In this prospective study, BMI loss in gastric cancer patients negatively correlated with serum active ghrelin, resistin, adiponectin and leptin levels, but positively correlated with the level of serum IGF-I. It was also noted that there was a correlation between resistin which was found to be high in cachectic patients, and insulin resistance, insulin and blood glucose.
Ghrelin an anabolic hormone, has several roles in metabolism, appetite, nutrition, weight gain, gastric motility, and gastric emptying. In addition, it has an important role in the regulation of synthesis of GH, IGF-I, insulin, and leptin[4–6
]. Total ghrelin levels in cachectic patients with colon, breast and lung cancer were significantly higher than the levels in non-cachectic patients[7,8
]. Garcia et al[20
] showed that the ratio of active to total ghrelin levels increased in cancer-induced cachexia. In the same study, it was stated that the increase in active ghrelin levels could have been explained by ghrelin resistance. As the ratio of active/total ghrelin levels were in favor of active ghrelin in cancer cachexia, we evaluated active ghrelin levels. Our study showed that active ghrelin levels were higher in healthy subjects and non-cachectic cancer patients, especially females. Although we were not able to confirm the ghrelin resistance mentioned by Garcia et al[20
], we saw the indirect effects. Under normal conditions, endogenous ghrelin increases GH secretion and indirectly increases IGF-I by stimulation of its own receptors. However in our study, the existence of a negative correlation between decreased IGF-I and ghrelin may show that efficiency decreases while the levels of active ghrelin increase. These findings support the presence of ghrelin resistance. It is also possible that ghrelin levels could increase to compensate for the increased metabolic rate and energy need, which was hypothesized by Nagaya et al[21
] Several experimental studies have shown that ghrelin has an important role in the regulation of insulin via
controlling pancreatic endocrine functions[22,23
]. No significant relationship between ghrelin and insulin, fasting glucose level and HOMA-IR were found in the present study.
Resistin is a member of the newly discovered family of cysteine-rich secretory proteins, called resistin-like proteins. The role of resistin in pathogenesis of insulin resistance remains questionable, with conflicting data in animal models and negative findings in clinical observation[13,14
]. The role of insulin resistance in cancer cachexia occurrence is not fully understood[1,2
]. From this point of view, it came to mind whether resistin can have effect in gastric cancer cachexia occurrence. There are no clinical studies of serum resistin levels in cancer cachexia. It has been shown that serum resistin levels are high in lymphoma patients[24
], but the resistin-tumor cachexia relationship was not investigated in this study. From this point of view, our study is the first study in the literature. We found that serum resistin levels in cachectic gastric cancer patients were significantly higher than the noncachectic patients and healthy controls. Resistin showed negative correlation with BMI loss. The effect of resistin on cachexia is probably due to insulin resistance and ineffective usage of glucose. The existence of a correlation between serum resistin levels and insulin, insulin resistance and blood glucose levels supports this idea[25
]. The role of leptin in modulating the immune response and inflammation has become increasingly evident and has been reviewed recently[26,27
]. Complex interactions among the nervous, endocrine and immune systems affect the leptin loop and the potential role of these mediators in cancer-related cachexia-anorexia syndrome[8,11,12
]. Wallace et al[10
] showed that serum levels of leptin did not differ between normal subjects and patients with gastrointestinal cancer. Other studies have shown that there is a relationship between cachexia and leptin levels in pancreatic, lung, breast, and colon cancer patients[8,11,12
]. Wolf et al[8
] showed that changes in leptin levels in cancer cachexia were significantly higher. Our results were similar to this last study. It is known that leptin receptors are found in β islet cells of the pancreas and inhibit insulin secretion[28,29
]. However, our study revealed that there was a reverse correlation between leptin and fasting glucose levels, whereas no relation was found between leptin, insulin resistance, and insulin levels.
It also has been showed that insulin resistance and low serum IGF-I levels are important factors for cancer cachexia. These hormones are strongly anabolic and increase muscle protein synthesis[1,2
]. IGF-I concentrations increase with growth hormone and testosterone administration, thereby accounting for some of the effects of these hormones on muscle bulk and strength. Low IGF-I concentrations in malnourished humans suggest a role for IGF-I in the pathogenesis of cachexia[30
]. These findings showed that IGF-I was one of the most important factors in the gastric cancer cachexia.
GPS was found to be an important parameter for determining the prognosis of advanced cancers[17,18
]. In our study, besides the strong correlation between GPS and BMI loss, significant correlations were found between the GPS and the levels of hormones and cytokines which could be very important for clinical evaluation. GPS which is calculated using routine measurements of albumin and CRP can help us in evaluation and management of the cancer cachexia in clinical practice.
Adiponectin, which has an obvious anti-inflamma-tory effect, is inversely related to weight gain[4
]. Serum adiponectin levels were low in cases with increased insulin resistance like obesity, type 2 diabetics, and non-alcoholic fatty liver diseases[30
]. However, serum adiponectin levels decreased in patients who lost weight voluntarily. High adiponectin levels are risk factors for endometrial and breast cancer, whereas low levels are risk factors for gastric cancers[31,32
]. No relationship was found between adiponectin and cachexia in breast and colon cancer. In our study, a significant positive correlation was found between adiponectin and BMI loss, but multivariate analysis did not show BMI loss as predictive for adiponectin. Adiponectin, which is predominantly secreted from adipose tissues, might have increased due to lipolysis which occurred with muscle loss in the catabolic state. No correlation was found between adiponectin, whose close relationship with insulin resistance was known, and insulin, blood glucose levels, HOMA-IR, or IGF-I[4
As a result, cachexia in gastric cancer is a complex process in which ghrelin, resistin, leptin, adiponectin, and IGF-I function. It is of note that these hormones have important roles in occurrence of cachexia in gastric cancer patients. This study will be one of the corner stones of the further studies about prevention and treatment of cachexia.