Investigating the relationship between glucose metabolism, insulin resistance and some adipokines in cases with hematologic malignancy

Obesity, insulin resistance, chronic hyperinsulinemia and glucose metabolism disorders at different levels seem to be related with the increase of risk and mortality in hemotologic malignancies as in many different cancer types. Although insulin plays the main role in carcinogenesis process of organs and tissues, insulin-like growth factors, adipokines, sex steroids, obesity-related inflammatory cytokines, nuclear factor kappa beta system and oxidative stress are the other major systems which held accountable.In the light of all these data, in this study, we aimed to reveal the relationship between glucose metabolism and insulin resistance, IGF-1, IGFBP-3 level and adiponectine, leptine and TNF-alpha levels released from adipose tissue and hemothologic malignancies in cases diagnosed with hematologic malignancies. For this purpose; 59 patients who applied to the hematology polyclinic and, as control group, 20 healthy volunteers with similar demographic features were included in the study after taken their consent. Patients who received treatment for hemotologic malignancy, diabetic patients using insuline or oral anti-diabetic drugs and pregnant women were excluded from the study.Cardiovascular risk factors related with insulin resistance and metabolic syndrome were examined. Blood pressure, arterial, waist-hip circumference and height-weight were measured, body mass indexes (BMI) were calculated. Ure, creatine, AST, ALT, ALP, GGT, triglyceride, total cholesterol, HDL-Cholesterol, c-reactive protein, fasting blood glucose, fasting insulin, c-peptide, IGF-1, IGFBP-3, TNF-alpha, leptin and adiponectin levels were studied and a 75-gr OGTT was performed.In our study, 29% DM and 32% prediabetes were identified in HM patients, however, when diabetic and prediabetic patients were evaluated together, the ratio of the presence of a glucose metabolism disorder were observed to rise up to 61%. Considering that in our country, diabetes prevalence and impaired glucose tolerance are 7.2% and 6.7% respectively, a significant enhanced association between HM and glucose metabolism disorders and diabetes is seen (p=0.002).In our study, postprandial blood glucose (PBG) levels in the 2nd hour of OGTT were found to be considerably higher in HM patients (p=0.005). Also, there was evidence indicating that hematopoietic cancer mortality risk increases together with the PBG increase. It can also be thought that glucose metabolism will impair with steroid treatment in some hematologic malignancies like MM and NHL. It would be useful to explain the relationship between blood glucose level and prognosis and mortality with additional studies.Despite the insulin resistance and BMI indicators (existence of insulin resistance, insulin and HOMA levels) in patients with hematologic malignancy similar to that in control group, identification of higher levels of diabetes has made us think that other factors independent of insulin resistance may have an effect on glucose metabolism.Although there are existing data indicating an association between obesity and lymphoma, no correlation between increasing weight gain and HM and NHL was observed in our study.There is not a significant difference between early stage (stage I) and late stage (stage II-IV) NHL patients, in terms of obesity and overweight. The fact that PBG averages were higher while the number of patients with insulin resistance, insulin and HOMA levels were lower in patients of stage II-IV than that of stage I-II, and also the presence of patients with pre-diabetes and diabetes which have increased at a similar ratio in both groups suggest that factors independent of insulin resistance may have an effect on glucose metabolism.Adiponectine, which prevents tumor growth and also is a potentially anti-inflammatory adipocytokine, declines with obesity and establishes an environment suitable for cancer growth. While in some studies, the decline of adiponectine level during the formation of hematologic malignancies were regarded as a risk factor, in others, the exact opposite results were obtained and it was stated that high adiponectine level and NHL and HL correlated positively with each other and even related with relapse, poor prognosis and increased B symptoms frequency.In our study, adiponectine level was significantly higher in patients with HM, compared to control group (p=0.00). When the sub diagnosis groups of patients with HM were examined, it was found that the high adiponectine levels resulted from the NHL and KLL groups. Compared to early stage patients, adiponectine levels were observed to increase significantly, especially in late stage-NHL patients. However adiponectine has a positive impact on insulin resistance, especially the fact that PBG was found higher in late stage NHL patients and that diabetes frequency was observed to be at a ratio similar to that of early stage NHL patients strengthens the possibility that factors other than adiponectine and insulin resistance may have an effect on glucose metabolism.The results of the study aimed at explaining the relationship between leptin, which have pro-oncogenic effects, and hematologic malignancies are different from each other. In our study, the level of leptin was found to be significantly lower in patients with HM and in the sub group with NHL compared to that in control group (p=0.004). The contribution of low levels of leptin to HM growth seems to be contradictory and further studies shedding light on this subject are needed.It was suggested that elevated TNF-? levels may contribute to insulin resistance in patients with hematologic malignancies or, contrarily, elevating TNF-? levels, together with other major factors, may contribute to malign process in cases with abdominal obesity and insulin resistance. However, in our study, though TNF- ? levels were higher in HM and sub group with NHL than control group, the difference was not statistically significant.When groups with and without insulin resistance were compared, no significant difference was found in terms adiponectine, leptin and TNF- ? levels which are cytokines related with insulin resistance and obesity. This suggests that adiponectine, leptin and TNF- ? levels, apart from their relationships with insuline resistance, may be effected by the current primary malign disease in patients with HM.Insulin resistance and hyperinsulinemia result in an increase in IGF-1 levels and a decrease in IGFBP levels (IGFBP-3), which, together with the loss of mitogenic, anti-apoptotic, pro-inflammatory effect and anti-tumorigenic features, establishes an environment prone to cancer growth. In our study, the level of IGFBP-3 was statistically significantly lower in patiens with HM than in control group (p=0.00) whereas, no significant difference was observed between IGF-1 levels. At this point, in order to explain the relationship between IGF-1, IGFBP levels and hematologic cancer growth, further studies are needed.The number of studies aimed at explaining the relationship between c-peptide and hematologic malignancies are insufficient. In our study, c-peptide levels was found to be significantly higher in patients with HM than in control group. However, no correlation between c-peptide and insulin was observed, which made us think that c-peptide levels may show increase independent of insulin in hematologic malignancies.In our study, adiponectine, leptin, IGFBP-3 and PBG levels in the 2nd hour of OGTT, which were found to be statistically significantly different between HM and control groups, were identified not to be affected by age, gender, and BMI.In conclusion, in our study, the frequency of glucose metabolism disorders and diabetes was found to be increased in patients with malignancy. Although the results of the studies aimed at explaining the association between the changes in obesity and insulin resistance-related adipokine levels and hematologic malignancies are different from each other, in our study, it was observed that adiponectine levels increased, leptin levels decreased, and TNF-alpha levels did not differ in patients with hematologic malignancies, compared to the control group. Large-scale studies including larger number of patients and also a follow-up process would be useful in order to better understand the roles of adipokines like adiponectine, leptin and TNF-alpha which their mechanisms of action in the process of insulin resistance and carcinogenesis have not yet been explained completely, in the formation, progression and prognosis of these diseases and possibly to identify their places in the treatment.