Insulin-like growth factor I preserves host lean tissue mass in cancer cachexia

Abstract

Insulin-like growth factor I (IGF-I) has been implicated in the regulation and maintenance of skeletal muscle protein balance and thus may be of potential benefit in attenuating the cancer-cachectic process. To examine this hypothesis, 47 sham or tumor-implanted Fischer 344 rats were randomized to receive either continuous subcutaneous IGF-I (220 or 400 micrograms/day) or saline as control. In the tumor-bearing (TB) population, IGF-I-treated groups showed a dose-dependent increase in host weight gain (P less than 0.05), final carcass weight (P less than 0.05), and gastrocnemius muscle weights (P less than 0.05) and protein contents (0.50 +/- 0.02, 0.40 +/- 0.01, and 0.52 +/- 0.03 g/100 g host wt, for non-TB saline, TB saline, and TB 400 mg IGF-I groups, respectively; P less than 0.01, IGF-I vs. saline). Similar increases in muscle RNA and DNA contents (P less than 0.01) were induced by IGF-I treatment (P less than 0.05). IGF-I treatment in this rat sarcoma model significantly reduced the proportion of aneuploid cells in the tumor (aneuploid-to-diploid ratio: TB saline 1.1 +/- 0.2 vs. TB IGF-I 0.5 +/- 0.1; P less than 0.05). IGF-I treatment attenuated host muscle protein and lean tissue depletion without stimulation of tumor growth. The tumor aneuploid population was reduced in response to IGF-I treatment. Thus IGF-I may be a potential therapeutic agent in cancer-induced cachexia.

Insulin Treatment in Cancer Cachexia: Effects on Survival, Metabolism, and Physical Functioning

“…Defective insulin production and increased insulin clearance during feeding may also contribute to glucose intolerance in cancer. However, graded doses of insulin infusions to cancer patients confirmed insulin resistance in glucose homeostasis of peripheral tissues (36), whereas insulin effects on amino acid flux did not indicate resistance (35,37), which agrees with the findings of insignificant effects on muscle mass by insulin in the present study, although IGF-I had clearcut effects to protect muscle wasting in experimental tumor bearers (38).…”

“…However, complex in vivo conditions are usually the net result of both positive and negative factors. Although there is no doubt that both insulin and IGF-I may stimulate tumor growth, such effects may be overcome by counteracting or improved metabolic status by insulin, a concept which has support in experimental models (30,31,38), in which recent conclusions on the Warburg effect and anaerobic glycolysis in malignant tumors seem to be increasingly interesting in light of the present results with improved survival of insulin-treated patients (48). There are also other clinical conditions in which insulin decreased mortality, in part, unrelated to effects on glucose homeostasis (49).…”

Functional and morphological skeletal muscle abnormalities correlate with reduced electromyographic activity in chronic heart failure

“…This is well in line with previous findings that demonstrated a correlation between systemic markers of inflammation and signs of muscular atrophy in other chronic illnesses [1,31]. Both, proinflammatory cytokines and IGF-1 have been implicated in the development of myopathic alterations in chronic diseases such as cancer [32], renal failure [33] and CHF [1,30,31]. Intriguingly, TNFa induces a catabolic metabolism as well as muscular atrophy and reduces skeletal muscle contractility in experimental studies [34].…”

Implications of chronic heart failure on peripheral vasculature and skeletal muscle before and after exercise training

“…Catabolic syndromes in chronic inflammation, sepsis, or cancer show an altered state of the GH/IGF-1 axis due in part to peripheral IGF-1 deficiency and also because of an impaired IGF-1 response to GH [77,78]. Elevated levels of GH with inappropriately normal serum levels of IGF-1 have been described in cardiac cachexia [79].…”