Mediating Effects Of The IGF-1 System On Associations Between Cancer Phenotypes And Hematological Malignancies In Type 2 Diabetes

Objective:Genetics and environment play major and important roles in the occurrence and development of cancer.The biological relationship between type 2 diabetes mellitus（T2DM）and cancer is complex and controversial,and there is no final conclusion yet.Our previous relevant investigations have found that T2DM patients with certain phenotypes were associated with an increased risk of cancer including HDL-C<1.0 mmol/L,LDL-C<2.8 mmol/L plus TG<1.7 mmol/L,LDL-C<2.8 mmol/L plus albuminuria.The relationship between these phenotypes and cancer risk was more concerned with the total risk or with the risk of solid tumors in patients with T2DM.As far as we know,the relationship between these phenotypes and the risk of hematological malignancies in patients with T2DM has not been reported.The dysregulations of insulin-like growth factor（IGF）system have been shown to play an important role in the development of some phenotypes related to cancer.IGF-1and IGFBP-3,as the most important components of the system,have been proved to be related to some cancers.In the IGF system,IGF-1 mainly works by combining with IGFBP-3.However,few studies have reported the expression of IGF-1 and IGFBP-3 in hematological malignancies.The expression of IGF-1 and IGFBP-3 in T2DM patients with hematological malignancies,together with the association of IGF-1 and IGFBP-3with the risk of hematological malignancies in patients with T2DM have not been reported.And it is unknown the effects of IGF-1 and IGFBP-3 in the association of risk of hematological malignancies and cancer phenotypes in T2DM.The purpose of this study was to investigate the association of the risk of hematological malignancies and cancer phenotypes in T2DM patients,and to investigate whether IGF-1 system mediate the association between these cancer phenotypes and the risk of hematological malignancies.If the possible mechanism of IGF-1 system in the cancer phenotypes and the risk of hematological malignancies was explored,on the one hand,it should provide the basis for the follow-up studies in mechanisms.On the other hand,it will provide the preliminary data for the future research of the prediction model of hemotolgical malignancies in patients with T2DM.Methods:Based on the preliminary work,the epidemiological investigation was conducted on the cancer phenotypes and its related factors with the risk of hematological malignancies according to the questionnaire（see appendix）in a case-control study in which T2DM patients complicated with hematological malignancies were admitted to the case group and T2DM patients to the control group.Meanwhile,peripheral blood of T2DM patients with or without hematological malignancies were collected to detect the phenotypes-related indicators,the levels of IGF-1 and IGFBP-3.The odds ratio（OR）and95%confidence interval were obtained by using binary logistic regression to estimate the association between cancer phenotype and hematological malignancies in T2DM patients.First,univariate analysis was conducted,and then the following confounding factors were adjusted,including social and economic factors,lifestyle,history of diabetes,BMI（body mass index）and blood pressure.Finally,we observed whether IGF-1 and IGFBP-3 could explain the association between cancer phenotype and hematologcial malignancies.Results:（1）The associations of cancer phenotypes and the risk of hematological malignancies in patients with T2DM.The results showed that the risk of hematological malignancies in T2DM patients with phenotype HDL-C<1.0 mmol/L was 2.32 times higher than that in patients with HDL-C≥1.0 mmol/L(OR_adjusted=2.84,P<0.01).T2DM patients with cancer phenotype LDL-C<2.8 mmol/L and albuminuria had a 1.49-fold risk of hematological malignancies compared with patients without this phenotype(OR_adjusted=1.35,P>0.05).The risk of hematological malignancies in T2DM patients with LDL-C level<2.8 mmol/L and triglyceride level<1.7 mmol/L was 8.36 times higher than that in T2DM patients without this phenotype(OR_adjusted=6.41,P<0.001).When T2DM patients with cancer phenotypes,the risk of hematological malignancies significantly increased,especially those with the phenotype HDL-C<1.0mmol/L or LDL-C<2.8 mmol/L combined with TG<1.7 mmol/L.（2）The associations of IGF-1,IGFBP-3 and the risk of hematological malignancies in patients with T2DM,respectively.The levels of IGF-1 and IGFBP-3 were 126.12 ng/m L and 2.80μg/m L respectively in T2DM patients with hematological malignancies.The levels of IGF-1 and IGFBP-3 in T2DM patients were 132.59 ng/m L and 3.32μg/m L respectively.There was no significant difference in the expression of IGF-1 between the two groups（P>0.05）.However,levels of IGFBP-3 in T2DM patients with hematological malignancies was significantly lower than that in patients with T2DM（P<0.05）.According to the levels of IGF-1,the subjects were divided into high（≥148 ng/m L）,middle（≥100.67 ng/m L and<148 ng/m L）and low（<100.67 ng/m L）groups.IGF-1 levels of the middle-level group was as a reference,the risk of hematological malignancies in the low-level group of IGF-1 was 2.16 times than that in the reference group(P=0.046,OR _adjusted=2.25 and P_adjusted=0.055).Patients with lower levels of IGF-1 seemed to have a higher risk of hematological malignancies.According to the levels of IGFBP-3,the subjects were also divided into high（≥3.54μg/m L）,middle（≥2.17μg/m L and<3.54μg/m L）and low（<2.17μg/m L）groups.With the high-level of IGFBP-3 as a reference,the risk of hematological malignancies in the low-level group of IGFBP-3 was 3.50 times than that in the reference(P=0.027,OR_adjusted=3.08 and P_adjusted=0.080).The risk of hematological malignancies in T2DM patients with low level of IGFBP-3 was significantly higher than that in patients with high-level IGFBP-3.（3）Low level of IGFBP-3 and the risk of hematological malignancies in T2DM patients with cancer phenotypes HDL-C<1.0 mmol/L and LDL-C<2.8 mmol/L plus TG<1.7 mmol/L.On the basis of the above analysis,when the confounding factors such as age,sex,body mass index,smoking status,drinking status,course of diabetes,glycosylated hemoglobin（%）and drug uses at the time of admission were adjusted,the risks of hematological malignancies still increased in the T2DM patients with the three phenotypes,especially with HDL-C<1.0 mmol/L（OR=2.81,95%CI:1.38-5.69,P=0.004）and with LDL-C<2.8 mmol/L plus TG<1.7 mmol/L（OR=6.41,95%CI:2.22-18.50,P=0.001）.When IGF-1 and IGFBP-3 were introduced into the model,the risk of hematological malignancies changed differenctly in patients with T2DM.The risk of hematological malignancies in T2DM patients with phenotype HDL-C<1.0 mmol/L decreased to 1.52times（95%CI:0.49-4.75,P>0.05）.T2DM patients with phenotype LDL-C<2.8 mmol/L plus albuminuria had a 1.37-fold risk of hematological malignancies（95%CI:0.38-4.89,P>0.05）,and the risk of hematological malignancies of T2DM patients with phenotype LDL-C<2.8 mmol/L plus triglyceride<1.7 mmol/L was 3.30 times（95%CI:0.73-0.91,P>0.05）which was a marked drop in the cancer risk.Meanwhile,the OR value of the association between low levels of IGF-1 and the risk of hematological malignancies in patients with T2DM was 1.96（95%CI:0.89-4.30,P=0.094）.Compared with the high-level of IGFBP-3,the OR value of the association between the middle levels of IGFBP-3,especially the low-level of IGFBP-3 and the risk of hematological malignancies increased significantly(OR_middle-level=6.95,95%CI:1.31-36.84,P=0.023;OR_low-level=19.80,95%CI:2.97-132.07,P=0.002).With the decrease of IGFBP-3 levels,the risk of hematological malignancies in patients with T2DM increased significantly(P_{for trend}=0.019).Conclusions:In this study,the cancer phenotypes HDL-C<1.0 mmol/L and LDL-C<2.8 mmol/L plus triglyceride<1.7 mmol/L were associated with an increased risk of hematological malignancies in patients with T2DM.Independent of the above-metioned cancer phenotypes,low-IGFBP-3 was significantly related to the cocurrence of hematological malignancies,and possibly mediated the effects of HDL-C<1.0 mmol/L,LDL-C<2.8mmol/L plus TG<1.7 mmol/L and the risk of hematological malignancies.Our findings supported the hypothesis that insulin insufficiency up-regulates IGF-cholesterol synthesis pathway lead to the increased risk of hematological malignancies.Additionally,IGFBP-3involved in multiple signaling pathways and linked to the dysregulation of the AMPK pathway by insulin resistance resulted in the occurrence of hematological malignancies.This study was a case-control study.It is impossible to determine whether these associations are causal,which needs to be verified by prospective cohort studies.At the same time,these findings also suggested the urgency for related mechanism research to explore the molecular mechanism involved in the mentioned associations.Through in-depth mechanism research to explore the mediating effects of IGF-1 system in the association between cancer phenotypes and hematologcial malignancies in T2DM patients,it could provide a basis for the study of the relationship between diabetes mellitus and cancer.Meanwhile,it could provide a new idea for the research and development of IGFBP-3 as a tumor suppressor in the research and development of tumor-targeted drugs.