Abstract Cancer cachexia, weight loss with altered body composition, is a multifactorial syndrome propagated by symptoms that impair caloric intake, tumor byproducts, chronic inflammation, altered metabolism, and hormonal abnormalities. Cachexia is associated with reduced performance status, decreased tolerance to chemotherapy, and increased mortality in cancer patients. Insulin resistance as a consequence of tumor byproducts, chronic inflammation, and endocrine dysfunction has been associated with weight loss in cancer patients. Insulin resistance in cancer patients is characterized by increased hepatic glucose production and gluconeogenesis, and unlike type 2 diabetes, normal fasting glucose with high, normal or low levels of insulin. Cancer cachexia results in altered body composition with the loss of lean muscle mass with or without the loss of adipose tissue. Alteration in visceral adiposity, accumulation of intramuscular adipose tissue, and secretion of adipocytokines from adipose cells may play a role in promoting the metabolic derangements associated with cachexia including a proinflammatory environment and insulin resistance. Increased production of ghrelin, testosterone deficiency, and low vitamin D levels may also contribute to altered metabolism of glucose. Cancer cachexia cannot be easily reversed by standard nutritional interventions and identifying and treating cachexia at the earliest stage of development is advocated. Experts advocate for multimodal therapy to address symptoms that impact caloric intake, reduce chronic inflammation, and treat metabolic and endocrine derangements, which propagate the loss of weight. Treatment of insulin resistance may be a critical component of multimodal therapy for cancer cachexia and more research is needed. cancer cachexia, insulin resistance, body composition Key Message Cancer cachexia is a multifactorial syndrome characterized by impaired caloric intake, chronic inflammation and altered metabolism resulting in loss of lean muscle mass with or without loss of adipose tissue. Insulin resistance due to tumor byproducts, chronic inflammation, altered body composition, and endocrine dysfunction may contribute to the development of cachexia in cancer patients and treatment may be warranted to prevent weight loss. Introduction Cancer cachexia is defined by loss of muscle mass with or without a reduction in fat mass (FM) . Roughly 30–90% of cancer patients develop cachexia , which is associated with reductions in performance status (PS), decreased tolerance to cancer therapies , and increased mortality, accounting for 10–20% of cancer-related deaths . Loss of weight in cancer patients cannot be easily reversed by standard nutritional interventions and treatment directed at normalizing underlying metabolic abnormalities is critical in order to utilize nutrients effectively . Recently, a panel of experts recognized cancer cachexia to span three distinct stages: precachexia, cachexia, and a refractory cachectic stage . Expert consensus definition of cancer cachexia highlights metabolic abnormalities resulting in altered glucose, lipid, and protein metabolism . In the majority of clinical studies in this review, cancer cachexia has been defined as ≥5% weight loss over 3 months or ≥10% within the previous 6 months or body mass index (BMI) <18.5. Sarcopenia, which is distinct from cachexia, is a progressive decline in muscle mass associated with aging and independent of any underlying disease . Figure 1 highlights variations in body composition in healthy, cancer, and elderly patients . In elderly cancer patients, sarcopenia and cachexia can coexist; however, the underlying pathophysiology of cachexia differs from sarcopenia. Cachexia is characterized by increased muscle protein degradation, elevated basal metabolic rate and total energy expenditure, and either no change or reduction in FM . While sarcopenic obesity is characterized by unchanged muscle protein degradation, overall decreased metabolic rate and total energy expenditure, and increased FM . Figure 1. View largeDownload slide Body compartments and composition illustration. Figure 1. View largeDownload slide Body compartments and composition illustration. The following review article will highlight the contribution of insulin resistance and other metabolic derangements which lead to the development of cancer cachexia, Figure 2, with an emphasis on glucose metabolism, effect of insulin resistance on protein metabolism, influence of adipose tissue (AT) on insulin resistance, endocrine abnormalities associated with insulin resistance, and summarize potential therapeutic interventions to targeting insulin resistance, which can be incorporated into a multimodal therapy, for the treatment of cancer cachexia. Figure 2. View largeDownload slide Potential role of insulin resistance in development of anorexia-cancer cachexia syndrome. Figure 2. View largeDownload slide Potential role of insulin resistance in development of anorexia-cancer cachexia syndrome. Insulin, insulin resistance, and cancer Insulin, an anabolic hormone, coordinates glucose to either oxidation or to storage in the body. Insulin sensitivity is coordinated by glucose uptake in insulin-sensitive cells in the muscle, fat, and liver in conjunction with glucose removal from the circulation when glucose is elevated. Insulin decreases hepatic glucose production and increases glucose uptake in fat and muscle tissue. Insulin promotes growth of cells by stimulating lipogenesis and inhibiting lipolysis, increasing protein synthesis and inhibiting protein breakdown. Catabolic stress hormones, catecholamines and cortisol, and glucagon act in opposition to insulin resulting in lipolysis. Insulin has been shown to have tumorigenic effects on preneoplastic cells that have insulin receptors , and insulin-like growth factors (IGFs) have also been implicated in tumorigenesis  which has been a focus of investigation. Alternatively, glucose intake has also been shown to stimulate cancer growth via the inflammatory cascade, the 12-lipoxygenase pathway, in mice fed sucrose enriched diet . Insulin resistance has been recognized as a physiological adaptive response in the setting of pregnancy, fasting, exercise, and acute stress , and is also found in various chronic diseases such as obesity, type 2 diabetes (T2D), and cancer cachexia . Chronic insulin resistance is noted in malignant, but not benign tumors, and is hypothesized to develop in cancer cachexia due to chronic exposure of proinflammatory cytokines, TNF-α, IL-6, and insulin growth factor binding protein , which results in insulin resistance . Using the gold standard hyperinsulinemic-euglycemic clamp technique for measuring insulin sensitivity, peripheral insulin resistance was recognized in patients with colorectal , non-small-cell lung (NSCLC) , gastrointestinal , and mixed malignancies . In a study examining various cancers, insulin resistance was not associated with disease stage, tumor burden, or degree of weight loss, but was weakly associated with degree of inflammation . In mice with colon-26 tumors, insulin resistance was noted in early stages of cachexia, prior to the development of weight loss . In sarcoma patients without significant weight loss, intravenous glucose tolerance testing revealed impaired glucose tolerance that was lower in patients with less body weight; however, patients were not followed longitudinally to associate with the development of cachexia . Of note, after surgical tumor removal, insulin sensitivity has been restored [23, 24] implicating the presence of the tumor as the underlying cause. The exact etiology of abnormal glucose intolerance in cancer patients is unclear. Increased glucose requirements of cancer cells may result in hypoglycemia resulting in compensatory hormonal signals, increased growth hormone, epinephrine, or glucagon. Alternatively, tumor byproducts may result in insulin resistance. In the fruit fly, Drosophila melanogaster, researchers have reported that overproduction of an insulin growth factor binding protein, ImpL2, inhibits insulin signaling and results in wasting of the muscles . In patients with lung cancer, tumor byproducts including adrecorticotropic hormone and corticotropin-releasing factors could potentially result in abnormal glucose metabolism . Glucose metabolism in cancer cachexia Glucose intolerance, similar to T2D, was recognized as early as 1919 in patients with cancer . In cancer cachexia, higher endogenous glucose production with increased gluconeogenesis (GNG) and insulin resistance has been noted, but unlike T2D, fasting glucose is within normal values [28, 29]. In the fasting state, endogenous insulin secretion is increased by 25–50% in most studies in patients with cancer cachexia, but also has been reported to be normal or low [28, 30]. Decreased insulin levels have been reported in cancer patients with severe malnutrition or weight loss [31, 32], and abnormally low insulin secretion was noted in response to oral and intravenous glucose challenges which correlated with degree of weight loss . The chronic inflammatory state of patients with severe weight loss potentially can contribute to pancreatic β-cell dysfunction resulting in impaired insulin secretion . These findings highlight the changing nature of metabolic abnormalities involving glucose regulation as weight loss progresses through various stages of cachexia: precachectic, cachexia, or the refractory stage. Active malignant cells have been noted to rely predominantly on glucose as the main energy fuel via glycolysis, as opposed to oxidative phosphorylation, which is 18 times less efficient in ATP production . In undernourished cancer patients, extensive glucose cycling has been reported to occur in the majority, but not all, studies reviewed . In malignant cells, the resulting pyruvate produced from glycolysis is reduced to lactate even in an aerobic environment, the Warburg effect , and subsequently, the lactate is recycled to glucose by the liver or other tissues through the inefficient Cori Cycle  resulting in increased energy expenditure. Insulin resistance and protein metabolism The negative affect of insulin resistance on protein anabolism, suppression of protein synthesis, has been reported in the obese , elderly , and T2D . In a mouse model of colon adenocarcinoma, insulin resistance was shown to exist prior to the development of the losses in weight, muscle, and AT; however, 20% reduction in food intake has also been demonstrated in cancer mice . In a study of 10 male NSCLC patients with moderate weight loss insulin resistance was associated with 26% less protein anabolism which correlated with C-reactive protein (CRP), a marker for inflammation, but not with weight loss . However, in another study of six gastrointestinal cancer patients, insulin resistance was not significantly associated with altered protein anabolism . More longitudinal research is needed examining insulin resistance and protein metabolism in cancer patients. In addition, researchers have proposed that amino acids released from muscle protein degradation are utilized for GNG in cancer patients. Evidence of GNG from alanine turnover has been reported in several studies that included esophageal , lung , and other cancer types , and shown to be significantly higher in weight losing when compared with weight stable lung cancer patients . In moderately cachectic lung cancer patients, increased fasting GNG was positively correlated with resting energy expenditure, CRP and negatively with insulin-induced protein anabolism . Also, insulin resistance and its interaction with ATP-dependent ubiquitin-proteasome pathway (UPP) via caspase-3 have been identified as another potential mechanism contributing to protein degradation . Insulin-resistant states results in decreased phosphatidylinositol 3-kinase and Akt phosphorylation, which release inhibition of FoxO and caspase-3 resulting in increased proteolytic activity . Body composition and insulin resistance in cancer cachexia Researchers stress that a patient’s BMI by itself can be misleading and assessment of body composition is needed in patients with cancer . Magnetic resonance imaging and computed tomography (CT) allow for accurate differentiation of AT [i.e. subcutaneous (SAT), visceral (VAT), intramuscular ([IMAT)] and fat-free mass [i.e. skeletal muscle mass (SMM) and bone] [50, 51]. Body composition parameters VAT, SMM, IMAT have been shown to significantly correlate with insulin signaling [52, 53], and affect clinical outcomes including survival in cancer [54–57]. Obesity, increased adiposity, is a well-recognized risk factor for insulin resistance and T2D. With rising obesity prevalence, patients are increasingly found to be overweight/obese with impaired glucose control on cancer diagnosis. AT is biologically active, regulates appetite, inflammation, insulin sensitivity, energy balance, and fat metabolism . Excess AT leads to the production of inflammatory cytokines, upregulation of nuclear factor-κB leading to increased nitric oxide and reactive oxygen species contributing to insulin resistance and excess glucose, and increased FFA, which further propagate inflammation . AT location is deemed important in terms of severity of metabolic deregulation. VAT is metabolically more active than SAT [60, 61], and highly associated with glucose and lipid disorders [52, 53]. Visceral obesity is a key component of the metabolic syndrome (MetSyn) that also includes dyslipidemia, hyperglycemia, and hypertension . Visceral obesity is strongly associated with disrupted insulin signaling, resulting in hyperinsulinemia, insulin resistance, higher bioavailability of IGF-1, which along with systemic inflammation, and alterations in sex hormones and adipokine expression, perpetuate a protumorigenic environment [52, 63]. MetSyn and its individual components particularly central obesity and insulin resistance have been associated with cancer development [64–67], and increased mortality . High VAT at baseline has been shown to decrease treatment response and survival in several cancer such as breast, pancreatic, prostate, and colorectal cancers [69–75], and associated with higher losses in weight, VAT, and SMM . In locally advanced pancreatic cancer, obese patients experienced disproportionately greater losses in weight (median 10% versus 4%), VAT (31% versus 11%), and SMM (10% versus 2%) than nonobese patients . Cachectic cancer patents have been shown to have increased VAT loss irrespective of BMI [76, 77], and have lower AT when compared with weight-stable patients [78–81]. In gastrointestinal cancer, newly diagnosed cachectic patients with gastrointestinal-obstructions experienced twice the degree of weight loss but had higher VAT when compared with patients without obstruction . A study in colorectal and NSCLC cancer patients suggested AT loss begins about 7 months prior to death . VAT is most sensitive to lipolytic factors , and tumor byproducts  are hypothesized to increase lipolysis resulting in increased FFA and other mediators, thereby perpetuating systemic inflammation, insulin resistance, and wasting. In addition, studies have examined the impact of SMM in cancer and observed sarcopenia to be associated with decreased survival [49, 57] but not all studies . In longitudinal studies, higher SMM loss was associated with lower survival in patients with metastatic melanoma , colorectal , and ovarian cancers . In another study, while sarcopenia alone was not significant, the presence of obesity and sarcopenia was prognostic for survival . In advanced cancer patients with cachexia, excess or the gain of AT is generally not present and accumulation of IMAT may play a role in weight loss. Muscle steatosis, characterized by IMAT and intramyocellular lipids, has been identified in cancer patients and associated with muscle weakness and poor muscle quality . IMAT, identified by low muscle attenuation on CT imaging, is predictive of higher mortality in cancers such as renal , melanoma , lung, and GI malignancies . In obese patients, research has implicated the accumulation of lipid-derived diacylglycerols, ceramides, and acylcarnitines in muscle tissue in the interference of proper insulin signaling and glucose uptake . In addition, a switch, induced by proinflammatory factors, from white to brown AT associated with higher mitochondria containing UCP-1, promotes thermogenesis and thereby increasing energy expenditure in cancer patients, as demonstrated in rodent models, may contribute to the development of cancer cachexia . Adipocytokines and insulin resistance AT is the sources for two of the most abundant adipocytokines: leptin and adiponectin. Due to influence of the cancer microenvironment, inflamed VAT can alter the production of adipocytokines. In T2D, low concentration of adiponectin in combination with increased cytokines, TNF-α, IL-6, and IL-1β, results in altered glucose homeostasis resulting in increased insulin and insulin resistance . Adinopectin is the most abundant adipocytokine and has anti-inflammatory, insulin-sensitizing, and anti-atherogenic properties . Its secretion is stimulated by insulin and IGF-I . Low adinopectin levels were reported in cachectic patients with lung  and gastric cancers . However, no correlation was reported with weight loss in patients with breast and colon cancer . In gastric cancer, no relation was reported with adinopectin and insulin resistance , but more research is needed. Leptin, a cytokine, is an important signaling molecule that stimulates appetite and weight gain . Serum level of leptin corresponds with fat stores and is secreted by adipocytes, gastric, colorectal, and mammary epithelial tissue . Conflicting reports regarding serum leptin levels in cancer patients have been published with decreased leptin levels noted in gastrointestinal malignancies [101, 102] and increased levels in breast , gastrointestinal , and gynecologic cancer patients . In a recent review, leptin plays a role in modulating inflammation and the immune response , and leptin receptors were recognized in β-islet cells of the pancreas and inhibited secretion [107, 108]. In patients with gastrointestinal tumors, a positive association was noted between leptin levels and insulin resistance  but another study reported no association . Endocrine abnormalities and cancer cachexia Ghrelin is an anabolic peptide hormone produced in gastric enteroendocrine cells and is crucial in the regulation of food intake and energy homeostasis . Increased serum level of ghrelin has been reported in lung , breast, and colon  cancers. Resistance to ghrelin signaling is associated with development of anorexia and cancer cachexia . Broglio et al. was the first researcher to report that ghrelin administration raises blood glucose levels in healthy patients followed by a decrease in insulin levels ; however, subsequent studies have shown ambiguous results with some studies confirming lower insulin levels, other reporting no changes and a few noting increased insulin secretion . Studies of parenteral ghrelin therapy and oral ghrelin mimetic for the treatment of cancer cachexia are ongoing. In male cancer patients, testosterone deficiency is noted to be frequent and associated with chronic opioid use, steroids, and chemotherapy . In obese patients, low testosterone is associated with increased inflammation  and insulin resistance . An inverse relationship exists between testosterone concentration and adiposity in men but is positively related in women , while estrogen levels have been reported to determine the distribution of AT . In addition, gender influences proportion of VAT adiposity and men have twice the amount of VAT fat as women, which is associated with a higher prevalence of insulin resistance and MetSyn . Testosterone replacement in hypogonadic men with cancer cachexia may improve insulin resistance and has the potential to increase muscle mass but clinical trials are needed. Vitamin D deficiency is not uncommon in the general population and also noted to present in 47% of ambulatory patients with cancer and more common in nonwhite cancer patients, females and hypogonadal men . Vitamin D supplementation has been shown to improve insulin sensitivity in the noncancer population . In a small study of 16 patients with advanced hormone refractory prostate cancer, vitamin D replacement reported to be a useful adjunct to improve muscle strength but no assessment of weight loss or body composition were reported. In addition, vitamin D supplementation is known to inhibit the aromatase enzyme that prevents the conversion of androgens to estrogens, which may account for its anabolic properties . Potential interventions for insulin resistance in cancer cachexia Cancer cachexia is a complex multifactorial syndrome and propagated by symptoms that impair caloric intake, tumor byproducts, chronic inflammation, altered metabolism, and hormonal abnormalities. Experts advocate multimodal therapy and treatment addressing underlying insulin resistance may be an integral component of treatment of cancer cachexia. Currently, no guidelines exist for optimal treatment of cancer patients with cachexia. Current expert opinion recommends interventions directed at stimulating anabolism and addressing the metabolic derangements at an earlier stage in the development of cancer cachexia, which requires early detection of patients in a precachectic stage . Nonpharmacological Dietary counseling  and selective nutritional support  have the potential to maintain muscle mass or even reverse weight loss in cancer patients. In clinical trials, protein-enriched supplementation, either ingested or infused intravenously, has been reported to improve weight, exercise capacity, and lean body mass in cancer patients [127, 128], but not all studies [129, 130]. In T2D, supplementation with leucine and phenylalanine was shown to improve insulin response , and the amino acid arginine, also, has been reported to improve the secretion of insulin . The discrepancies in studies examining amino acid supplementation in cancer cachexia may be due to variable composition of amino acids prescribed and more research is warranted evaluating amino acid supplementation targeted to address the metabolic derangements such as insulin resistance underlying cancer cachexia. Omega-3 fatty acids, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) have potential to reverse cancer cachexia  and have also been reported to improve insulin sensitivity in animal and human studies by modulation of lipid metabolism, stimulation of mitochondrial biogenesis, and altering the pattern of secreted adipokines . In a recent study, evaluating fish oil-derived EPA effect on SMM and AT, as quantified by CT images in NSCLC patients receiving chemotherapy, fish oil supplementation resulted in significant declines in IMAT accompanied by maintenance of weight and SMM . Researchers hypothesized that EPAs ability to suppress lipogenesis and stimulate lipid oxidation resulted in decreased IMAT, which is linked to insulin resistance and cachexia. Other studies on fish oil supplementation have had mixed results with some reporting improvements in PS and muscle mass [136, 137] while others reporting no benefits [138, 139]. In addition, EPA and DHA, when incorporated into a nutritional supplement, were reported to improve protein synthesis in cancer patients . Via a number of mechanisms including enhancing insulin sensitivity, fish oil supplementation may improve cancer cachexia and warrant more research. Moderate aerobic exercise has been proposed as a nonpharmacological treatment option for cancer cachexia and prevents muscle loss ; however, the benefits for the treatment of cancer cachexia have not been studied extensively and compliance in frail patients remains problematic. In obese patients, moderate aerobic exercise has been shown to reduce low-grade inflammation  and improve glucose sensitivity . Pharmacological Since insulin resistance may contribute to the development of cancer cachexia, administration of insulin or medications that improve insulin resistance have the potential to improve or maintain muscle mass in patients with cancer. Exogenous insulin administration was examined in a study of 138 patients mainly with advanced gastrointestinal cancers randomized to receive best supportive care with or without daily insulin (0.11 ± 0.05 units/kg/d) reported increased carbohydrate intake and whole body fat, no change in fat-free lean tissue mass, and decreased serum-free fatty acids . Insulin administration improved metabolic efficiency in exercise without significant improvement in exercise capacity or spontaneous physical activity. No change in tumor markers was highlighted as well as improved survival of insulin-treated patients which would temper concerns of insulin stimulating tumor growth ; however, in animal models of cachexia, insulin has been shown to promote tumor growth [145, 146] limiting enthusiasm as a treatment for cancer cachexia. Insulin sensitizers, such as metformin and thiazolidinediones (TZDs), have the potential to counter muscle wasting in cancer patients. A commonly used T2D medication, metformin can suppress lipolysis in adipocytes in response to catecholamine or TNF-α , decreasing plasma-free fatty acids and improving insulin sensitivity and decreasing hepatic glucose production . Also, metformin may prevent muscle wasting by its ability to increase activity of AMP-activated protein kinase , which leads to increased glucose transporter 4 activity leading to increased glucose uptake in muscle cells . In a randomized clinical trial of 40 men with prostate cancer receiving androgen deprivation therapy, metformin combined with low glycemic index diet and exercise reported improvement in weight and BMI compared with controls . In addition, metformin, unlike exogenous insulin administration, has been noted to have antineoplastic effects and researchers have reported a role in cancer prevention in pancreatic cancer, hepatocellular malignancies, breast, and colon cancers  which makes it desirable as a component of multimodal treatment of cancer cachexia for these malignancies. Other insulin sensitizers, TZDs, have also been shown to have antitumor effects on various types of cancer  and have the potential to prevent muscle wasting in cancer cachexia. In colon-26 tumor-bearing mice with early stage cachexia, researchers have treatment with rosiglitazone significantly improved insulin sensitivity, reduced inflammation and restored adinopectin levels, an insulin-sensitizing adipocytokine, which prevented weight loss primarily by maintaining fat stores ; however, in late stage disease, once weight loss developed, no retention of muscle mass was noted . Rosiglitazone may have potential anabolic effects in the prevention of cancer cachexia in the precachectic stage, but cardiovascular side effects limits enthusiasm . Agonist of β2-adrenoceptors, including albutamol, clenbuterol, and calmeterol, can modulate insulin secretion and increase glucose uptake into muscle and have been reported to improve SMM in animal models of cancer cachexia [156, 157]. Researchers note that chronic use β2-adrenergic agonists have no effect on caloric intake but redistribute nutrients promoting muscle mass over FM via mechanism involving UPP . In the 1990s, hydrazine sulfate, an inhibitor of GNG, was publicized as a treatment of cancer cachexia but subsequent trials failed to demonstrate any benefits in patients with advanced cancer . Discussion Conclusion Cancer cachexia, a multifactorial syndrome, results in altered body composition, loss of SMM with or without the loss of AT. Alterations in body composition, loss of VAT, accumulation of IMAT, and changes in adipocytokines secreted from adipose cells may play a role in promoting the metabolic derangements associated with cachexia including a proinflammatory environment and insulin resistance. Increased production of ghrelin, testosterone deficiency, and low vitamin D levels may also contribute to altered metabolism of glucose. Cancer cachexia cannot be easily reversed by standard nutritional interventions and identifying and treating cachexia at the earliest stage of development is advocated. Experts advocate for multimodal therapy to address symptoms that impact caloric intake, reduce chronic inflammation, and treat metabolic and endocrine derangements, which propagate the loss of weight. Treatment of insulin resistance may be a critical component of multimodal therapy for cancer cachexia and more research is needed. Funding This supplement was made possible by funding support from Helsinn. 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Annals of Oncology – Oxford University Press
Published: Feb 1, 2018
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