Insulin resistance and body composition in cancer patients

Insulin resistance and body composition in cancer patients 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) [1]. Roughly 30–90% of cancer patients develop cachexia [2], which is associated with reductions in performance status (PS), decreased tolerance to cancer therapies [3], and increased mortality, accounting for 10–20% of cancer-related deaths [4]. 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 [5]. Recently, a panel of experts recognized cancer cachexia to span three distinct stages: precachexia, cachexia, and a refractory cachectic stage [1]. Expert consensus definition of cancer cachexia highlights metabolic abnormalities resulting in altered glucose, lipid, and protein metabolism [6]. 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 [7]. Figure 1 highlights variations in body composition in healthy, cancer, and elderly patients [8]. 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 [9]. While sarcopenic obesity is characterized by unchanged muscle protein degradation, overall decreased metabolic rate and total energy expenditure, and increased FM [9]. 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 [10], and insulin-like growth factors (IGFs) have also been implicated in tumorigenesis [11] 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 [12]. Insulin resistance has been recognized as a physiological adaptive response in the setting of pregnancy, fasting, exercise, and acute stress [13], and is also found in various chronic diseases such as obesity, type 2 diabetes (T2D), and cancer cachexia [14]. 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 [15], which results in insulin resistance [16]. Using the gold standard hyperinsulinemic-euglycemic clamp technique for measuring insulin sensitivity, peripheral insulin resistance was recognized in patients with colorectal [17], non-small-cell lung (NSCLC) [18], gastrointestinal [19], and mixed malignancies [20]. 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 [20]. In mice with colon-26 tumors, insulin resistance was noted in early stages of cachexia, prior to the development of weight loss [21]. 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 [22]. 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 [25]. In patients with lung cancer, tumor byproducts including adrecorticotropic hormone and corticotropin-releasing factors could potentially result in abnormal glucose metabolism [26]. Glucose metabolism in cancer cachexia Glucose intolerance, similar to T2D, was recognized as early as 1919 in patients with cancer [27]. 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 [33]. The chronic inflammatory state of patients with severe weight loss potentially can contribute to pancreatic β-cell dysfunction resulting in impaired insulin secretion [34]. 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 [35]. In undernourished cancer patients, extensive glucose cycling has been reported to occur in the majority, but not all, studies reviewed [28]. In malignant cells, the resulting pyruvate produced from glycolysis is reduced to lactate even in an aerobic environment, the Warburg effect [36], and subsequently, the lactate is recycled to glucose by the liver or other tissues through the inefficient Cori Cycle [37] 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 [38], elderly [39], and T2D [40]. 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 [41]. 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 [42]. However, in another study of six gastrointestinal cancer patients, insulin resistance was not significantly associated with altered protein anabolism [19]. 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 [43], lung [44], and other cancer types [45], and shown to be significantly higher in weight losing when compared with weight stable lung cancer patients [44]. In moderately cachectic lung cancer patients, increased fasting GNG was positively correlated with resting energy expenditure, CRP and negatively with insulin-induced protein anabolism [46]. 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 [47]. 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 [48]. 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 [49]. 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 [58]. 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 [59]. 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 [62]. 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 [68]. 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 [55]. 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 [55]. 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 [81]. A study in colorectal and NSCLC cancer patients suggested AT loss begins about 7 months prior to death [77]. VAT is most sensitive to lipolytic factors [82], and tumor byproducts [78] 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 [83]. In longitudinal studies, higher SMM loss was associated with lower survival in patients with metastatic melanoma [84], colorectal [85], and ovarian cancers [86]. In another study, while sarcopenia alone was not significant, the presence of obesity and sarcopenia was prognostic for survival [57]. 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 [87]. IMAT, identified by low muscle attenuation on CT imaging, is predictive of higher mortality in cancers such as renal [88], melanoma [89], lung, and GI malignancies [90]. 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 [91]. 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 [92]. 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 [93]. Adinopectin is the most abundant adipocytokine and has anti-inflammatory, insulin-sensitizing, and anti-atherogenic properties [94]. Its secretion is stimulated by insulin and IGF-I [95]. Low adinopectin levels were reported in cachectic patients with lung [96] and gastric cancers [97]. However, no correlation was reported with weight loss in patients with breast and colon cancer [98]. In gastric cancer, no relation was reported with adinopectin and insulin resistance [97], but more research is needed. Leptin, a cytokine, is an important signaling molecule that stimulates appetite and weight gain [99]. Serum level of leptin corresponds with fat stores and is secreted by adipocytes, gastric, colorectal, and mammary epithelial tissue [100]. 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 [103], gastrointestinal [104], and gynecologic cancer patients [105]. In a recent review, leptin plays a role in modulating inflammation and the immune response [106], 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 [102] but another study reported no association [109]. 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 [110]. Increased serum level of ghrelin has been reported in lung [111], breast, and colon [112] cancers. Resistance to ghrelin signaling is associated with development of anorexia and cancer cachexia [113]. 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 [114]; 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 [115]. 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 [116]. In obese patients, low testosterone is associated with increased inflammation [117] and insulin resistance [118]. An inverse relationship exists between testosterone concentration and adiposity in men but is positively related in women [119], while estrogen levels have been reported to determine the distribution of AT [120]. 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 [121]. 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 [122]. Vitamin D supplementation has been shown to improve insulin sensitivity in the noncancer population [123]. 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 [124]. 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 [1]. Nonpharmacological Dietary counseling [125] and selective nutritional support [126] 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 [131], and the amino acid arginine, also, has been reported to improve the secretion of insulin [132]. 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 [133] 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 [134]. 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 [135]. 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 [140]. 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 [141]; 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 [142] and improve glucose sensitivity [143]. 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 [144]. 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 [144]; 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 [147], decreasing plasma-free fatty acids and improving insulin sensitivity and decreasing hepatic glucose production [148]. Also, metformin may prevent muscle wasting by its ability to increase activity of AMP-activated protein kinase [149], which leads to increased glucose transporter 4 activity leading to increased glucose uptake in muscle cells [150]. 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 [151]. 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 [152] 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 [153] 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 [41]; however, in late stage disease, once weight loss developed, no retention of muscle mass was noted [154]. Rosiglitazone may have potential anabolic effects in the prevention of cancer cachexia in the precachectic stage, but cardiovascular side effects limits enthusiasm [155]. 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 [157]. 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 [158]. 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. Helsinn did not have any influence on the content and all items are subject to independent peer-review. Disclosure The authors have declared no conflicts of interest. References 1 Fearon K, Strasser F, Anker SD. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol  2011; 12( 5): 489– 495. Google Scholar CrossRef Search ADS PubMed  2 Dewys WD, Begg C, Lavin PT. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. Am J Med  1980; 69( 4): 491– 497. Google Scholar CrossRef Search ADS PubMed  3 Bachmann J, Heiligensetzer M, Krakowski-Roosen H. Cachexia worsens prognosis in patients with resectable pancreatic cancer. J Gastrointest Surg  2008; 12( 7): 1193– 1201. Google Scholar CrossRef Search ADS PubMed  4 Inagaki J, Rodriguez V, Bodey GP. Proceedings: causes of death in cancer patients. Cancer  1974; 33( 2): 568– 573. Google Scholar CrossRef Search ADS PubMed  5 Argiles JM, Lopez-Soriano FJ, Busquets S. Novel approaches to the treatment of cachexia. Drug Discov Today  2008; 13( 1-2): 73– 78. Google Scholar CrossRef Search ADS PubMed  6 Evans WJ, Morley JE, Argiles J et al.   Cachexia: a new definition. Clin Nutr  2008; 27( 6): 793– 799. Google Scholar CrossRef Search ADS PubMed  7 Berger MJ, Doherty TJ. Sarcopenia: prevalence, mechanisms, and functional consequences. Interdiscip Top Gerontol  2010; 37: 94– 114. Google Scholar CrossRef Search ADS PubMed  8 Jacquelin-Ravel N, Pichard C. Clinical nutrition, body composition and oncology: a critical literature review of the synergies. Crit Rev Oncol Hematol  2012; 84( 1): 37– 46. Google Scholar CrossRef Search ADS PubMed  9 Roubenoff R. Sarcopenic obesity: the confluence of two epidemics. Obes Res  2004; 12( 6): 887– 888. Google Scholar CrossRef Search ADS PubMed  10 Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer  2004; 4( 8): 579– 591. Google Scholar CrossRef Search ADS PubMed  11 Samani AA, Yakar S, LeRoith D, Brodt P. The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev  2007; 28( 1): 20– 47. Google Scholar CrossRef Search ADS PubMed  12 Jiang Y, Pan Y, Rhea PR et al.   A sucrose-enriched diet promotes tumorigenesis in mammary gland in part through the 12-lipoxygenase pathway. Cancer Res  2016; 76( 1): 24– 29. Google Scholar CrossRef Search ADS PubMed  13 Soeters MR, Soeters PB. The evolutionary benefit of insulin resistance. Clin Nutr  2012; 31( 6): 1002– 1007. Google Scholar CrossRef Search ADS PubMed  14 Odegaard JI, Chawla A. Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis. Science  2013; 339( 6116): 172– 177. Google Scholar CrossRef Search ADS PubMed  15 Wagner EF, Petruzzelli M. Cancer metabolism: a waste of insulin interference. Nature  2015; 521( 7553): 430– 431. Google Scholar CrossRef Search ADS PubMed  16 Wang H, Ye J. Regulation of energy balance by inflammation: common theme in physiology and pathology. Rev Endocr Metab Disord  2015; 16( 1): 47– 54. Google Scholar CrossRef Search ADS PubMed  17 Copeland GP, Leinster SJ, Davis JC, Hipkin LJ. Insulin resistance in patients with colorectal cancer. Br J Surg  1987; 74( 11): 1031– 1035. Google Scholar CrossRef Search ADS PubMed  18 Winter A, MacAdams J, Chevalier S. Normal protein anabolic response to hyperaminoacidemia in insulin-resistant patients with lung cancer cachexia. Clin Nutr  2012; 31( 5): 765– 773. Google Scholar CrossRef Search ADS PubMed  19 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; 111( 3): 301– 310. Google Scholar PubMed  20 Yoshikawa T, Noguchi Y, Doi C et al.   Insulin resistance in patients with cancer: relationships with tumor site, tumor stage, body-weight loss, acute-phase response, and energy expenditure. Nutrition  2001; 17( 7-8): 590– 593. Google Scholar CrossRef Search ADS PubMed  21 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– 763. Google Scholar CrossRef Search ADS PubMed  22 Norton JA, Maher M, Wesley R et al.   Glucose intolerance in sarcoma patients. Cancer  1984; 54( 12): 3022– 3027. Google Scholar CrossRef Search ADS PubMed  23 Yoshikawa T, Noguchi Y, Matsumoto A. Effects of tumor removal and body weight loss on insulin resistance in patients with cancer. Surgery  1994; 116( 1): 62– 66. Google Scholar PubMed  24 Permert J, Ihse I, Jorfeldt L et al.   Improved glucose metabolism after subtotal pancreatectomy for pancreatic cancer. Br J Surg  1993; 80( 8): 1047– 1050. Google Scholar CrossRef Search ADS PubMed  25 Kwon Y, Song W, Droujinine IA et al.   Systemic organ wasting induced by localized expression of the secreted insulin/IGF antagonist ImpL2. Dev Cell  2015; 33( 1): 36– 46. Google Scholar CrossRef Search ADS PubMed  26 Tsirona S, Tzanela M, Botoula E et al.   Clinical presentation and long-term outcome of patients with ectopic ACTH syndrome due to bronchial carcinoid tumors: A one-center experience. Endocr Pract  2015; 21( 10): 1104– 1110. Google Scholar CrossRef Search ADS PubMed  27 Rohdenburg GL, Bernhard A, Brehbiel O. Sugar tolerance in cancer. JAMA  1919; 72( 21): 1528– 1530. Google Scholar CrossRef Search ADS   28 Tayek JA. A review of cancer cachexia and abnormal glucose metabolism in humans with cancer. J Am Coll Nutr  1992; 11( 4): 445– 456. Google Scholar CrossRef Search ADS PubMed  29 Winter A, MacAdams J, Chevalier S. Normal protein anabolic response to hyperaminacidemia in insulin-resistant patients with lung cancer cachexia. Clin Nutr  2012; 31( 5): 765– 773. Google Scholar CrossRef Search ADS PubMed  30 Sauerwein HP, Romijn JA. Alterations in glucose metabolism in non-endocrine disease: potential implication in wasting. Clin Nutr  2001; 20( 1): 2– 8. Google Scholar CrossRef Search ADS PubMed  31 Bennegard K, Lundgren F, Lundholm K. Mechanisms of insulin resistance in cancer associated malnutrition. Clin Physiol  1986; 6( 6): 539– 547. Google Scholar CrossRef Search ADS PubMed  32 Eden E, Edstrin S, Bennegard K et al.   Glucose flux in relation to energy expenditure in malnourished patients with and without cancer during periods of fasting and feeding. Cancer Res  1984; 44( 4): 1718– 1724. Google Scholar PubMed  33 Rofe A, Bourgeois CS, Coyle P et al.   Altered insulin response to glucose in weight-losing cancer patients. Anticancer Res  1994; 14( 2B): 647– 650. Google Scholar PubMed  34 Novotny GW, Lundh M, Backe MB et al.   Transcriptional and translational regulation of cytokine signaling in inflammatory beta-cell dysfunction and apoptosis. Arch Biochem Biophys  2012; 528( 2): 171– 184. Google Scholar CrossRef Search ADS PubMed  35 Chen Z, Lu W, Garcia-Prieto C, Huang P. The Warburg effect and its cancer therapeutic implications. J Bioenerg Biomembr  2007; 39( 3): 267– 274. Google Scholar CrossRef Search ADS PubMed  36 Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol  1927; 8( 6): 519– 530. Google Scholar CrossRef Search ADS PubMed  37 Cori CF, Cori GT. Carbohydrate metabolism. Annu Rev Biochem  1946; 15: 193– 218. Google Scholar CrossRef Search ADS PubMed  38 Chevalier S, Marliss EB, Morais JA et al.   Whole-body protein anabolic response is resistant to the action of insulin in obese women. Am J Clin Nutr  2005; 82( 2): 355– 365. Google Scholar CrossRef Search ADS PubMed  39 Chevalier S, Burgess SC, Malloy CR et al.   The greater contribution of gluconeogenesis to glucose production in obesity is related to increased whole-body protein catabolism. Diabetes  2006; 55( 3): 675– 681. Google Scholar CrossRef Search ADS PubMed  40 Pereira S, Marliss EB, Morais JA et al.   Insulin resistance of protein metabolism in type 2 diabetes. Diabetes  2008; 57( 1): 56– 63. Google Scholar CrossRef Search ADS PubMed  41 Asp ML, Tian M, Wendel AA, Belury MA. Evidence for contribution of insulin resistance to the development of cachexia in tumor-bearing mice. Int J Cancer  2010; 126( 3): 756– 763. Google Scholar CrossRef Search ADS PubMed  42 Winter A, MacAdams J, Chevalier S. Normal protein anabolic response to hyparaminoacidemia in insulin-resistant patients with lung cancer cachexia. Clin Nutr  2012; 31( 5): 765– 773. Google Scholar CrossRef Search ADS PubMed  43 Waterhouse C, Jeanpretre N, Keilson J. Gluconeogenesis from alanine in patients with progressive malignant disease. Cancer Res  1979; 39( 6 Pt 1): 1968– 1972. Google Scholar PubMed  44 Leij-Halfwerk S, Dagnelie PC, van Den Berg JW et al.   Weight loss and elevated gluconeogenesis from alanine in lung cancer patients. Am J Clin Nutr  2000; 71( 2): 583– 589. Google Scholar CrossRef Search ADS PubMed  45 Burt ME, Gorschboth CM, Brennan MF. A controlled, prospective, randomized trial evaluating the metabolic effects of enteral and parenteral nutrition in the cancer patient. Cancer  1982; 49( 6): 1092– 1105. Google Scholar CrossRef Search ADS PubMed  46 MacAdams J, Winter A, Morais JA et al.   Elevated gluconeogenesis in aging and lung cancer is related to inflammation and blunted insulin-induced protein anabolism. FASEB J  2013; 27(no. 1 Supplement): 1074.1010 (abstract). 47 Lecker SH, Solomon V, Mitch WE, Goldberg AL. Muscle protein breakdown and the critical role of the ubiquitin-proteasome pathway in normal and disease states. J Nutr  1999; 129(1S Suppl): 227S– 237S. Google Scholar CrossRef Search ADS   48 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– 1819. Google Scholar CrossRef Search ADS PubMed  49 Prado CM, Lieffers JR, McCargar LJ et al.   Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study. Lancet Oncol  2008; 9( 7): 629– 635. Google Scholar CrossRef Search ADS PubMed  50 Heymsfield SB, Wang Z, Baumgartner RN, Ross R. Human body composition: advances in models and methods. Annu Rev Nutr  1997; 17: 527– 558. Google Scholar CrossRef Search ADS PubMed  51 Janssen I, Ross R. Effects of sex on the change in visceral, subcutaneous adipose tissue and skeletal muscle in response to weight loss. Int J Obes  1999; 23( 10): 1035– 1046. Google Scholar CrossRef Search ADS   52 Fujioka Y, Matsuzawa K, Tokunaga K, Tarui S. Contribution of intra-abdominal fat accumulation to the impairment of glucose and lipid metabolism in human obesity. Metabolism  1987; 36( 1): 54– 59. Google Scholar CrossRef Search ADS PubMed  53 Doyle SL, Donohoe CL, Lysaght J, Reynolds JV. Visceral obesity, metabolic syndrome, insulin resistance and cancer. Proc Nutr Soc  2012; 71( 1): 181– 190. Google Scholar CrossRef Search ADS PubMed  54 Balentine CJ, Enriquez J, Fisher W et al.   Intra-abdominal fat predicts survival in pancreatic cancer. J Gastrointest Surg  2010; 14( 11): 1832– 1837. Google Scholar CrossRef Search ADS PubMed  55 Dalal S, Hui D, Bidaut L et al.   Relationships among body mass index, longitudinal body composition alterations, and survival in patients with locally advanced pancreatic cancer receiving chemoradiation: a pilot study. J Pain Symptom Manage  2012; 44( 2): 181– 191. Google Scholar CrossRef Search ADS PubMed  56 Murphy RA, Wilke MS, Perrine M et al.   Loss of adipose tissue and plasma phospholipids: relationship to survival in advanced cancer patients. Clin Nutr  2010; 29( 4): 482– 487. Google Scholar CrossRef Search ADS PubMed  57 Tan BH, Birdsell LA, Martin L et al.   Sarcopenia in an overweight or obese patient is an adverse prognostic factor in pancreatic cancer. Clin Cancer Res  2009; 15( 22): 6973– 6979. Google Scholar CrossRef Search ADS PubMed  58 Ibrahim MM. Subcutaneous and visceral adipose tissue: Structural and functional differences. Obes Rev  2010; 11( 1): 11– 18. Google Scholar CrossRef Search ADS PubMed  59 Sonnenberg GE, Krakower GR, Kissebah AH. A novel pathway to the manifestations of metabolic syndrome. Obes Res  2004; 12( 2): 180– 186. Google Scholar CrossRef Search ADS PubMed  60 Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab  2004; 89( 6): 2548– 2556. Google Scholar CrossRef Search ADS PubMed  61 Galic S, Oakhill JS, Steinberg GR. Adipose tissue as an endocrine organ. Mol Cell Endocrinol  2010; 316( 2): 129– 139. Google Scholar CrossRef Search ADS PubMed  62 Despres JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature  2006; 444( 7121): 881– 887. Google Scholar CrossRef Search ADS PubMed  63 van Kruijsdijk RCM, van del Wall E, Visseren FLJ. Obesity and cancer: the role of dysfunctional adipose tissue. Cancer Epidemiol Biomark Prev  2009; 18( 10): 2569– 2578. Google Scholar CrossRef Search ADS   64 Borena W, Edlinger M, Bjorge T et al.   A prospective study on metabolic risk factors and gallbladder cancer in the metabolic syndrome and cancer (Me-Can) collaborative study. PLoS One  2014; 9( 2): e89368. Google Scholar CrossRef Search ADS PubMed  65 Haggstrom C, Rapp K, Stocks T et al.   Metabolic factors associated with risk of renal cell carcinoma. PLoS One  2013; 8( 2): e57475. Google Scholar CrossRef Search ADS PubMed  66 Häggström C, Stocks T, Ulmert D et al.   Prospective study on metabolic factors and risk of prostate cancer. Cancer  2012; 118( 24): 6199– 6206. Google Scholar CrossRef Search ADS PubMed  67 Häggström C, Stocks T, Rapp K et al.   Metabolic syndrome and risk of bladder cancer: prospective cohort study in the metabolic syndrome and cancer project (Me-Can). Int J Cancer  2011; 128( 8): 1890– 1898. Google Scholar CrossRef Search ADS PubMed  68 Lohmann AE, Goodwin PJ, Chlebowski RT et al.   Association of obesity-related metabolic disruptions with cancer risk and outcome. J Clin Oncol  2016; 34( 35): 4249– 4255. Google Scholar CrossRef Search ADS PubMed  69 Dalal S, Hui D, Yeung SJ, Gary B et al.   Association between visceral adiposity, BMI, and clinical outcomes in postmenopausal women with operable breast cancer. J Clin Oncol  2014; 32(no. 15 suppl): 513 (Abstract). 70 Healy LA, Howard J, Ryan AM et al.   Metabolic syndrome and leptin are associated with adverse pathological features in male colorectal cancer patients. Colorectal Dis  2012; 14 ( 2): 157– 165. Google Scholar CrossRef Search ADS PubMed  71 Healy LA, Ryan AM, Carroll P et al.   Metabolic syndrome, central obesity and insulin resistance are associated with adverse pathological features in postmenopausal breast cancer. Clin Oncol (R Coll Radiol)  2010; 22( 4): 281– 288. Google Scholar CrossRef Search ADS PubMed  72 Shen Z, Wang S, Ye Y et al.   Clinical study on the correlation between metabolic syndrome and colorectal carcinoma. ANZ J Surg  2009; 80( 5): 331– 336. Google Scholar CrossRef Search ADS   73 Moon HG, Ju YT, Jeong CY et al.   Visceral obesity may affect oncologic outcome in patients with colorectal cancer. Ann Surg Oncol  2008; 15( 7): 1918– 1922. Google Scholar CrossRef Search ADS PubMed  74 Balentine CJ, Enriquez J, Fisher W et al.   Intra-abdominal fat predicts survival in pancreatic cancer. J Gastrointest Surg. Surg  2010; 14( 11): 1832– 1837. Google Scholar CrossRef Search ADS   75 Wu W, Liu X, Chaftari P et al.   Association of body composition with outcome of docetaxel chemotherapy in metastatic prostate cancer: a retrospective review. PLoS One  2015; 10( 3): e0122047. Google Scholar CrossRef Search ADS PubMed  76 Ogiwara H, Takahashi S, Kato Y et al.   Diminished visceral adipose tissue in cancer cachexia. J Surg Oncol  1994; 57( 2): 129– 133. Google Scholar CrossRef Search ADS PubMed  77 Murphy RA, Wilke MS, Perrine M et al.   Loss of adipose tissue and plasma phospholipids: Relationship to survival in advanced cancer patients. Clin Nutr  2010; 29( 4): 482– 487. Google Scholar CrossRef Search ADS PubMed  78 Agustsson T, Ryden M, Hoffstedt J et al.   Mechanism of increased lipolysis in cancer cachexia. Cancer Res  2007; 67( 11): 5531– 5537. Google Scholar CrossRef Search ADS PubMed  79 Ryden M, Agustsson T, Laurencikiene J et al.   Lipolysis—not inflammation, cell death, or lipogenesis—is involved in adipose tissue loss in cancer cachexia. Cancer  2008; 113( 7): 1695– 1704. Google Scholar CrossRef Search ADS PubMed  80 Dahlman I, Mejhert N, Linder K et al.   Adipose tissue pathways involved in weight loss of cancer cachexia. Br J Cancer  2010; 102( 10): 1541– 1548. Google Scholar CrossRef Search ADS PubMed  81 Agustsson T, Wikrantz P, Ryden M et al.   Adipose tissue volume is decreased in recently diagnosed cancer patients with cachexia. Nutrition  2012; 28( 9): 851– 855. Google Scholar CrossRef Search ADS PubMed  82 Freedland ES. Role of a critical visceral adipose tissue threshold (CVATT) in metabolic syndrome: implications for controlling dietary carbohydrates: a review. Nutr Metab (Lond)  2004; 1( 1): 12. Google Scholar CrossRef Search ADS PubMed  83 Stene GB, Helbostad JL, Amundsen T et al.   Changes in skeletal muscle mass during palliative chemotherapy in patients with advanced lung cancer. Acta Oncol  2015; 54( 3): 340– 348. Google Scholar CrossRef Search ADS PubMed  84 Daly LE, Power DG, O'Reilly Á et al.   The impact of body composition parameters on ipilimumab toxicity and survival in patients with metastatic melanoma. Br J Cancer  2017; 116( 3): 310– 317. Google Scholar CrossRef Search ADS PubMed  85 Blauwhoff-Buskermolen S, Versteeg KS, de van der Schueren MAE et al.   Loss of muscle mass during chemotherapy is predictive for poor survival of patients with metastatic colorectal cancer. J Clin Oncol  2016; 34( 12): 1339– 1344. Google Scholar CrossRef Search ADS PubMed  86 Rutten IJ, van Dijk DP, Kruitwagen RF et al.   Loss of skeletal muscle during neoadjuvant chemotherapy is related to decreased survival in ovarian cancer patients. J Cachexia Sarcopenia Muscle  2016; 7( 4): 458– 466. Google Scholar CrossRef Search ADS PubMed  87 Petersen KF, Shulman GI. New insights into the pathogenesis of insulin resistance in humans using magnetic resonance spectroscopy. Obesity  2006; 14 Suppl 1: 34S– 40S. Google Scholar CrossRef Search ADS PubMed  88 Antoun S, Lanoy E, Iacovelli R et al.   Skeletal muscle density predicts prognosis in patients with metastatic renal cell carcinoma treated with targeted therapies. Cancer  2013; 119( 18): 3377– 3384. Google Scholar CrossRef Search ADS PubMed  89 Sabel MS, Lee J, Cai S et al.   Sarcopenia as a prognostic factor among patients with stage III melanoma. Ann Surg Oncol  2011; 18( 13): 3579– 3585. Google Scholar CrossRef Search ADS PubMed  90 Hamaguchi Y, Kaido T, Okumura S et al.   Preoperative intramuscular adipose tissue content is a novel prognostic predictor after hepatectomy for hepatocellular carcinoma. J Hepatobiliary Pancreat Sci  2015; 22( 6): 475– 485. Google Scholar CrossRef Search ADS PubMed  91 Kewalramani G, Bilan PJ, Klip A. Muscle insulin resistance: assault by lipids, cytokines and local macrophages. Curr Opin Clin Nutr Metab Care  2010; 13( 4): 382– 390. Google Scholar CrossRef Search ADS PubMed  92 Kir S, White JP, Kleiner S et al.   Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Nature  2014; 513( 7516): 100– 104. Google Scholar CrossRef Search ADS PubMed  93 Greenberg AS, McDaniel ML. Identifying the links between obesity, insulin resistance and beta-cell function: potential role of adipocyte-derived cytokines in the pathogenesis of type 2 diabetes. Eur J Clin Invest  2002; 32( s3): 24– 34. Google Scholar CrossRef Search ADS PubMed  94 Ziemke F, Mantzoros CS. Adiponectin in insulin resistance: lessons from translational research. Am J Clin Nutr  2010; 91( 1): 258S– 261S. Google Scholar CrossRef Search ADS PubMed  95 Meier U, Gressner AM. Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistin. Clin Chem  2004; 50( 9): 1511– 1525. Google Scholar CrossRef Search ADS PubMed  96 Jamieson NB, Brown DJ, Michael Wallace A, McMillan DC. Adiponectin and the systemic inflammatory response in weight-losing patients with non-small cell lung cancer. Cytokine  2004; 27( 2-3): 90– 92. Google Scholar CrossRef Search ADS PubMed  97 Kerem M, Ferahkose Z, Yilmaz UT et al.   Adiopkines and ghrelin in gastric cancer cachexia. World J Gastroenterol  2008; 14( 23): 3633– 3641. Google Scholar CrossRef Search ADS PubMed  98 Wolf I, Sadetzki S, Kanety H et al.   Adiponectin, ghrelin, and leptin in cancer cachexia in breast and colon cancer patients. Cancer  2006; 106( 4): 966– 973. Google Scholar CrossRef Search ADS PubMed  99 Stępień M, Wlazeł RN, Paradowski M et al.   Serum concentrations of adiponectin, leptin, resistin, ghrelin and insulin and their association with obesity indices in obese normo- and hypertensive patients – pilot study. Arch Med Sci  2012; 8( 3): 431– 436. Google Scholar CrossRef Search ADS PubMed  100 Ismail NA, Ragab S, El Dayem SM et al.   Fetuin-A levels in obesity: differences in relation to metabolic syndrome and correlation with clinical and laboratory variables. Arch Med Sci  2012; 5( 5): 826– 833. Google Scholar CrossRef Search ADS   101 Wallace AM, Kelly A, Sattar N et al.   Circulating concentrations of “free” leptin in relation to fat mass and appetite in gastrointestinal cancer patients. Nutr Cancer  2002; 44( 2): 157– 160. Google Scholar CrossRef Search ADS PubMed  102 Begenik H, Aslan M, Dulger AC et al.   Serum leptin levels in gastric cancer patients and the relationship with insulin resistance. Arch Med Sci  2015; 2( 2): 346– 352. Google Scholar CrossRef Search ADS   103 Bruun JM, Lihn AS, Verdich C et al.   Regulation of adiponectin by adipose tissue-derived cytokines: in vivo and in vitro investigations in humans. Am J Physiol Endocrinol Metab  2003; 285( 3): E527– E533. Google Scholar CrossRef Search ADS PubMed  104 Stattin P, Lukanova A, Biessy C et al.   Obesity and colon cancer; does leptin provide a link? Int J Cancer  2004; 109( 1): 149– 152. Google Scholar CrossRef Search ADS PubMed  105 Tessitore L, Vizio B, Jenkins O et al.   Leptin expression in colorectal and breast cancer patients. Int J Mol Med  2000; 5( 4): 421– 426. Google Scholar PubMed  106 La Cava A, Matarese G. The weight of leptin in immunity. Nat Rev Immunol  2004; 4( 5): 371– 379. Google Scholar CrossRef Search ADS PubMed  107 Kieffer TJ, Heller RS, Habener JF. Leptin receptors expressed on pancreatic beta-cells. Biochem Biophys Res Commun  1996; 224( 2): 522– 527. Google Scholar CrossRef Search ADS PubMed  108 Ahren B, Havel PJ. Leptin inhibits insulin secretion induced by cellular cAMP in a pancreatic B cell line (INS-1 cells). Am J Physiol  1999; 277( 4 Pt 2): R959– R966. Google Scholar PubMed  109 Kerem M, Ferahkose Z, Yilmaz UT et al.   Adipokines and ghrelin in gastric cancer cachexia. World J Gastroenterol. J. Gastroenterol  2008; 14( 23): 3633– 3641. Google Scholar CrossRef Search ADS   110 Kojima M, Hosoda H, Date Y et al.   Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature  1999; 402( 6762): 656– 660. Google Scholar CrossRef Search ADS PubMed  111 Shimizu Y, Nagaya N, Isobe T et al.   Increased plasma ghrelin level in lung cancer cachexia. Clin Cancer Res  2003; 9( 2): 774– 778. Google Scholar PubMed  112 Wolf I, Sadetzki S, Kanety H et al.   Adiponectin, ghrelin, and leptin in cancer cachexia in breast and colon cancer patients. Cancer  2006; 106( 4): 966– 973. Google Scholar CrossRef Search ADS PubMed  113 Garcia JM, Garcia-Touza M, Hijazi RA et al.   Active ghrelin levels and active total ghrelin ratio in cancer-induced cachecia. J Clin Endocrinol Metab  2005; 90( 5): 2920– 2926. Google Scholar CrossRef Search ADS PubMed  114 Broglio F, Arvat E, Benso A et al.   Ghrelin, a natural GH secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans. J Clin Endocrinol Metab  2001; 86( 10): 5083– 5086. Google Scholar CrossRef Search ADS PubMed  115 Verhulst P-J, Depoortere I. Ghrelin’s second life: From appetite stimulator to glucose regulator. World J Gastroenterol  2012; 18( 25): 3183– 3195. Google Scholar PubMed  116 Rajagopal A, Vassilopoulou-Sellin R, Palmer JL et al.   Symptomatic hypogonadism in male survivors of cancer with chronic exposure to opioids. Cancer  2004; 100( 4): 851– 858. Google Scholar CrossRef Search ADS PubMed  117 Bhatia V, Chaudhuri A, Tomar R et al.   Low testosterone and high C-reactive protein concentrations predict low hematocrit in type 2 diabetes. Diabetes Care  2006; 29( 10): 2289– 2294. Google Scholar CrossRef Search ADS PubMed  118 Tsai EC, Matsumoto AM, Fujimoto WY, Boyko EJ. Association of bioavailable, free, and total testosterone with insulin resistance: influence of sex hormone-binding globulin and body fat. Diabetes Care  2004; 27( 4): 861– 868. Google Scholar CrossRef Search ADS PubMed  119 Derby CA, Zilber S, Brambilla D et al.   Body mass index, waist circumference and waist to hip ration and change in sex steroid hormones: the Massachusetts Male Ageing Study. Clin Endocrinol (Oxf)  2006; 65( 1): 125– 131. Google Scholar CrossRef Search ADS PubMed  120 Nedungadi TP, Clegg DJ. Sexual dimorphism in body fat distribution and risk for cardiovascular diseases. J Cardiovasc Transl Res  2009; 2( 3): 321– 327. Google Scholar CrossRef Search ADS PubMed  121 Ford ES, Li C, Zhao G et al.   Prevalence of the metabolic syndrome among U.S. adolescents using the definition from the International Diabetes Federation. Diabetes Care  2008; 31( 3): 587– 589. Google Scholar CrossRef Search ADS PubMed  122 Dev R, Del Fabbro E, Schwartz GG et al.   Preliminary report: vitamin D deficiency in advanced cancer patients with symptoms of fatigue or anorexia. Oncologist  2011; 16( 11): 1637– 1641. Google Scholar CrossRef Search ADS PubMed  123 von Hurst PR, Stonehouse W, Coad J. Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient-a randomized placebo-controlled trial. Br J Nutr  2010; 103( 04): 549– 555. Google Scholar CrossRef Search ADS PubMed  124 Krishnan AV, Swami S, Peng L et al.   Tissue-selective regulation of aromatase expression by calitriol: Implications for breast cancer therapy. Endocrinology  2010; 151( 1): 32– 42. Google Scholar CrossRef Search ADS PubMed  125 Ravasco P, Monteiro-Grillo I, Vidal PM, Camilo ME. Dietary counseling improves patient outcomes: a prospective, randomized, controlled trial in colorectal cancer patients undergoing radiotherapy. J Clin Oncol  2005; 23( 7): 1431– 1438. Google Scholar CrossRef Search ADS PubMed  126 Deutz NE, Safar A, Schutzler S et al.   Muscle protein synthesis in cancer patients can be stimulated with specially formulated medical food. Clin Nutr  2011; 30( 6): 759– 768. Google Scholar CrossRef Search ADS PubMed  127 Winkler MF. Quality of life in adult home parenteral nutrition patients. JPEN J Parenter Enteral Nutr  2005; 29( 3): 162– 170. Google Scholar CrossRef Search ADS PubMed  128 Lundholm K, Daneryd P, Bosaeus I et al.   Palliative nutritional intervention in addition to cyclooxygenase and erythropoietin treatment for patients with malignant disease: effects on survival, metabolism, and function. Cancer  2004; 100( 9): 1967– 1977. Google Scholar CrossRef Search ADS PubMed  129 Elia M, Van Bokhorst-de vand der Schueren MA, Garvey J et al.   Enteral (oral or tube administration) nutritional support and eicosapentaenoic acid in patients with cancer: a systematic review. Int J Oncol  2006; 28( 1): 5– 23. Google Scholar PubMed  130 Berk L, James J, Schwartz A et al.   A randomized, double-blind, placebo-controlled trial of a beta-hydroxyl beta-methyl butyrate, glutamine, and arginine mixture for the treatment of cancer cachexia (RTOG 0122). Support Care Cancer  2008; 16( 10): 1179– 1188. Google Scholar CrossRef Search ADS PubMed  131 van Loon LJ, Kruijshoop M, Menheere PP et al.   Amino acid ingestion strongly enhances insulin secretion in patients with long-term type 2 diabetes. Diabetes Care  2003; 26( 3): 626– 630. Google Scholar CrossRef Search ADS   132 Schmidt HH, Warner TD, Ishii K et al.   Insulin secretion from pancreatic B cells cause by L-arginine-derived nitrogen oxides. Science  1992; 255( 5045): 721– 723. Google Scholar CrossRef Search ADS PubMed  133 Whitehouse AS, Smith HJ, Drake JL, Tisdale MJ. Mechanism of attenuation of skeletal muscle protein catabolism in cancer cachexia by eicosapentaenoic acid. Cancer Res  2001; 61( 9): 3604– 3609. Google Scholar PubMed  134 Flachs P, Rossmeisl M, Bryhn M, Kopecky J. Cellular and molecular effects on n-3 polyunsaturated fatty acids on adipose tissue biology and metabolism. Clin Sci  2009; 116( 1): 1– 16. Google Scholar CrossRef Search ADS PubMed  135 Murphy RA, Mourtzakis M, Chu QS et al.   Nutritional intervention with fish oil provides a benefit over standard of care for weight and skeletal muscle mass in patients with nonsmall cell lung cancer receiving chemotherapy. Cancer  2011; 117( 8): 1775– 1782. Google Scholar CrossRef Search ADS PubMed  136 Barber MD, Ross JA, Voss AC et al.   The effect of an oral nutritional supplement enriched with fish oil on weight-loss in patients with pancreatic cancer. Br J Cancer  1999; 81( 1): 80– 86. Google Scholar CrossRef Search ADS PubMed  137 Wigmore SJ, Barber MD, Ross JA et al.   Effect of oral eicosapentaenoic acid on weight loss in patients with pancreatic cancer. Nutr Cancer  2000; 36( 2): 177– 184. Google Scholar CrossRef Search ADS PubMed  138 Fearon KC, Barber MD, Moses AG et al.   Double-blind, placebo-controlled, randomized study of eicosapentaenoic acid diester in patients with cancer cachexia. J Clin Oncol  2006; 24( 21): 3401– 3407. Google Scholar CrossRef Search ADS PubMed  139 Jatoi A, Rowland K, Loprinzi CL et al.   An eicosapentaenoic acid supplement versus megestrol acetate versus both for patients with cancer-associated wasting: a North Centeral Cancer Treatment Group and National Cancer institute of Canada collaborative effort. J Clin Oncol  2004; 22( 12): 2469– 2476. Google Scholar CrossRef Search ADS PubMed  140 Deutz NE, Safar A, Schutzler S et al.   Muscle protein synthesis in cancer patients can be stimulated with a specially formulated medical food. Clin Nutr  2011; 30( 6): 759– 768. Google Scholar CrossRef Search ADS PubMed  141 Lira FS, Neto JC, Seelaender M. Exercise training as treatment in cancer cachexia. Appl Physiol Nutr Metab  2014; 39( 6): 679– 686. Google Scholar CrossRef Search ADS PubMed  142 Krause M, Rodrigues-Krause J, O’Hagan C et al.   The effects of aerobic exercise training at two different intensities in obesity and type 2 diabetes: implications for oxidative stress, low-grade inflammation and nitric oxide production. Eur J Appl Physiol  2014; 114( 2): 251– 260. Google Scholar CrossRef Search ADS PubMed  143 Abbott MJ, Turcotte LP. AMPK-α2 is involved in exercise training-induced adaptations in insulin-stimulated metabolism in skeletal muscle following high-fat diet. J Appl Physiol  2014; 117( 8): 869– 879. Google Scholar CrossRef Search ADS PubMed  144 Lundholm K, Korner U, Gunnebo L et al.   Insulin treatment in cancer cachexia: effects on survival, metabolism, and physical functioning. Clin Cancer Res  2007; 13( 9): 2699– 2706. Google Scholar CrossRef Search ADS PubMed  145 Peacock JL, Norton JA. Impact of insulin on survival of cachectic tumor-bearing rats. JPEN J Parenter Enteral Nutr  1988; 12( 3): 260– 264. Google Scholar CrossRef Search ADS PubMed  146 Beck SA, Tisdale MJ. Effect of insulin on weight loss and tumour growth in cachexia model. Br J Cancer  1989; 59( 5): 677– 681. Google Scholar CrossRef Search ADS PubMed  147 Zhang T, He J, Xu C et al.   Mechanisms of metformin inhibiting lipolytic response to isoproterenol in primary rat adipocytes. J Mol Endocrinol  2008; 42( 1): 57– 66. Google Scholar CrossRef Search ADS PubMed  148 Foretz M, Hébrard S, Leclerc J et al.   Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest  2010; 120( 7): 2355– 2369. Google Scholar CrossRef Search ADS PubMed  149 Musi N, Hirshman MF, Nygren J et al.   Metformin increased AMP-activated protein kinase activity in skeletal muscle of subjects in type 2 diabetes. Diabetes  2002; 51( 7): 2074– 2081. Google Scholar CrossRef Search ADS PubMed  150 Towler MC, Hardie DG. AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res  2007; 100( 3): 328– 341. Google Scholar CrossRef Search ADS PubMed  151 Nobes JP, Langley SE, Klopper T et al.   A prospective, randomized pilot study evaluating the effects of metformin and lifestyle intervention on patients with prostate cancer receiving androgen deprivation therapy. BJU Int  2012; 109( 10): 1495– 1502. Google Scholar CrossRef Search ADS PubMed  152 Decensi A, Puntoni M, Goodwin P et al.   Metformin and cancer risk in diabetic patients; a systematic review and meta-analysis. Cancer Prev Res (Phila)  2010; 3( 11): 1451– 1461. Google Scholar CrossRef Search ADS PubMed  153 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. Google Scholar CrossRef Search ADS PubMed  154 Asp ML, Tian M, Kliewer KL, Belury MA. Rosiglitaxone delayed weight loss and anorexia while attenuating adipose depletion in mice with cancer cachexia. Cancer Bio Ther  2011; 12( 11): 957– 965. Google Scholar CrossRef Search ADS   155 Psaty BM, Furberg CD. Rosiglitazaone and cardiovascular risk. N Engl J Med  2007; 356( 24): 2522– 2524. Google Scholar CrossRef Search ADS PubMed  156 Joassard OR, Durieux A-C, Freyssenet DG. Β2-Adremergic agonists and the treatment of skeletal muscle wasting disorders. Int J Biochem Cell Biol  2013; 45( 10): 2309– 2321. Google Scholar CrossRef Search ADS PubMed  157 Castle A, Yaspelkis BB3rd, Kuo C, Ivy JL. Attenuation of insulin resistance by chronic β2-adrenergic agonists treatment: possible muscle specific contributions. Life Sci  2001; 69( 5): 599– 611. Google Scholar CrossRef Search ADS PubMed  158 Loprinzi CL, Goldberg RM, Su JQ et al.   Placebo-controlled trial of hydrazine sulfate in patients with newly diagnosed non-small-cell lung cancer. J Clin Oncol  1994; 12( 6): 1126– 1129. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Annals of Oncology Oxford University Press

Insulin resistance and body composition in cancer patients

Loading next page...
 
/lp/ou_press/insulin-resistance-and-body-composition-in-cancer-patients-m0pYIiK72c
Publisher
Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
ISSN
0923-7534
eISSN
1569-8041
D.O.I.
10.1093/annonc/mdx815
Publisher site
See Article on Publisher Site

Abstract

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) [1]. Roughly 30–90% of cancer patients develop cachexia [2], which is associated with reductions in performance status (PS), decreased tolerance to cancer therapies [3], and increased mortality, accounting for 10–20% of cancer-related deaths [4]. 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 [5]. Recently, a panel of experts recognized cancer cachexia to span three distinct stages: precachexia, cachexia, and a refractory cachectic stage [1]. Expert consensus definition of cancer cachexia highlights metabolic abnormalities resulting in altered glucose, lipid, and protein metabolism [6]. 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 [7]. Figure 1 highlights variations in body composition in healthy, cancer, and elderly patients [8]. 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 [9]. While sarcopenic obesity is characterized by unchanged muscle protein degradation, overall decreased metabolic rate and total energy expenditure, and increased FM [9]. 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 [10], and insulin-like growth factors (IGFs) have also been implicated in tumorigenesis [11] 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 [12]. Insulin resistance has been recognized as a physiological adaptive response in the setting of pregnancy, fasting, exercise, and acute stress [13], and is also found in various chronic diseases such as obesity, type 2 diabetes (T2D), and cancer cachexia [14]. 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 [15], which results in insulin resistance [16]. Using the gold standard hyperinsulinemic-euglycemic clamp technique for measuring insulin sensitivity, peripheral insulin resistance was recognized in patients with colorectal [17], non-small-cell lung (NSCLC) [18], gastrointestinal [19], and mixed malignancies [20]. 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 [20]. In mice with colon-26 tumors, insulin resistance was noted in early stages of cachexia, prior to the development of weight loss [21]. 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 [22]. 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 [25]. In patients with lung cancer, tumor byproducts including adrecorticotropic hormone and corticotropin-releasing factors could potentially result in abnormal glucose metabolism [26]. Glucose metabolism in cancer cachexia Glucose intolerance, similar to T2D, was recognized as early as 1919 in patients with cancer [27]. 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 [33]. The chronic inflammatory state of patients with severe weight loss potentially can contribute to pancreatic β-cell dysfunction resulting in impaired insulin secretion [34]. 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 [35]. In undernourished cancer patients, extensive glucose cycling has been reported to occur in the majority, but not all, studies reviewed [28]. In malignant cells, the resulting pyruvate produced from glycolysis is reduced to lactate even in an aerobic environment, the Warburg effect [36], and subsequently, the lactate is recycled to glucose by the liver or other tissues through the inefficient Cori Cycle [37] 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 [38], elderly [39], and T2D [40]. 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 [41]. 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 [42]. However, in another study of six gastrointestinal cancer patients, insulin resistance was not significantly associated with altered protein anabolism [19]. 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 [43], lung [44], and other cancer types [45], and shown to be significantly higher in weight losing when compared with weight stable lung cancer patients [44]. In moderately cachectic lung cancer patients, increased fasting GNG was positively correlated with resting energy expenditure, CRP and negatively with insulin-induced protein anabolism [46]. 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 [47]. 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 [48]. 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 [49]. 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 [58]. 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 [59]. 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 [62]. 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 [68]. 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 [55]. 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 [55]. 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 [81]. A study in colorectal and NSCLC cancer patients suggested AT loss begins about 7 months prior to death [77]. VAT is most sensitive to lipolytic factors [82], and tumor byproducts [78] 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 [83]. In longitudinal studies, higher SMM loss was associated with lower survival in patients with metastatic melanoma [84], colorectal [85], and ovarian cancers [86]. In another study, while sarcopenia alone was not significant, the presence of obesity and sarcopenia was prognostic for survival [57]. 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 [87]. IMAT, identified by low muscle attenuation on CT imaging, is predictive of higher mortality in cancers such as renal [88], melanoma [89], lung, and GI malignancies [90]. 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 [91]. 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 [92]. 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 [93]. Adinopectin is the most abundant adipocytokine and has anti-inflammatory, insulin-sensitizing, and anti-atherogenic properties [94]. Its secretion is stimulated by insulin and IGF-I [95]. Low adinopectin levels were reported in cachectic patients with lung [96] and gastric cancers [97]. However, no correlation was reported with weight loss in patients with breast and colon cancer [98]. In gastric cancer, no relation was reported with adinopectin and insulin resistance [97], but more research is needed. Leptin, a cytokine, is an important signaling molecule that stimulates appetite and weight gain [99]. Serum level of leptin corresponds with fat stores and is secreted by adipocytes, gastric, colorectal, and mammary epithelial tissue [100]. 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 [103], gastrointestinal [104], and gynecologic cancer patients [105]. In a recent review, leptin plays a role in modulating inflammation and the immune response [106], 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 [102] but another study reported no association [109]. 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 [110]. Increased serum level of ghrelin has been reported in lung [111], breast, and colon [112] cancers. Resistance to ghrelin signaling is associated with development of anorexia and cancer cachexia [113]. 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 [114]; 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 [115]. 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 [116]. In obese patients, low testosterone is associated with increased inflammation [117] and insulin resistance [118]. An inverse relationship exists between testosterone concentration and adiposity in men but is positively related in women [119], while estrogen levels have been reported to determine the distribution of AT [120]. 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 [121]. 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 [122]. Vitamin D supplementation has been shown to improve insulin sensitivity in the noncancer population [123]. 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 [124]. 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 [1]. Nonpharmacological Dietary counseling [125] and selective nutritional support [126] 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 [131], and the amino acid arginine, also, has been reported to improve the secretion of insulin [132]. 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 [133] 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 [134]. 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 [135]. 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 [140]. 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 [141]; 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 [142] and improve glucose sensitivity [143]. 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 [144]. 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 [144]; 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 [147], decreasing plasma-free fatty acids and improving insulin sensitivity and decreasing hepatic glucose production [148]. Also, metformin may prevent muscle wasting by its ability to increase activity of AMP-activated protein kinase [149], which leads to increased glucose transporter 4 activity leading to increased glucose uptake in muscle cells [150]. 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 [151]. 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 [152] 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 [153] 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 [41]; however, in late stage disease, once weight loss developed, no retention of muscle mass was noted [154]. Rosiglitazone may have potential anabolic effects in the prevention of cancer cachexia in the precachectic stage, but cardiovascular side effects limits enthusiasm [155]. 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 [157]. 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 [158]. 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. Helsinn did not have any influence on the content and all items are subject to independent peer-review. Disclosure The authors have declared no conflicts of interest. References 1 Fearon K, Strasser F, Anker SD. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol  2011; 12( 5): 489– 495. Google Scholar CrossRef Search ADS PubMed  2 Dewys WD, Begg C, Lavin PT. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. Am J Med  1980; 69( 4): 491– 497. Google Scholar CrossRef Search ADS PubMed  3 Bachmann J, Heiligensetzer M, Krakowski-Roosen H. Cachexia worsens prognosis in patients with resectable pancreatic cancer. J Gastrointest Surg  2008; 12( 7): 1193– 1201. Google Scholar CrossRef Search ADS PubMed  4 Inagaki J, Rodriguez V, Bodey GP. Proceedings: causes of death in cancer patients. Cancer  1974; 33( 2): 568– 573. Google Scholar CrossRef Search ADS PubMed  5 Argiles JM, Lopez-Soriano FJ, Busquets S. Novel approaches to the treatment of cachexia. Drug Discov Today  2008; 13( 1-2): 73– 78. Google Scholar CrossRef Search ADS PubMed  6 Evans WJ, Morley JE, Argiles J et al.   Cachexia: a new definition. Clin Nutr  2008; 27( 6): 793– 799. Google Scholar CrossRef Search ADS PubMed  7 Berger MJ, Doherty TJ. Sarcopenia: prevalence, mechanisms, and functional consequences. Interdiscip Top Gerontol  2010; 37: 94– 114. Google Scholar CrossRef Search ADS PubMed  8 Jacquelin-Ravel N, Pichard C. Clinical nutrition, body composition and oncology: a critical literature review of the synergies. Crit Rev Oncol Hematol  2012; 84( 1): 37– 46. Google Scholar CrossRef Search ADS PubMed  9 Roubenoff R. Sarcopenic obesity: the confluence of two epidemics. Obes Res  2004; 12( 6): 887– 888. Google Scholar CrossRef Search ADS PubMed  10 Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer  2004; 4( 8): 579– 591. Google Scholar CrossRef Search ADS PubMed  11 Samani AA, Yakar S, LeRoith D, Brodt P. The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev  2007; 28( 1): 20– 47. Google Scholar CrossRef Search ADS PubMed  12 Jiang Y, Pan Y, Rhea PR et al.   A sucrose-enriched diet promotes tumorigenesis in mammary gland in part through the 12-lipoxygenase pathway. Cancer Res  2016; 76( 1): 24– 29. Google Scholar CrossRef Search ADS PubMed  13 Soeters MR, Soeters PB. The evolutionary benefit of insulin resistance. Clin Nutr  2012; 31( 6): 1002– 1007. Google Scholar CrossRef Search ADS PubMed  14 Odegaard JI, Chawla A. Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis. Science  2013; 339( 6116): 172– 177. Google Scholar CrossRef Search ADS PubMed  15 Wagner EF, Petruzzelli M. Cancer metabolism: a waste of insulin interference. Nature  2015; 521( 7553): 430– 431. Google Scholar CrossRef Search ADS PubMed  16 Wang H, Ye J. Regulation of energy balance by inflammation: common theme in physiology and pathology. Rev Endocr Metab Disord  2015; 16( 1): 47– 54. Google Scholar CrossRef Search ADS PubMed  17 Copeland GP, Leinster SJ, Davis JC, Hipkin LJ. Insulin resistance in patients with colorectal cancer. Br J Surg  1987; 74( 11): 1031– 1035. Google Scholar CrossRef Search ADS PubMed  18 Winter A, MacAdams J, Chevalier S. Normal protein anabolic response to hyperaminoacidemia in insulin-resistant patients with lung cancer cachexia. Clin Nutr  2012; 31( 5): 765– 773. Google Scholar CrossRef Search ADS PubMed  19 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; 111( 3): 301– 310. Google Scholar PubMed  20 Yoshikawa T, Noguchi Y, Doi C et al.   Insulin resistance in patients with cancer: relationships with tumor site, tumor stage, body-weight loss, acute-phase response, and energy expenditure. Nutrition  2001; 17( 7-8): 590– 593. Google Scholar CrossRef Search ADS PubMed  21 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– 763. Google Scholar CrossRef Search ADS PubMed  22 Norton JA, Maher M, Wesley R et al.   Glucose intolerance in sarcoma patients. Cancer  1984; 54( 12): 3022– 3027. Google Scholar CrossRef Search ADS PubMed  23 Yoshikawa T, Noguchi Y, Matsumoto A. Effects of tumor removal and body weight loss on insulin resistance in patients with cancer. Surgery  1994; 116( 1): 62– 66. Google Scholar PubMed  24 Permert J, Ihse I, Jorfeldt L et al.   Improved glucose metabolism after subtotal pancreatectomy for pancreatic cancer. Br J Surg  1993; 80( 8): 1047– 1050. Google Scholar CrossRef Search ADS PubMed  25 Kwon Y, Song W, Droujinine IA et al.   Systemic organ wasting induced by localized expression of the secreted insulin/IGF antagonist ImpL2. Dev Cell  2015; 33( 1): 36– 46. Google Scholar CrossRef Search ADS PubMed  26 Tsirona S, Tzanela M, Botoula E et al.   Clinical presentation and long-term outcome of patients with ectopic ACTH syndrome due to bronchial carcinoid tumors: A one-center experience. Endocr Pract  2015; 21( 10): 1104– 1110. Google Scholar CrossRef Search ADS PubMed  27 Rohdenburg GL, Bernhard A, Brehbiel O. Sugar tolerance in cancer. JAMA  1919; 72( 21): 1528– 1530. Google Scholar CrossRef Search ADS   28 Tayek JA. A review of cancer cachexia and abnormal glucose metabolism in humans with cancer. J Am Coll Nutr  1992; 11( 4): 445– 456. Google Scholar CrossRef Search ADS PubMed  29 Winter A, MacAdams J, Chevalier S. Normal protein anabolic response to hyperaminacidemia in insulin-resistant patients with lung cancer cachexia. Clin Nutr  2012; 31( 5): 765– 773. Google Scholar CrossRef Search ADS PubMed  30 Sauerwein HP, Romijn JA. Alterations in glucose metabolism in non-endocrine disease: potential implication in wasting. Clin Nutr  2001; 20( 1): 2– 8. Google Scholar CrossRef Search ADS PubMed  31 Bennegard K, Lundgren F, Lundholm K. Mechanisms of insulin resistance in cancer associated malnutrition. Clin Physiol  1986; 6( 6): 539– 547. Google Scholar CrossRef Search ADS PubMed  32 Eden E, Edstrin S, Bennegard K et al.   Glucose flux in relation to energy expenditure in malnourished patients with and without cancer during periods of fasting and feeding. Cancer Res  1984; 44( 4): 1718– 1724. Google Scholar PubMed  33 Rofe A, Bourgeois CS, Coyle P et al.   Altered insulin response to glucose in weight-losing cancer patients. Anticancer Res  1994; 14( 2B): 647– 650. Google Scholar PubMed  34 Novotny GW, Lundh M, Backe MB et al.   Transcriptional and translational regulation of cytokine signaling in inflammatory beta-cell dysfunction and apoptosis. Arch Biochem Biophys  2012; 528( 2): 171– 184. Google Scholar CrossRef Search ADS PubMed  35 Chen Z, Lu W, Garcia-Prieto C, Huang P. The Warburg effect and its cancer therapeutic implications. J Bioenerg Biomembr  2007; 39( 3): 267– 274. Google Scholar CrossRef Search ADS PubMed  36 Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol  1927; 8( 6): 519– 530. Google Scholar CrossRef Search ADS PubMed  37 Cori CF, Cori GT. Carbohydrate metabolism. Annu Rev Biochem  1946; 15: 193– 218. Google Scholar CrossRef Search ADS PubMed  38 Chevalier S, Marliss EB, Morais JA et al.   Whole-body protein anabolic response is resistant to the action of insulin in obese women. Am J Clin Nutr  2005; 82( 2): 355– 365. Google Scholar CrossRef Search ADS PubMed  39 Chevalier S, Burgess SC, Malloy CR et al.   The greater contribution of gluconeogenesis to glucose production in obesity is related to increased whole-body protein catabolism. Diabetes  2006; 55( 3): 675– 681. Google Scholar CrossRef Search ADS PubMed  40 Pereira S, Marliss EB, Morais JA et al.   Insulin resistance of protein metabolism in type 2 diabetes. Diabetes  2008; 57( 1): 56– 63. Google Scholar CrossRef Search ADS PubMed  41 Asp ML, Tian M, Wendel AA, Belury MA. Evidence for contribution of insulin resistance to the development of cachexia in tumor-bearing mice. Int J Cancer  2010; 126( 3): 756– 763. Google Scholar CrossRef Search ADS PubMed  42 Winter A, MacAdams J, Chevalier S. Normal protein anabolic response to hyparaminoacidemia in insulin-resistant patients with lung cancer cachexia. Clin Nutr  2012; 31( 5): 765– 773. Google Scholar CrossRef Search ADS PubMed  43 Waterhouse C, Jeanpretre N, Keilson J. Gluconeogenesis from alanine in patients with progressive malignant disease. Cancer Res  1979; 39( 6 Pt 1): 1968– 1972. Google Scholar PubMed  44 Leij-Halfwerk S, Dagnelie PC, van Den Berg JW et al.   Weight loss and elevated gluconeogenesis from alanine in lung cancer patients. Am J Clin Nutr  2000; 71( 2): 583– 589. Google Scholar CrossRef Search ADS PubMed  45 Burt ME, Gorschboth CM, Brennan MF. A controlled, prospective, randomized trial evaluating the metabolic effects of enteral and parenteral nutrition in the cancer patient. Cancer  1982; 49( 6): 1092– 1105. Google Scholar CrossRef Search ADS PubMed  46 MacAdams J, Winter A, Morais JA et al.   Elevated gluconeogenesis in aging and lung cancer is related to inflammation and blunted insulin-induced protein anabolism. FASEB J  2013; 27(no. 1 Supplement): 1074.1010 (abstract). 47 Lecker SH, Solomon V, Mitch WE, Goldberg AL. Muscle protein breakdown and the critical role of the ubiquitin-proteasome pathway in normal and disease states. J Nutr  1999; 129(1S Suppl): 227S– 237S. Google Scholar CrossRef Search ADS   48 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– 1819. Google Scholar CrossRef Search ADS PubMed  49 Prado CM, Lieffers JR, McCargar LJ et al.   Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study. Lancet Oncol  2008; 9( 7): 629– 635. Google Scholar CrossRef Search ADS PubMed  50 Heymsfield SB, Wang Z, Baumgartner RN, Ross R. Human body composition: advances in models and methods. Annu Rev Nutr  1997; 17: 527– 558. Google Scholar CrossRef Search ADS PubMed  51 Janssen I, Ross R. Effects of sex on the change in visceral, subcutaneous adipose tissue and skeletal muscle in response to weight loss. Int J Obes  1999; 23( 10): 1035– 1046. Google Scholar CrossRef Search ADS   52 Fujioka Y, Matsuzawa K, Tokunaga K, Tarui S. Contribution of intra-abdominal fat accumulation to the impairment of glucose and lipid metabolism in human obesity. Metabolism  1987; 36( 1): 54– 59. Google Scholar CrossRef Search ADS PubMed  53 Doyle SL, Donohoe CL, Lysaght J, Reynolds JV. Visceral obesity, metabolic syndrome, insulin resistance and cancer. Proc Nutr Soc  2012; 71( 1): 181– 190. Google Scholar CrossRef Search ADS PubMed  54 Balentine CJ, Enriquez J, Fisher W et al.   Intra-abdominal fat predicts survival in pancreatic cancer. J Gastrointest Surg  2010; 14( 11): 1832– 1837. Google Scholar CrossRef Search ADS PubMed  55 Dalal S, Hui D, Bidaut L et al.   Relationships among body mass index, longitudinal body composition alterations, and survival in patients with locally advanced pancreatic cancer receiving chemoradiation: a pilot study. J Pain Symptom Manage  2012; 44( 2): 181– 191. Google Scholar CrossRef Search ADS PubMed  56 Murphy RA, Wilke MS, Perrine M et al.   Loss of adipose tissue and plasma phospholipids: relationship to survival in advanced cancer patients. Clin Nutr  2010; 29( 4): 482– 487. Google Scholar CrossRef Search ADS PubMed  57 Tan BH, Birdsell LA, Martin L et al.   Sarcopenia in an overweight or obese patient is an adverse prognostic factor in pancreatic cancer. Clin Cancer Res  2009; 15( 22): 6973– 6979. Google Scholar CrossRef Search ADS PubMed  58 Ibrahim MM. Subcutaneous and visceral adipose tissue: Structural and functional differences. Obes Rev  2010; 11( 1): 11– 18. Google Scholar CrossRef Search ADS PubMed  59 Sonnenberg GE, Krakower GR, Kissebah AH. A novel pathway to the manifestations of metabolic syndrome. Obes Res  2004; 12( 2): 180– 186. Google Scholar CrossRef Search ADS PubMed  60 Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab  2004; 89( 6): 2548– 2556. Google Scholar CrossRef Search ADS PubMed  61 Galic S, Oakhill JS, Steinberg GR. Adipose tissue as an endocrine organ. Mol Cell Endocrinol  2010; 316( 2): 129– 139. Google Scholar CrossRef Search ADS PubMed  62 Despres JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature  2006; 444( 7121): 881– 887. Google Scholar CrossRef Search ADS PubMed  63 van Kruijsdijk RCM, van del Wall E, Visseren FLJ. Obesity and cancer: the role of dysfunctional adipose tissue. Cancer Epidemiol Biomark Prev  2009; 18( 10): 2569– 2578. Google Scholar CrossRef Search ADS   64 Borena W, Edlinger M, Bjorge T et al.   A prospective study on metabolic risk factors and gallbladder cancer in the metabolic syndrome and cancer (Me-Can) collaborative study. PLoS One  2014; 9( 2): e89368. Google Scholar CrossRef Search ADS PubMed  65 Haggstrom C, Rapp K, Stocks T et al.   Metabolic factors associated with risk of renal cell carcinoma. PLoS One  2013; 8( 2): e57475. Google Scholar CrossRef Search ADS PubMed  66 Häggström C, Stocks T, Ulmert D et al.   Prospective study on metabolic factors and risk of prostate cancer. Cancer  2012; 118( 24): 6199– 6206. Google Scholar CrossRef Search ADS PubMed  67 Häggström C, Stocks T, Rapp K et al.   Metabolic syndrome and risk of bladder cancer: prospective cohort study in the metabolic syndrome and cancer project (Me-Can). Int J Cancer  2011; 128( 8): 1890– 1898. Google Scholar CrossRef Search ADS PubMed  68 Lohmann AE, Goodwin PJ, Chlebowski RT et al.   Association of obesity-related metabolic disruptions with cancer risk and outcome. J Clin Oncol  2016; 34( 35): 4249– 4255. Google Scholar CrossRef Search ADS PubMed  69 Dalal S, Hui D, Yeung SJ, Gary B et al.   Association between visceral adiposity, BMI, and clinical outcomes in postmenopausal women with operable breast cancer. J Clin Oncol  2014; 32(no. 15 suppl): 513 (Abstract). 70 Healy LA, Howard J, Ryan AM et al.   Metabolic syndrome and leptin are associated with adverse pathological features in male colorectal cancer patients. Colorectal Dis  2012; 14 ( 2): 157– 165. Google Scholar CrossRef Search ADS PubMed  71 Healy LA, Ryan AM, Carroll P et al.   Metabolic syndrome, central obesity and insulin resistance are associated with adverse pathological features in postmenopausal breast cancer. Clin Oncol (R Coll Radiol)  2010; 22( 4): 281– 288. Google Scholar CrossRef Search ADS PubMed  72 Shen Z, Wang S, Ye Y et al.   Clinical study on the correlation between metabolic syndrome and colorectal carcinoma. ANZ J Surg  2009; 80( 5): 331– 336. Google Scholar CrossRef Search ADS   73 Moon HG, Ju YT, Jeong CY et al.   Visceral obesity may affect oncologic outcome in patients with colorectal cancer. Ann Surg Oncol  2008; 15( 7): 1918– 1922. Google Scholar CrossRef Search ADS PubMed  74 Balentine CJ, Enriquez J, Fisher W et al.   Intra-abdominal fat predicts survival in pancreatic cancer. J Gastrointest Surg. Surg  2010; 14( 11): 1832– 1837. Google Scholar CrossRef Search ADS   75 Wu W, Liu X, Chaftari P et al.   Association of body composition with outcome of docetaxel chemotherapy in metastatic prostate cancer: a retrospective review. PLoS One  2015; 10( 3): e0122047. Google Scholar CrossRef Search ADS PubMed  76 Ogiwara H, Takahashi S, Kato Y et al.   Diminished visceral adipose tissue in cancer cachexia. J Surg Oncol  1994; 57( 2): 129– 133. Google Scholar CrossRef Search ADS PubMed  77 Murphy RA, Wilke MS, Perrine M et al.   Loss of adipose tissue and plasma phospholipids: Relationship to survival in advanced cancer patients. Clin Nutr  2010; 29( 4): 482– 487. Google Scholar CrossRef Search ADS PubMed  78 Agustsson T, Ryden M, Hoffstedt J et al.   Mechanism of increased lipolysis in cancer cachexia. Cancer Res  2007; 67( 11): 5531– 5537. Google Scholar CrossRef Search ADS PubMed  79 Ryden M, Agustsson T, Laurencikiene J et al.   Lipolysis—not inflammation, cell death, or lipogenesis—is involved in adipose tissue loss in cancer cachexia. Cancer  2008; 113( 7): 1695– 1704. Google Scholar CrossRef Search ADS PubMed  80 Dahlman I, Mejhert N, Linder K et al.   Adipose tissue pathways involved in weight loss of cancer cachexia. Br J Cancer  2010; 102( 10): 1541– 1548. Google Scholar CrossRef Search ADS PubMed  81 Agustsson T, Wikrantz P, Ryden M et al.   Adipose tissue volume is decreased in recently diagnosed cancer patients with cachexia. Nutrition  2012; 28( 9): 851– 855. Google Scholar CrossRef Search ADS PubMed  82 Freedland ES. Role of a critical visceral adipose tissue threshold (CVATT) in metabolic syndrome: implications for controlling dietary carbohydrates: a review. Nutr Metab (Lond)  2004; 1( 1): 12. Google Scholar CrossRef Search ADS PubMed  83 Stene GB, Helbostad JL, Amundsen T et al.   Changes in skeletal muscle mass during palliative chemotherapy in patients with advanced lung cancer. Acta Oncol  2015; 54( 3): 340– 348. Google Scholar CrossRef Search ADS PubMed  84 Daly LE, Power DG, O'Reilly Á et al.   The impact of body composition parameters on ipilimumab toxicity and survival in patients with metastatic melanoma. Br J Cancer  2017; 116( 3): 310– 317. Google Scholar CrossRef Search ADS PubMed  85 Blauwhoff-Buskermolen S, Versteeg KS, de van der Schueren MAE et al.   Loss of muscle mass during chemotherapy is predictive for poor survival of patients with metastatic colorectal cancer. J Clin Oncol  2016; 34( 12): 1339– 1344. Google Scholar CrossRef Search ADS PubMed  86 Rutten IJ, van Dijk DP, Kruitwagen RF et al.   Loss of skeletal muscle during neoadjuvant chemotherapy is related to decreased survival in ovarian cancer patients. J Cachexia Sarcopenia Muscle  2016; 7( 4): 458– 466. Google Scholar CrossRef Search ADS PubMed  87 Petersen KF, Shulman GI. New insights into the pathogenesis of insulin resistance in humans using magnetic resonance spectroscopy. Obesity  2006; 14 Suppl 1: 34S– 40S. Google Scholar CrossRef Search ADS PubMed  88 Antoun S, Lanoy E, Iacovelli R et al.   Skeletal muscle density predicts prognosis in patients with metastatic renal cell carcinoma treated with targeted therapies. Cancer  2013; 119( 18): 3377– 3384. Google Scholar CrossRef Search ADS PubMed  89 Sabel MS, Lee J, Cai S et al.   Sarcopenia as a prognostic factor among patients with stage III melanoma. Ann Surg Oncol  2011; 18( 13): 3579– 3585. Google Scholar CrossRef Search ADS PubMed  90 Hamaguchi Y, Kaido T, Okumura S et al.   Preoperative intramuscular adipose tissue content is a novel prognostic predictor after hepatectomy for hepatocellular carcinoma. J Hepatobiliary Pancreat Sci  2015; 22( 6): 475– 485. Google Scholar CrossRef Search ADS PubMed  91 Kewalramani G, Bilan PJ, Klip A. Muscle insulin resistance: assault by lipids, cytokines and local macrophages. Curr Opin Clin Nutr Metab Care  2010; 13( 4): 382– 390. Google Scholar CrossRef Search ADS PubMed  92 Kir S, White JP, Kleiner S et al.   Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Nature  2014; 513( 7516): 100– 104. Google Scholar CrossRef Search ADS PubMed  93 Greenberg AS, McDaniel ML. Identifying the links between obesity, insulin resistance and beta-cell function: potential role of adipocyte-derived cytokines in the pathogenesis of type 2 diabetes. Eur J Clin Invest  2002; 32( s3): 24– 34. Google Scholar CrossRef Search ADS PubMed  94 Ziemke F, Mantzoros CS. Adiponectin in insulin resistance: lessons from translational research. Am J Clin Nutr  2010; 91( 1): 258S– 261S. Google Scholar CrossRef Search ADS PubMed  95 Meier U, Gressner AM. Endocrine regulation of energy metabolism: review of pathobiochemical and clinical chemical aspects of leptin, ghrelin, adiponectin, and resistin. Clin Chem  2004; 50( 9): 1511– 1525. Google Scholar CrossRef Search ADS PubMed  96 Jamieson NB, Brown DJ, Michael Wallace A, McMillan DC. Adiponectin and the systemic inflammatory response in weight-losing patients with non-small cell lung cancer. Cytokine  2004; 27( 2-3): 90– 92. Google Scholar CrossRef Search ADS PubMed  97 Kerem M, Ferahkose Z, Yilmaz UT et al.   Adiopkines and ghrelin in gastric cancer cachexia. World J Gastroenterol  2008; 14( 23): 3633– 3641. Google Scholar CrossRef Search ADS PubMed  98 Wolf I, Sadetzki S, Kanety H et al.   Adiponectin, ghrelin, and leptin in cancer cachexia in breast and colon cancer patients. Cancer  2006; 106( 4): 966– 973. Google Scholar CrossRef Search ADS PubMed  99 Stępień M, Wlazeł RN, Paradowski M et al.   Serum concentrations of adiponectin, leptin, resistin, ghrelin and insulin and their association with obesity indices in obese normo- and hypertensive patients – pilot study. Arch Med Sci  2012; 8( 3): 431– 436. Google Scholar CrossRef Search ADS PubMed  100 Ismail NA, Ragab S, El Dayem SM et al.   Fetuin-A levels in obesity: differences in relation to metabolic syndrome and correlation with clinical and laboratory variables. Arch Med Sci  2012; 5( 5): 826– 833. Google Scholar CrossRef Search ADS   101 Wallace AM, Kelly A, Sattar N et al.   Circulating concentrations of “free” leptin in relation to fat mass and appetite in gastrointestinal cancer patients. Nutr Cancer  2002; 44( 2): 157– 160. Google Scholar CrossRef Search ADS PubMed  102 Begenik H, Aslan M, Dulger AC et al.   Serum leptin levels in gastric cancer patients and the relationship with insulin resistance. Arch Med Sci  2015; 2( 2): 346– 352. Google Scholar CrossRef Search ADS   103 Bruun JM, Lihn AS, Verdich C et al.   Regulation of adiponectin by adipose tissue-derived cytokines: in vivo and in vitro investigations in humans. Am J Physiol Endocrinol Metab  2003; 285( 3): E527– E533. Google Scholar CrossRef Search ADS PubMed  104 Stattin P, Lukanova A, Biessy C et al.   Obesity and colon cancer; does leptin provide a link? Int J Cancer  2004; 109( 1): 149– 152. Google Scholar CrossRef Search ADS PubMed  105 Tessitore L, Vizio B, Jenkins O et al.   Leptin expression in colorectal and breast cancer patients. Int J Mol Med  2000; 5( 4): 421– 426. Google Scholar PubMed  106 La Cava A, Matarese G. The weight of leptin in immunity. Nat Rev Immunol  2004; 4( 5): 371– 379. Google Scholar CrossRef Search ADS PubMed  107 Kieffer TJ, Heller RS, Habener JF. Leptin receptors expressed on pancreatic beta-cells. Biochem Biophys Res Commun  1996; 224( 2): 522– 527. Google Scholar CrossRef Search ADS PubMed  108 Ahren B, Havel PJ. Leptin inhibits insulin secretion induced by cellular cAMP in a pancreatic B cell line (INS-1 cells). Am J Physiol  1999; 277( 4 Pt 2): R959– R966. Google Scholar PubMed  109 Kerem M, Ferahkose Z, Yilmaz UT et al.   Adipokines and ghrelin in gastric cancer cachexia. World J Gastroenterol. J. Gastroenterol  2008; 14( 23): 3633– 3641. Google Scholar CrossRef Search ADS   110 Kojima M, Hosoda H, Date Y et al.   Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature  1999; 402( 6762): 656– 660. Google Scholar CrossRef Search ADS PubMed  111 Shimizu Y, Nagaya N, Isobe T et al.   Increased plasma ghrelin level in lung cancer cachexia. Clin Cancer Res  2003; 9( 2): 774– 778. Google Scholar PubMed  112 Wolf I, Sadetzki S, Kanety H et al.   Adiponectin, ghrelin, and leptin in cancer cachexia in breast and colon cancer patients. Cancer  2006; 106( 4): 966– 973. Google Scholar CrossRef Search ADS PubMed  113 Garcia JM, Garcia-Touza M, Hijazi RA et al.   Active ghrelin levels and active total ghrelin ratio in cancer-induced cachecia. J Clin Endocrinol Metab  2005; 90( 5): 2920– 2926. Google Scholar CrossRef Search ADS PubMed  114 Broglio F, Arvat E, Benso A et al.   Ghrelin, a natural GH secretagogue produced by the stomach, induces hyperglycemia and reduces insulin secretion in humans. J Clin Endocrinol Metab  2001; 86( 10): 5083– 5086. Google Scholar CrossRef Search ADS PubMed  115 Verhulst P-J, Depoortere I. Ghrelin’s second life: From appetite stimulator to glucose regulator. World J Gastroenterol  2012; 18( 25): 3183– 3195. Google Scholar PubMed  116 Rajagopal A, Vassilopoulou-Sellin R, Palmer JL et al.   Symptomatic hypogonadism in male survivors of cancer with chronic exposure to opioids. Cancer  2004; 100( 4): 851– 858. Google Scholar CrossRef Search ADS PubMed  117 Bhatia V, Chaudhuri A, Tomar R et al.   Low testosterone and high C-reactive protein concentrations predict low hematocrit in type 2 diabetes. Diabetes Care  2006; 29( 10): 2289– 2294. Google Scholar CrossRef Search ADS PubMed  118 Tsai EC, Matsumoto AM, Fujimoto WY, Boyko EJ. Association of bioavailable, free, and total testosterone with insulin resistance: influence of sex hormone-binding globulin and body fat. Diabetes Care  2004; 27( 4): 861– 868. Google Scholar CrossRef Search ADS PubMed  119 Derby CA, Zilber S, Brambilla D et al.   Body mass index, waist circumference and waist to hip ration and change in sex steroid hormones: the Massachusetts Male Ageing Study. Clin Endocrinol (Oxf)  2006; 65( 1): 125– 131. Google Scholar CrossRef Search ADS PubMed  120 Nedungadi TP, Clegg DJ. Sexual dimorphism in body fat distribution and risk for cardiovascular diseases. J Cardiovasc Transl Res  2009; 2( 3): 321– 327. Google Scholar CrossRef Search ADS PubMed  121 Ford ES, Li C, Zhao G et al.   Prevalence of the metabolic syndrome among U.S. adolescents using the definition from the International Diabetes Federation. Diabetes Care  2008; 31( 3): 587– 589. Google Scholar CrossRef Search ADS PubMed  122 Dev R, Del Fabbro E, Schwartz GG et al.   Preliminary report: vitamin D deficiency in advanced cancer patients with symptoms of fatigue or anorexia. Oncologist  2011; 16( 11): 1637– 1641. Google Scholar CrossRef Search ADS PubMed  123 von Hurst PR, Stonehouse W, Coad J. Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient-a randomized placebo-controlled trial. Br J Nutr  2010; 103( 04): 549– 555. Google Scholar CrossRef Search ADS PubMed  124 Krishnan AV, Swami S, Peng L et al.   Tissue-selective regulation of aromatase expression by calitriol: Implications for breast cancer therapy. Endocrinology  2010; 151( 1): 32– 42. Google Scholar CrossRef Search ADS PubMed  125 Ravasco P, Monteiro-Grillo I, Vidal PM, Camilo ME. Dietary counseling improves patient outcomes: a prospective, randomized, controlled trial in colorectal cancer patients undergoing radiotherapy. J Clin Oncol  2005; 23( 7): 1431– 1438. Google Scholar CrossRef Search ADS PubMed  126 Deutz NE, Safar A, Schutzler S et al.   Muscle protein synthesis in cancer patients can be stimulated with specially formulated medical food. Clin Nutr  2011; 30( 6): 759– 768. Google Scholar CrossRef Search ADS PubMed  127 Winkler MF. Quality of life in adult home parenteral nutrition patients. JPEN J Parenter Enteral Nutr  2005; 29( 3): 162– 170. Google Scholar CrossRef Search ADS PubMed  128 Lundholm K, Daneryd P, Bosaeus I et al.   Palliative nutritional intervention in addition to cyclooxygenase and erythropoietin treatment for patients with malignant disease: effects on survival, metabolism, and function. Cancer  2004; 100( 9): 1967– 1977. Google Scholar CrossRef Search ADS PubMed  129 Elia M, Van Bokhorst-de vand der Schueren MA, Garvey J et al.   Enteral (oral or tube administration) nutritional support and eicosapentaenoic acid in patients with cancer: a systematic review. Int J Oncol  2006; 28( 1): 5– 23. Google Scholar PubMed  130 Berk L, James J, Schwartz A et al.   A randomized, double-blind, placebo-controlled trial of a beta-hydroxyl beta-methyl butyrate, glutamine, and arginine mixture for the treatment of cancer cachexia (RTOG 0122). Support Care Cancer  2008; 16( 10): 1179– 1188. Google Scholar CrossRef Search ADS PubMed  131 van Loon LJ, Kruijshoop M, Menheere PP et al.   Amino acid ingestion strongly enhances insulin secretion in patients with long-term type 2 diabetes. Diabetes Care  2003; 26( 3): 626– 630. Google Scholar CrossRef Search ADS   132 Schmidt HH, Warner TD, Ishii K et al.   Insulin secretion from pancreatic B cells cause by L-arginine-derived nitrogen oxides. Science  1992; 255( 5045): 721– 723. Google Scholar CrossRef Search ADS PubMed  133 Whitehouse AS, Smith HJ, Drake JL, Tisdale MJ. Mechanism of attenuation of skeletal muscle protein catabolism in cancer cachexia by eicosapentaenoic acid. Cancer Res  2001; 61( 9): 3604– 3609. Google Scholar PubMed  134 Flachs P, Rossmeisl M, Bryhn M, Kopecky J. Cellular and molecular effects on n-3 polyunsaturated fatty acids on adipose tissue biology and metabolism. Clin Sci  2009; 116( 1): 1– 16. Google Scholar CrossRef Search ADS PubMed  135 Murphy RA, Mourtzakis M, Chu QS et al.   Nutritional intervention with fish oil provides a benefit over standard of care for weight and skeletal muscle mass in patients with nonsmall cell lung cancer receiving chemotherapy. Cancer  2011; 117( 8): 1775– 1782. Google Scholar CrossRef Search ADS PubMed  136 Barber MD, Ross JA, Voss AC et al.   The effect of an oral nutritional supplement enriched with fish oil on weight-loss in patients with pancreatic cancer. Br J Cancer  1999; 81( 1): 80– 86. Google Scholar CrossRef Search ADS PubMed  137 Wigmore SJ, Barber MD, Ross JA et al.   Effect of oral eicosapentaenoic acid on weight loss in patients with pancreatic cancer. Nutr Cancer  2000; 36( 2): 177– 184. Google Scholar CrossRef Search ADS PubMed  138 Fearon KC, Barber MD, Moses AG et al.   Double-blind, placebo-controlled, randomized study of eicosapentaenoic acid diester in patients with cancer cachexia. J Clin Oncol  2006; 24( 21): 3401– 3407. Google Scholar CrossRef Search ADS PubMed  139 Jatoi A, Rowland K, Loprinzi CL et al.   An eicosapentaenoic acid supplement versus megestrol acetate versus both for patients with cancer-associated wasting: a North Centeral Cancer Treatment Group and National Cancer institute of Canada collaborative effort. J Clin Oncol  2004; 22( 12): 2469– 2476. Google Scholar CrossRef Search ADS PubMed  140 Deutz NE, Safar A, Schutzler S et al.   Muscle protein synthesis in cancer patients can be stimulated with a specially formulated medical food. Clin Nutr  2011; 30( 6): 759– 768. Google Scholar CrossRef Search ADS PubMed  141 Lira FS, Neto JC, Seelaender M. Exercise training as treatment in cancer cachexia. Appl Physiol Nutr Metab  2014; 39( 6): 679– 686. Google Scholar CrossRef Search ADS PubMed  142 Krause M, Rodrigues-Krause J, O’Hagan C et al.   The effects of aerobic exercise training at two different intensities in obesity and type 2 diabetes: implications for oxidative stress, low-grade inflammation and nitric oxide production. Eur J Appl Physiol  2014; 114( 2): 251– 260. Google Scholar CrossRef Search ADS PubMed  143 Abbott MJ, Turcotte LP. AMPK-α2 is involved in exercise training-induced adaptations in insulin-stimulated metabolism in skeletal muscle following high-fat diet. J Appl Physiol  2014; 117( 8): 869– 879. Google Scholar CrossRef Search ADS PubMed  144 Lundholm K, Korner U, Gunnebo L et al.   Insulin treatment in cancer cachexia: effects on survival, metabolism, and physical functioning. Clin Cancer Res  2007; 13( 9): 2699– 2706. Google Scholar CrossRef Search ADS PubMed  145 Peacock JL, Norton JA. Impact of insulin on survival of cachectic tumor-bearing rats. JPEN J Parenter Enteral Nutr  1988; 12( 3): 260– 264. Google Scholar CrossRef Search ADS PubMed  146 Beck SA, Tisdale MJ. Effect of insulin on weight loss and tumour growth in cachexia model. Br J Cancer  1989; 59( 5): 677– 681. Google Scholar CrossRef Search ADS PubMed  147 Zhang T, He J, Xu C et al.   Mechanisms of metformin inhibiting lipolytic response to isoproterenol in primary rat adipocytes. J Mol Endocrinol  2008; 42( 1): 57– 66. Google Scholar CrossRef Search ADS PubMed  148 Foretz M, Hébrard S, Leclerc J et al.   Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest  2010; 120( 7): 2355– 2369. Google Scholar CrossRef Search ADS PubMed  149 Musi N, Hirshman MF, Nygren J et al.   Metformin increased AMP-activated protein kinase activity in skeletal muscle of subjects in type 2 diabetes. Diabetes  2002; 51( 7): 2074– 2081. Google Scholar CrossRef Search ADS PubMed  150 Towler MC, Hardie DG. AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res  2007; 100( 3): 328– 341. Google Scholar CrossRef Search ADS PubMed  151 Nobes JP, Langley SE, Klopper T et al.   A prospective, randomized pilot study evaluating the effects of metformin and lifestyle intervention on patients with prostate cancer receiving androgen deprivation therapy. BJU Int  2012; 109( 10): 1495– 1502. Google Scholar CrossRef Search ADS PubMed  152 Decensi A, Puntoni M, Goodwin P et al.   Metformin and cancer risk in diabetic patients; a systematic review and meta-analysis. Cancer Prev Res (Phila)  2010; 3( 11): 1451– 1461. Google Scholar CrossRef Search ADS PubMed  153 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. Google Scholar CrossRef Search ADS PubMed  154 Asp ML, Tian M, Kliewer KL, Belury MA. Rosiglitaxone delayed weight loss and anorexia while attenuating adipose depletion in mice with cancer cachexia. Cancer Bio Ther  2011; 12( 11): 957– 965. Google Scholar CrossRef Search ADS   155 Psaty BM, Furberg CD. Rosiglitazaone and cardiovascular risk. N Engl J Med  2007; 356( 24): 2522– 2524. Google Scholar CrossRef Search ADS PubMed  156 Joassard OR, Durieux A-C, Freyssenet DG. Β2-Adremergic agonists and the treatment of skeletal muscle wasting disorders. Int J Biochem Cell Biol  2013; 45( 10): 2309– 2321. Google Scholar CrossRef Search ADS PubMed  157 Castle A, Yaspelkis BB3rd, Kuo C, Ivy JL. Attenuation of insulin resistance by chronic β2-adrenergic agonists treatment: possible muscle specific contributions. Life Sci  2001; 69( 5): 599– 611. Google Scholar CrossRef Search ADS PubMed  158 Loprinzi CL, Goldberg RM, Su JQ et al.   Placebo-controlled trial of hydrazine sulfate in patients with newly diagnosed non-small-cell lung cancer. J Clin Oncol  1994; 12( 6): 1126– 1129. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Journal

Annals of OncologyOxford University Press

Published: Feb 1, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 12 million articles from more than
10,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Unlimited reading

Read as many articles as you need. Full articles with original layout, charts and figures. Read online, from anywhere.

Stay up to date

Keep up with your field with Personalized Recommendations and Follow Journals to get automatic updates.

Organize your research

It’s easy to organize your research with our built-in tools.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve Freelancer

DeepDyve Pro

Price
FREE
$49/month

$360/year
Save searches from Google Scholar, PubMed
Create lists to organize your research
Export lists, citations
Read DeepDyve articles
Abstract access only
Unlimited access to over
18 million full-text articles
Print
20 pages/month
PDF Discount
20% off