symptoms of renal cell carcinoma: implications for prognosis. J Urol. 2003;170(5):1742-6.
37. Stephens N, Fearon K. Anorexia, cachexia and nutrition. Medicine. 2008;36(2):78-81.
38. Johns N, Stephens NA, Fearon KCH. Muscle wasting in cancer. Int J Biochem Cell Biol. 2013;45(10):2215-29.
39. Martin L, Birdsell L, MacDonald N, et al. Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index. J Clin Oncol. 2013;31(12):1539-47.
40. Ge YZ, Ruan GT, Zhang KP, et al. Which anthropometric measurement is better for predicting survival of patients with cancer cachexia? Brit J Nutr. 2021:1-9.
41. Fujii T, Tokuda S, Nakazawa Y, et al. Implications of low serum albumin as a prognostic factor of long-term outcomes in patients with breast cancer. In Vivo. 2020;34(4):2033-6.
42. Fiorenza A, Branchi A, Cardena A, Molgora M, Rovellini A, Sommariva D. Serum cholesterol levels in patients with cancer. International Journal of Clinical and Laboratory Research. 1996;26(1):37-42.
43. Zwickl H, Zwickl-Traxler E, Pecherstorfer M. Is neuronal histamine signaling involved in cancer cachexia? Implications and perspectives. Front Oncol. 2019:1409.
44. Das SK, Hoefler G. The role of triglyceride lipases in cancer associated cachexia. Trends Mol Med. 2013;19(5):292-301.
45. Tisdale MJ. Mechanisms of cancer cachexia. Physiol Rev. 2009;89(2):381-410.
46. Yang QJ, Zhao JR, Hao J, et al. Serum and urine metabolomics study reveals a distinct diagnostic model for cancer cachexia. J Cachexia Sarcopenia Muscle. 2018;9(1):71-85.
47. Der-Torossian H, Wysong A, Shadfar S, Willis MS, McDunn J, Couch ME. Metabolic derangements in the gastrocnemius and the effect of Compound A therapy in a murine model of cancer cachexia. J Cachexia Sarcopenia Muscle. 2013;4(2):145-55.
48. Rosa-Caldwell ME, Brown JL, et al. Hepatic alterations during the development and progression of cancer cachexia. Appl Physiol Nutr Metab. 2020;45(5):500-12.
49. Pihlajamäki J, Gylling H, Miettinen TA, Laakso M. Insulin resistance is associated with increased cholesterol synthesis and decreased cholesterol absorption in normoglycemic men. Journal of Lipid Research. 2004;45(3):507-12.
50. Honors MA, Kinzig KP. The role of insulin resistance in the development of muscle wasting during cancer cachexia. J Cachexia Sarcopenia Muscle. 2012;3(1):5-11.
51. Bartlett DL, Charland SL, Torosian MH. Reversal of tumor-associated hyperglucagonemia as treatment for cancer cachexia. Surgery. 1995;118(1):87-97.
52. Schwarz S, Prokopchuk O, Esefeld K, et al. The clinical picture of cachexia: a mosaic of different parameters (experience of 503 patients). BMC Cancer. 2017;17(1):1-10.
53. Fonseca GWPd, Farkas J, Dora E, von Haehling S, Lainscak M. Cancer cachexia and related metabolic dysfunction. Int J Mol Sci. 2020;21(7):2321.
54. Finucane FM, Luan J, Wareham NJ, et al. Correlation of the leptin:adiponectin ratio with measures of insulin resistance in non-diabetic individuals. Diabetologia. 2009;52(11):2345-9.
2. Porporato P. Understanding cachexia as a cancer metabolism syndrome. Oncogenesis. 2016;5(2):e200.
3. 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. 2010;126(3):756-63.
4. Honors MA, Kinzig KP. The role of insulin resistance in the development of muscle wasting during cancer cachexia. J Cachexia Sarcopenia Muscle. 2012;3(1):5-11.
5. Zilbermint MF, Dobs AS. Nonsteroidal selective androgen receptor modulator Ostarine™ in cancer cachexia. Future Oncol. 2009;5(8):1211-20.
6. Stephens NA, Skipworth RJ, Fearon KC. Cachexia, survival and the acute phase response. Curr Opin Support Palliat Care. 2008;2(4):267-74.
7. Dąbrowski M, Szymańska-Garbacz E, Miszczyszyn Z, Dereziński T, Czupryniak L. Risk factors for cancer development in type 2 diabetes: a retrospective case-control study. BMC Cancer. 2016;16(1):1-9.
8. Jasani B, Donaldson L, Ratcliffe J, Sokhi G. Mechanism of impaired glucose tolerance in patients with neoplasia. Brit J Cancer. 1978;38(2):287-92.
9. Jaworski K, Sarkadi-Nagy E, Duncan RE, Ahmadian M, Sul HS. Regulation of triglyceride metabolism. IV. Hormonal regulation of lipolysis in adipose tissue. Am J Physiol Gastrointest Liver Physiol. 2007;293(1):G1-G4.
10. Argilés JM, López‐Soriano FJ. The role of cytokines in cancer cachexia. Med Res Rev. 1999;19(3):223-48.
11. Costelli P, Reffo P, Penna F, Autelli R, Bonelli G, Baccino FM. Ca2+-dependent proteolysis in muscle wasting. Int J Biochem Cell Biol. 2005;37(10):2134-46.
12. Lecker SH, Goldberg AL, Mitch WE. Protein degradation by the ubiquitin–proteasome pathway in normal and disease states. J Am Soc Nephrol. 2006;17(7):1807-19.
13. Maltoni M, Nanni O, Scarpi E, Rossi D, Serra P, Amadori D. High-dose progestins for the treatment of cancer anorexia–cachexia syndrome: a systematic review of randomised clinical trials. Ann Oncol. 2001;12(3):289-300.
14. Roubenoff R. Sarcopenic obesity: the confluence of two epidemics. Obesity. 2004;12(6):887.
15. Cahill G, Aoki T, Brennan M, Müller W. Insulin and muscle amino acid balance. Proc Nutr Soc. 1972;31(2):233-8.
16. Dev R, Bruera E, Dalal S. Insulin resistance and body composition in cancer patients. Ann Oncol. 2018;29:ii18-ii26.
17. Zhang X, Shao H, Zheng X. Amino acids at the intersection of nutrition and insulin sensitivity. Drug Discov Today. 2019;24(4):1038-43.
18. Stahl EP, Dhindsa DS, Lee SK, Sandesara PB, Chalasani NP, Sperling LS. Nonalcoholic Fatty Liver Disease and the Heart: JACC State-of-the-Art Review. J Am Coll Cardiol. 2019;73(8):948-63.
19. Novotny GW, Lundh M, Backe MB, et al. Transcriptional and translational regulation of cytokine signaling in inflammatory β-cell dysfunction and apoptosis. Arch Biochem Biophys. 2012;528(2):171-84.
20. Patel HJ, Patel BM. TNF-α and cancer cachexia: Molecular insights and clinical implications. Life Sci. 2017;170:56-63.
21. Holroyde CP, Gabuzda TG, Putnam RC, Paul P, Reichard GA. Altered glucose metabolism in metastatic carcinoma. Cancer Rese. 1975;35(12):3710-4.
22. Dewey A, Baughan C, Dean TP, Higgins B, Johnson I. Eicosapentaenoic acid (EPA, an omega‐3 fatty acid from fish oils) for the treatment of cancer cachexia. Cochrane Database Syst Rev. 2007;2007(1):CD004597.
23. Berenstein G, Ortiz Z. Megestrol acetate for treatment of anorexia‐cachexia syndrome. Cochrane Database Syst Rev. 2013;2013(3):CD004310.
24. McMillan D, Leen E, Smith J, et al. Effect of extended ibuprofen administration on the acute phase protein response in colorectal cancer patients. Eur J Surg Oncol. 1995;21(5):531-4.
25. Preston T, Fearon K, McMillan D, et al. Effect of ibuprofen on the acute-phase response and protein metabolism in patients with cancer and weight loss. J Brit Surg. 1995;82(2):229-34.
26. Kaasa S, Loge JH, Fayers P, et al. Symptom assessment in palliative care: a need for international collaboration. J Clin Oncol. 2008;26(23):3867-73.
27. Blum D, Stene G, Solheim T, et al. Validation of the Consensus-Definition for Cancer Cachexia and evaluation of a classification model-a study based on data from an international multicentre project (EPCRC-CSA). Ann Oncol. 2014;25(8):1635-42.
28. Matthews DR, Hosker J, Rudenski A, Naylor B, Treacher D, Turner R. Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412-9.
29. Jenkinson C. The SF-36 Physical and Mental Health Summary Measures: An Example of How to Interpret Scores. J Health Serv Res Policy. 1998;3(2):92-6.
30. Murphy SL, Xu J, Kochanek KD, Arias E, Tejada-Vera B. Deaths: final Data for 2018. Natl Vital Stat Rep. 2021;69(13):1-83.
31. Fearon KC, Glass DJ, Guttridge DC. Cancer cachexia: mediators, signaling, and metabolic pathways. Cell Metab. 2012;16(2):153-66.
32. Dunne RF, Mustian KM, Garcia JM, et al. Research Priorities in Cancer Cachexia: The University of Rochester Cancer Center NCI Community Oncology Research Program (NCORP) Research Base Symposium on Cancer Cachexia and Sarcopenia. Curr Opin Support Palliat Care.2017;11(4):278.
33. Millar C, Reid J, Porter S. Providing care for palliative cancer patients who have cachexia: are we meeting the challenge. Cancer Nursing Practice. 2009;8(4):24-7.
34. Mantovani G, Madeddu C, Macciò A. Drugs in development for treatment of patients with cancer-related anorexia and cachexia syndrome. Drug Des Devel Ther. 2013;7:645-56.
35. Dewys WD, Begg C, Lavin PT, et al . Prognostic effect of weiglet loss prior to chemotherapy in cancer patients. Am J Med. 1980; 69(4):91-497.
36. Kim HL, Belldegrun AS, Freitas DG, et al. Paraneoplastic signs and symptoms of renal cell carcinoma: implications for prognosis. J Urol. 2003;170(5):1742-6.
37. Stephens N, Fearon K. Anorexia, cachexia and nutrition. Medicine. 2008;36(2):78-81.
38. Johns N, Stephens NA, Fearon KCH. Muscle wasting in cancer. Int J Biochem Cell Biol. 2013;45(10):2215-29.
39. Martin L, Birdsell L, MacDonald N, et al. Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index. J Clin Oncol. 2013;31(12):1539-47.
40. Ge YZ, Ruan GT, Zhang KP, et al. Which anthropometric measurement is better for predicting survival of patients with cancer cachexia? Brit J Nutr. 2021:1-9.
41. Fujii T, Tokuda S, Nakazawa Y, et al. Implications of low serum albumin as a prognostic factor of long-term outcomes in patients with breast cancer. In Vivo. 2020;34(4):2033-6.
42. Fiorenza A, Branchi A, Cardena A, Molgora M, Rovellini A, Sommariva D. Serum cholesterol levels in patients with cancer. International Journal of Clinical and Laboratory Research. 1996;26(1):37-42.
43. Zwickl H, Zwickl-Traxler E, Pecherstorfer M. Is neuronal histamine signaling involved in cancer cachexia? Implications and perspectives. Front Oncol. 2019:1409.
44. Das SK, Hoefler G. The role of triglyceride lipases in cancer associated cachexia. Trends Mol Med. 2013;19(5):292-301.
45. Tisdale MJ. Mechanisms of cancer cachexia. Physiol Rev. 2009;89(2):381-410.
46. Yang QJ, Zhao JR, Hao J, et al. Serum and urine metabolomics study reveals a distinct diagnostic model for cancer cachexia. J Cachexia Sarcopenia Muscle. 2018;9(1):71-85.
47. Der-Torossian H, Wysong A, Shadfar S, Willis MS, McDunn J, Couch ME. Metabolic derangements in the gastrocnemius and the effect of Compound A therapy in a murine model of cancer cachexia. J Cachexia Sarcopenia Muscle. 2013;4(2):145-55.
48. Rosa-Caldwell ME, Brown JL, et al. Hepatic alterations during the development and progression of cancer cachexia. Appl Physiol Nutr Metab. 2020;45(5):500-12.
49. Pihlajamäki J, Gylling H, Miettinen TA, Laakso M. Insulin resistance is associated with increased cholesterol synthesis and decreased cholesterol absorption in normoglycemic men. Journal of Lipid Research. 2004;45(3):507-12.
50. Honors MA, Kinzig KP. The role of insulin resistance in the development of muscle wasting during cancer cachexia. J Cachexia Sarcopenia Muscle. 2012;3(1):5-11.
51. Bartlett DL, Charland SL, Torosian MH. Reversal of tumor-associated hyperglucagonemia as treatment for cancer cachexia. Surgery. 1995;118(1):87-97.
52. Schwarz S, Prokopchuk O, Esefeld K, et al. The clinical picture of cachexia: a mosaic of different parameters (experience of 503 patients). BMC Cancer. 2017;17(1):1-10.
53. Fonseca GWPd, Farkas J, Dora E, von Haehling S, Lainscak M. Cancer cachexia and related metabolic dysfunction. Int J Mol Sci. 2020;21(7):2321.
54. Finucane FM, Luan J, Wareham NJ, et al. Correlation of the leptin:adiponectin ratio with measures of insulin resistance in non-diabetic individuals. Diabetologia. 2009;52(11):2345-9.
| Files | ||
| Issue | Vol 10, No 4 (Autumn 2022) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/jpc.v10i4.11578 | |
| Keywords | ||
| Insulin Resistance Cachexia Gastrointestinal Malignancies Cholesterol | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Farashi E, Mahmoodpour A, Movassaghpour Akbari A, Sanaat Z, Sarbakhsh P, Chavoshi SH, Raeisi M, Valizadeh P, Ghaffary S. An Investigation of Insulin Resistance and Cachexia Relation in Patients with Metastatic Gastrointestinal Malignancies. J Pharm Care. 2022;10(4):195-204.
