Revisiting insulin resistance in human cancer cachexia – a systematic review and meta-analysis
DOI:
https://doi.org/10.2340/1651-226X.2025.44280Keywords:
Cancer, cachexia, insulin resistance, metabolism, weight lossAbstract
Background: In patients with cancer, unintentional weight loss and cancer-associated cachexia (CAC) reduce overall survival and impair the quality of life. Because of insulin’s anabolic effects, insulin resistance could contribute to CAC progression. However, the role of insulin resistance in CAC remains unclear, and this study aimed to investigate the association between insulin resistance and CAC. Addressing this knowledge gap may help identify treatable targets to improve patient outcomes.
Methods: We performed a systematic review and meta-analysis. By including studies reporting both fasting levels of circulating insulin and glucose in patients with cancer and CAC according to the internationally accepted CAC definition, we calculated the HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) index to estimate the level of insulin resistance (defined as HOMA-IR above 2.0) in patients with CAC. A subgroup analysis was conducted from studies reporting a HOMA-IR index both from a group of patients with CAC and a group without CAC (nonCAC).
Results: Seventeen studies were included, with a total of 197 patients. The mean HOMA-IR of all studies was 1.84 (95% confidence interval [CI]: 1.77–1.91). Twelve studies found HOMA-IR below 2.0. Five of the 17 studies also reported HOMA-IR from a group of patients with cancer without CAC. We observed a mean difference of −0.42 (95% CI: −2.24 to 1.40) in favour of a lower HOMA-IR in patients with CAC compared to nonCAC, and thus no statistically significant difference between the groups.
Interpretation: This systematic review suggests no clear association between insulin resistance and CAC. However, the limited sample sizes and study heterogeneity highlight the need for larger, longitudinal investigations.
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Mytelka DS, Li L, Benoit K. Post‐diagnosis weight loss as a prognostic factor in non‐small cell lung cancer. J Cachexia Sarcopenia Muscle. 2018 Feb 4;9(1):86–92.
https://doi.org/10.1002/jcsm.12253 DOI: https://doi.org/10.1002/jcsm.12253
Sánchez-Lara K, Turcott JG, Juárez E, Guevara P, Núñez-Valencia C, Oñate-Ocaña LF, et al. Association of nutrition parameters including bioelectrical impedance and systemic inflammatory response with quality of life and prognosis in patients with advanced non-small-cell lung cancer: a prospective study. Nutr Cancer. 2012 May;64(4):526–34.
https://doi.org/10.1080/01635581.2012.668744 DOI: https://doi.org/10.1080/01635581.2012.668744
Martin L, Birdsell L, MacDonald N, Reiman T, Clandinin MT, McCargar LJ, 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 Apr 20;31(12):1539–47.
https://doi.org/10.1200/JCO.2012.45.2722 DOI: https://doi.org/10.1200/JCO.2012.45.2722
Argilés JM, López-Soriano FJ, Stemmler B, Busquets S. Cancer-associated cachexia – understanding the tumour macroenvironment and microenvironment to improve management. Nat Rev Clin Oncol. 2023 Apr 20;20(4):250–64.
https://doi.org/10.1038/s41571-023-00734-5 DOI: https://doi.org/10.1038/s41571-023-00734-5
Pryce BR, Oles A, Talbert EE, Romeo MJ, Vaena S, Sharma S, et al. Muscle inflammation is regulated by NF-κB from multiple cells to control distinct states of wasting in cancer cachexia. Cell Rep. 2024 Nov;43(11):114925.
https://doi.org/10.1016/j.celrep.2024.114925 DOI: https://doi.org/10.1016/j.celrep.2024.114925
Fearon K, Strasser F, Anker SD, Bosaeus I, Bruera E, Fainsinger RL, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011 May;12(5):489–95.
https://doi.org/10.1016/S1470-2045(10)70218-7 DOI: https://doi.org/10.1016/S1470-2045(10)70218-7
Sørensen J. Lung cancer cachexia: can molecular understanding guide clinical management? Integr Cancer Ther. 2018;17(3):1000-1008.
https://doi.org/10.1177/1534735418781743 DOI: https://doi.org/10.1177/1534735418781743
Miksza DR, Biazi GR, Frasson IG, de Souza Galia WB, Ferraz LS, Diaz BF, et al. Insulin in combination with pioglitazone prevents advanced cachexia in 256-Walker tumor-bearing rats: effect is greater than treatment alone and is associated with improved insulin sensitivity. Pharmacol Rep. 2023 Dec 7;75(6):1571–87.
https://doi.org/10.1007/s43440-023-00533-w DOI: https://doi.org/10.1007/s43440-023-00533-w
Raun SH, Ali MS, Han X, Henríquez‐Olguín C, Pham TCP, Meneses‐Valdés R, et al. Adenosine monophosphate‐activated protein kinase is elevated in human cachectic muscle and prevents cancer‐induced metabolic dysfunction in mice. J Cachexia Sarcopenia Muscle. 2023 Aug 16;14(4):1631–47.
https://doi.org/10.1002/jcsm.13238 DOI: https://doi.org/10.1002/jcsm.13238
Màrmol JM, Carlsson M, Raun SH, Grand MK, Sørensen J, Lang Lehrskov L, et al. Insulin resistance in patients with cancer: a systematic review and meta-analysis. Acta Oncol. 2023 Apr 12;(62)364–71.
https://doi.org/10.1080/0284186X.2023.2197124 DOI: https://doi.org/10.1080/0284186X.2023.2197124
Hwangbo Y, Kang D, Kang M, Kim S, Lee EK, Kim YA, et al. Incidence of diabetes after cancer development: a Korean National Cohort Study. JAMA Oncol. 2018 Aug 1;4(8):1099–105.
https://doi.org/10.1001/jamaoncol.2018.1684 DOI: https://doi.org/10.1001/jamaoncol.2018.1684
Sylow L, Grand MK, von Heymann A, Persson F, Siersma V, Kriegbaum M, et al. Incidence of new-onset type 2 diabetes after cancer: a Danish cohort study. Diabetes Care. 2022 Jun 2;45(6):e105–6.
https://doi.org/10.2337/dc22-0232 DOI: https://doi.org/10.2337/dc22-0232
Chovsepian A, Prokopchuk O, Petrova G, Gjini T, Kuzi H, Heisz S, et al. Diabetes increases mortality in patients with pancreatic and colorectal cancer by promoting cachexia and its associated inflammatory status. Mol Metab. 2023 Jul;73:101729.
https://doi.org/10.1016/j.molmet.2023.101729 DOI: https://doi.org/10.1016/j.molmet.2023.101729
Chevalier S, Farsijani S. Cancer cachexia and diabetes: similarities in metabolic alterations and possible treatment. Appl Physiol Nutr Metab. 2014 Jun;39(6):643–53.
https://doi.org/10.1139/apnm-2013-0369 DOI: https://doi.org/10.1139/apnm-2013-0369
Bennegård K, Lundgren F, Lundholm K. Mechanisms of insulin resistance in cancer associated malnutrition. Clin Physiol. 1986 Dec;6(6):539-47.
https://doi.org/10.1111/j.1475-097x.1986.tb00787.x DOI: https://doi.org/10.1111/j.1475-097X.1986.tb00787.x
Selberg O, McMillan DC, Preston T, Carse H, Shenkin A, Burns HJG. Palmitate turnover and its response to glucose infusion in weight-losing cancer patients. Clin Nutr. 1990 Jun;9(3):150–6.
https://doi.org/10.1016/0261-5614(90)90047-v DOI: https://doi.org/10.1016/0261-5614(90)90047-V
Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care. 1999 Sep 1;22(9):1462–70.
https://doi.org/10.2337/diacare.22.9.1462 DOI: https://doi.org/10.2337/diacare.22.9.1462
Hedblad B, Nilsson P, Janzon L, Berglund G. Relation between insulin resistance and carotid intima‐media thickness and stenosis in non‐diabetic subjects. Results from a cross‐sectional study in Malmö, Sweden. Diabet Med. 2000 Apr 13;17(4):299–307.
https://doi.org/10.1046/j.1464-5491.2000.00280.x DOI: https://doi.org/10.1046/j.1464-5491.2000.00280.x
Bonora E, Targher G, Alberiche M, Bonadonna RC, Saggiani F, Zenere MB, et al. Homeostasis model assessment closely mirrors the glucose clamp technique in the assessment of insulin sensitivity: studies in subjects with various degrees of glucose tolerance and insulin sensitivity. Diabetes Care. 2000 Jan 1;23(1):57–63.
https://doi.org/10.2337/diacare.23.1.57 DOI: https://doi.org/10.2337/diacare.23.1.57
Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021 Mar 29:372:n71.
https://doi.org/10.1136/bmj.n71 DOI: https://doi.org/10.1136/bmj.n71
Haddaway NR, Grainger MJ, Gray CT. Citationchaser: a tool for transparent and efficient forward and backward citation chasing in systematic searching. Res Synth Methods. 2022 Jul 7;13(4):533–45.
https://doi.org/10.1002/jrsm.1563 DOI: https://doi.org/10.1002/jrsm.1563
Thomas J, Graziosi S, Brunton J, Ghouze Z, O’Driscoll P, Bond M, Koryakina A. EPPI-Reviewer: advanced software for systematic reviews, maps and evidence synthesis. EPPI Centre, UCL Social Research Institute, University College London, London, UK, 2023.
Available from: https://jbi.global/critical-appraisal-tools
Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane handbook for systematic reviews of interventions version 6.5 (updated August 2024). Cochrane; 2024. [accessed Feb 12 2025] Available from: www.training.cochrane.org/handbook
Balkau B, Charles MA. Comment on the provisional report from the WHO consultation. Diabet Med. 1999 May 24;16(5):442–3.
https://doi.org/10.1046/j.1464-5491.1999.00059.x DOI: https://doi.org/10.1046/j.1464-5491.1999.00059.x
McCall JL, Tuckey JA, Parry BR. Serum tumour necrosis factor alpha and insulin resistance in gastrointestinal cancer. Br J Surg. 1992 Dec 8;79(12):1361–3.
https://doi.org/10.1002/bjs.1800791240 DOI: https://doi.org/10.1002/bjs.1800791240
Bennegård K, Edén E, Ekman L, Scherstén T, Lundholm K. Metabolic balance across the leg in weight-losing cancer patients compared to depleted patients without cancer. Cancer Res. 1982 Oct;42(10):4293–9.
Bennegård K, Edén E, Ekman L, Scherstén T, Lundholm K. Metabolic response of whole body and peripheral tissues to enteral nutrition in weight-losing cancer and noncancer patients. Gastroenterology. 1983 Jul;85(1):92–9.
https://doi.org/10.1016/S0016-5085(83)80234-0 DOI: https://doi.org/10.1016/S0016-5085(83)80234-0
Bell DM. Femoral arteriovenous sugar differences in fasting human beings. J Lab Clin Med. 1952 Sep;40(3):337–41.
Holroyde CP, Skutches CL, Boden G, Reichard GA. Glucose metabolism in cachectic patients with colorectal cancer. Cancer Res. 1984 Dec;44(12 Pt 1):5910–3.
Leij-Halfwerk S, van den Berg JW, Sijens PE, Wilson JH, Oudkerk M, Dagnelie PC. Altered hepatic gluconeogenesis during L-alanine infusion in weight-losing lung cancer patients as observed by phosphorus magnetic resonance spectroscopy and turnover measurements. Cancer Res. 2000 Feb 1;60(3):618–23.
Available from: https://plotdigitizer.com/app
Barber MD, McMillan DC, Preston T, Ross JA, Fearon KC. Metabolic response to feeding in weight-losing pancreatic cancer patients and its modulation by a fish-oil-enriched nutritional supplement. Clin Sci (Lond). 2000 Apr;98(4):389–99.
https://doi.org/10.1042/cs0980389 DOI: https://doi.org/10.1042/cs0980389
Rofe AM, Bourgeois CS, Coyle P, Taylor A, Abdi EA. Altered insulin response to glucose in weight-losing cancer patients. Anticancer Res. 1994 Mar-Apr;14(2B):647–50.
Yoshikawa T, Noguchi Y, Matsumoto A. Effects of tumor removal and body weight loss on insulin resistance in patients with cancer. Surgery. 1994 Jul;116(1):62–6.
Burt ME, Aoki TT, Gorschboth CM, Brennan MF. Peripheral tissue metabolism in cancer-bearing man. Ann Surg. 1983 Dec;198(6):685–91.
https://doi.org/10.1097/00000658-198312000-00003 DOI: https://doi.org/10.1097/00000658-198312000-00003
Cersosimo E, Pisters PW, Pesola G, Rogatko A, Vydelingum NA, Bajorunas D, et al. The effect of graded doses of insulin on peripheral glucose uptake and lactate release in cancer cachexia. Surgery. 1991 Apr;109(4):459–67.
Heslin MJ, Newman E, Wolf RF, Pisters PW, Brennan MF. Effect of systemic hyperinsulinemia in cancer patients. Cancer Res. 1992 Jul 15;52(14):3845–50.
Agustsson T, Rydén M, Hoffstedt J, van Harmelen V, Dicker A, Laurencikiene J, et al. Mechanism of increased lipolysis in cancer cachexia. Cancer Res. 2007 Jun 1;67(11):5531–7.
https://doi.org/10.1158/0008-5472.CAN-06-4585 DOI: https://doi.org/10.1158/0008-5472.CAN-06-4585
Heber D, Byerly LO, Chlebowski RT. Metabolic abnormalities in the cancer patient. Cancer. 1985 Apr 25;55(1 Suppl):225–9. DOI: https://doi.org/10.1002/1097-0142(19850101)55:1+<225::AID-CNCR2820551304>3.0.CO;2-7
https://doi.org/10.1002/1097-0142(19850101)
Pisters PW, Cersosimo E, Rogatko A, Brennan MF. Insulin action on glucose and branched-chain amino acid metabolism in cancer cachexia: differential effects of insulin. Surgery. 1992 Apr 23;111(3):301–10.
Eden E, Edström S, Bennegård K, Scherstén T, Lundholm K. Glucose flux in relation to energy expenditure in malnourished patients with and without cancer during periods of fasting and feeding. Cancer Res. 1984 Apr 25;44(4):1718–24.
Heber D, Chlebowski RT, Ishibashi DE, Herrold JN, Block JB. Abnormalities in glucose and protein metabolism in noncachectic lung cancer patients. Cancer Res. 1982 Nov;42(11):4815–9.
Norton JA, Maher M, Wesley R, White D, Brennan MF. Glucose intolerance in sarcoma patients. Cancer. 1984 Dec 15;54(12):3022–7.
https://doi.org/10.1002/1097-0142(19841215)54:12<3022::aid-cncr2820541234>3.0.co;2-k DOI: https://doi.org/10.1002/1097-0142(19841215)54:12<3022::AID-CNCR2820541234>3.0.CO;2-K
Li C, Ford ES, McGuire LC, Mokdad AH, Little RR, Reaven GM. Trends in hyperinsulinemia among nondiabetic adults in the U.S. diabetes care. 2006 Nov 1;29(11):2396–402.
https://doi.org/10.2337/dc06-0289 DOI: https://doi.org/10.2337/dc06-0289
Jasani B, Donaldson LJ, Ratcliffe JG, Sokhi GS. Mechanism of impaired glucose tolerance in patients with neoplasia. Br J Cancer. 1978 Aug;38(2):287–92.
https://doi.org/10.1038/bjc.1978.200 DOI: https://doi.org/10.1038/bjc.1978.200
Lundholm K, Holm G, Scherstén T. Insulin resistance in patients with cancer. Cancer Res. 1978 Dec;38(12):4665–70.
Tayek JA, Manglik S, Abemayor E. Insulin secretion, glucose production, and insulin sensitivity in underweight and normal-weight volunteers, and in underweight and normal-weight cancer patients: a clinical research center study. Metabolism. 1997 Feb;46(2):140–5.
https://doi.org/10.1016/s0026-0495(97)90291-2 DOI: https://doi.org/10.1016/S0026-0495(97)90291-2
Grace CJ, Swenne I, Kohn PG, Strain AJ, Milner RD. Protein-energy malnutrition induces changes in insulin sensitivity. Diabete Metab. 1990 Dec;16(6):484–91.
Das SK, Eder S, Schauer S, Diwoky C, Temmel H, Guertl B, et al. Adipose triglyceride lipase contributes to cancer-associated cachexia. Science. 2011 Jul 8;333(6039):233–8.
https://doi.org/10.1126/science.1198973 DOI: https://doi.org/10.1126/science.1198973
Morigny P, Zuber J, Haid M, Kaltenecker D, Riols F, Lima JDC, et al. High levels of modified ceramides are a defining feature of murine and human cancer cachexia. J Cachexia Sarcopenia Muscle. 2020 Dec 8;11(6):1459–75.
https://doi.org/10.1002/jcsm.12626 DOI: https://doi.org/10.1002/jcsm.12626
Han X, Raun SH, Carlsson M, Sjøberg KA, Henriquez-Olguín C, Ali M, et al. Cancer causes metabolic perturbations associated with reduced insulin-stimulated glucose uptake in peripheral tissues and impaired muscle microvascular perfusion. Metabolism. 2020 Apr;105:154169.
https://doi.org/10.1016/j.metabol.2020.154169 DOI: https://doi.org/10.1016/j.metabol.2020.154169
Op den Kamp CM, Langen RC, Snepvangers FJ, de Theije CC, Schellekens JM, Laugs F, et al. Nuclear transcription factor κ B activation and protein turnover adaptations in skeletal muscle of patients with progressive stages of lung cancer cachexia. Am J Clin Nutr. 2013 Sep;98(3):738–48.
https://doi.org/10.3945/ajcn.113.058388 DOI: https://doi.org/10.3945/ajcn.113.058388
Yule MS, Thompson J, Leesahatsawat K, Sousa MS, Anker SD, Arends J, et al. Biomarker endpoints in cancer cachexia clinical trials: systematic review 5 of the cachexia endpoint series. J Cachexia Sarcopenia Muscle. 2024 Jun;15(3):853–67.
https://doi.org/10.1002/jcsm.13491 DOI: https://doi.org/10.1002/jcsm.13491
Ebhardt HA, Degen S, Tadini V, Schilb A, Johns N, Greig CA, et al. Comprehensive proteome analysis of human skeletal muscle in cachexia and sarcopenia: a pilot study. J Cachexia Sarcopenia Muscle. 2017 Aug 15;8(4):567–82.
https://doi.org/10.1002/jcsm.12188 DOI: https://doi.org/10.1002/jcsm.12188
Langer HT, Rohm M, Goncalves MD, Sylow L. AMPK as a mediator of tissue preservation: time for a shift in dogma? Nat Rev Endocrinol. 2024 Sep 17;20(9):526–40.
https://doi.org/10.1038/s41574-024-00992-y DOI: https://doi.org/10.1038/s41574-024-00992-y
Hébuterne X, Lemarié E, Michallet M, de Montreuil CB, Schneider SM, Goldwasser F. Prevalence of malnutrition and current use of nutrition support in patients with cancer. J Parenter Enteral Nutr. 2014 Feb 23;38(2):196–204.
https://doi.org/10.1177/0148607113502674 DOI: https://doi.org/10.1177/0148607113502674
Tinsley-Vance SM, Mason TM, Komrokji RS. An integrative review of cancer-related cachexia and sarcopenia: a different focus in malignant hematology. Health Sci Rev. 2024 Dec;13:100205.
https://doi.org/10.1016/j.hsr.2024.100205 DOI: https://doi.org/10.1016/j.hsr.2024.100205
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