Insulin supplementation attenuates cancer-induced cardiomyopathy and slows tumor disease progression
James T. Thackeray, Stefan Pietzsch, Britta Stapel, Melanie Ricke-Hoch, Chun-Wei Lee, Jens P. Bankstahl, Michaela Scherr, Jörg Heineke, Gesine Scharf, Arash Haghikia, Frank M. Bengel, Denise Hilfiker-Kleiner
James T. Thackeray, Stefan Pietzsch, Britta Stapel, Melanie Ricke-Hoch, Chun-Wei Lee, Jens P. Bankstahl, Michaela Scherr, Jörg Heineke, Gesine Scharf, Arash Haghikia, Frank M. Bengel, Denise Hilfiker-Kleiner
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Research Article Cardiology Oncology

Insulin supplementation attenuates cancer-induced cardiomyopathy and slows tumor disease progression

Abstract

Advanced cancer induces fundamental changes in metabolism and promotes cardiac atrophy and heart failure. We discovered systemic insulin deficiency in cachectic cancer patients. Similarly, mice with advanced B16F10 melanoma (B16F10-TM) or colon 26 carcinoma (C26-TM) displayed decreased systemic insulin associated with marked cardiac atrophy, metabolic impairment, and function. B16F10 and C26 tumors decrease systemic insulin via high glucose consumption, lowering pancreatic insulin production and producing insulin-degrading enzyme. As tumor cells consume glucose in an insulin-independent manner, they shift glucose away from cardiomyocytes. Since cardiomyocytes in both tumor models remained insulin responsive, low-dose insulin supplementation by subcutaneous implantation of insulin-releasing pellets improved cardiac glucose uptake, atrophy, and function, with no adverse side effects. In addition, by redirecting glucose to the heart in addition to other organs, the systemic insulin treatment lowered glucose usage by the tumor and thereby decreased tumor growth and volume. Insulin corrected the cancer-induced reduction in cardiac Akt activation and the subsequent overactivation of the proteasome and autophagy. Thus, cancer-induced systemic insulin depletion contributes to cardiac wasting and failure and may promote tumor growth. Low-dose insulin supplementation attenuates these processes and may be supportive in cardio-oncologic treatment concepts.

Authors

James T. Thackeray, Stefan Pietzsch, Britta Stapel, Melanie Ricke-Hoch, Chun-Wei Lee, Jens P. Bankstahl, Michaela Scherr, Jörg Heineke, Gesine Scharf, Arash Haghikia, Frank M. Bengel, Denise Hilfiker-Kleiner

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Figure 1

Analyses of blood insulin levels in cancer patients and cardiac phenotype in mice with B16F10 melanoma or C26 carcinoma.

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Analyses of blood insulin levels in cancer patients and cardiac phenotyp...
(A) Serum insulin levels in cachectic cancer patients (n = 14) compared with healthy controls (n = 13). (B) Kaplan-Meyer survival curves for C57BL/6 mice with B16F10 melanoma tumors (B16F10-TM) (n = 46) and BALB/c mice with colon 26 carcinoma (C26-TM) (n = 37) versus corresponding healthy controls (n = 17 each). (C) Representative explanted hearts (each square = 1 mm2) of B16F10-TM and C26-TM mice and controls. (D–I) Quantitative mRNA levels (qRT-PCR) of (D and E) myosin heavy chain isoforms α (Myh6) and β (Myh7), (F and G) atrophy marker Atrogin1 and muscle-specific ring finger protein 1 (MuRF1), and (H and I) autophagy markers cathepsin L (CatL) and microtubule-associated protein 1 light chain 3 β (LC3b) in B16F10-TM mice (n = 14 vs. control n = 10) or C26-TM mice and corresponding controls (n = 8 each). (J and L) Western blots depicting protein levels and Ponceau S staining as loading control for LC3bI and LC3bII. (K and M) LC3bII/LC3bI ratio in left ventricular (LV) tissue from B16F10-TM mice (n = 9) and controls (n = 5) and C26-TM mice and controls (n = 8 each). B16F10-TM and C26-TM mice in C–M were analyzed at an advanced disease stage (14–21 days after tumor inoculation). Healthy control mice were injected with PBS as vehicle. Data are depicted as median with interquartile range (A) or mean ± SD (D–I, K, and M); *P < 0.05, **P < 0.01 vs. respective healthy controls, using 2-tailed Student’s unpaired t tests with or without Welch’s correction as required or Mann-Whitney test as required (A, D–I, K, and M) or log-rank (Mantel-Cox) test (B).