Effect And Mechanism Of Insulin-like Growth Factor-1 And Prognosis And Target Organ Damage In Acromegaly

Objective:(1)To analyze the clinical characteristics and features of patients with acromegaly and to investigate the association between insulin-like growth factor-1(IGF-1)and clinical prognosis of patients with acromegaly.(2)To investigate the relationship between IGF-1 and the risk of developing interventricular septal(IVS)thickening and to find the dose-response relationship between them.(3)To analyze differentially expressed genes and related biological functions and signaling pathways using bioinformatics approaches based on gene microarray data of acromegaly patients in public databases.Methods:(1)Part I: Patients with acromegaly diagnosed at the People’s Hospital of Xinjiang Uygur Autonomous Region from January 2004 to December 2021 were included,demographic data and clinical characteristics of all patients were recorded,IGF-1 and growth hormone levels of patients were measured,and clinical characteristics and features of patients with acromegaly were described.A retrospective cohort study was conducted to analyze the factors influencing biochemical remission at 3 months after surgery in patients with acromegaly using logistic regression equations.Part II: Patients who were hospitalized in the People’s Hospital of Xinjiang Uygur Autonomous Region from May2012 to April 2022 and completed IGF-1 testing and cardiac ultrasound were included,their clinical data were recorded,and the patients were divided into two groups(IVS thickening and non-IVS thickening),and the differences in each variable between the two groups were analyzed,and logistic regression equations were used to analyze the relationship between IGF-1 and the occurrence of ventricular IVS thickening was analyzed by using logistic regression equation,and the dose-response relationship between IGF-1 and the occurrence of ventricular IVS thickening by different sex and age was explored by sample bar regression.Part III: To analyze differentially expressed genes by finding gene microarray data of acromegaly in public databases,and to analyze the biological functions and pathways associated with pathway enrichment using gene ontology and biological pathway function databases.Results: Part I: i)In this part of the study,229 patients with acromegaly were included,of whom 41.7% were male,the mean age was 44.62 years,the proportion of those aged between 40-60 years was 61.7%,the proportions of Han and Uyghur were 48.00% and 35.69%,respectively,and the number of hospitalization days ≥10 days was 54.54%.The main clinical manifestations of patients were headache/dizziness(59.53%),decreased visual acuity(52.09%),extremity changes(29.30%),hypertension(33.76%),and abnormal glucose metabolism(35.44%).Most patients had 2 or more comorbidities,with hypertension and abnormal blood glucose levels being the most common;patients often had preoperative combined anterior pituitary impairment,with hypogonadism being the most common.The median growth hormone level at diagnosis was 10.90 ng/m L,and the median serum and IGF-1 index were 592ng/m L and 2.39.ii)Patients were placed in biochemical remission group(n=26)and non-remission group(n=37)according to their IGF-1 levels at 3 months postoperatively,and the overall patient biochemical remission rate was 41.27%.Compared with patients in the biochemical remission group,patients in the biochemical unremitted group had higher preoperative and postoperative growth hormone levels and IGF-1 index(all P<0.05).iii)Logistic regression analysis showed that preoperative growth hormone level(OR=1.100,95% CI: 1.020-1.187)and IGF-1 index(OR=3.839,95% CI: 1.242-11.863)were independent risk factors for biochemical unremission at 3 months after surgery for acromegaly,correcting for age,sex,adenoma size,and invasion of the cavernous sinus.independent risk factors(both P<0.05).iv)ROC curve analysis showed that preoperative growth hormone levels(AUC=0.843,95% CI: 0.739-0.946)and IGF-1 index(AUC=0.800,95% CI: 0.679-0.922)were strongly associated with non-remission of biochemistry at 3months postoperatively in patients with acromegaly(both P < 0.001),with cut-point values of 18.39 ng/m L and 1.40.Part II: i)A total of 2144 subjects were enrolled in this part of the study,divided into a IVS thickening(n=180)and a non-IVS thickening group(n=1964),with a mean age of 50.6 years and 59.1% being female.ii)Compared with the non-IVS thickening group,patients in the IVS thickening group had significantly higher age,body mass index,systolic blood pressure,diastolic blood pressure,blood creatinine,triglycerides,fasting glucose,plasma cortisol,thyrotropin,free thyroxine,growth hormone levels,and the proportion of smoking,diabetes mellitus,coronary artery disease,and acromegaly,and lower HDL cholesterol levels(all P values <0.001).iii)Logistic regression analysis showed IGF-1 was the independent risk factor for IVS thickening.When IGF-1 was used as independent variable,IVS thickening was regarded as dependent variable,and propensity score of confounding variable as covariable,the risk of IVS thickening occurred significantly with each 1 and 5 unit increase in IGF-1 level,with OR values of 1.002(95% CI: 1.001-1.003,P<0.001)and 1.011(95% CI: 1.007-1.016,P<0.001),respectively;when IGF-1 was used as categorical variable,the risk of developing IVS thickening was significantly increased in those in the third quartile of serum IGF-1levels compared with those in the first quartile of IGF-1 levels(OR=1.74,95% CI:1.15-2.65,P=0.010).iv)Sample bar regression analysis showed a linear dose-response relationship between IGF-1 and the risk of developing IVS thickening in men and women across age groups.After excluding confounding factors such as hypertension,acromegaly,and connective tissue disease,the linear dose-response relationship between IGF-1 and the risk of developing IVS thickening still exist(all P<0.001).Part III: i)We found there were a certain number of differentially expressed genes in the adipose tissue of patients with acromegaly based on the gene expression database(GEO).Among them,IGF1,SMAD3,UBB,ESR1,JUN,MAPK3,HRAs,GAPDH,AKT1 and RELA are the hub genes.ii)Analysis using the Gene Ontology(GO)database revealed that the main biological processes of differentially expressed gene enrichment include protein localization,cellular response to endogenous stimulus,cell population proliferation,intracellular signal transduction,lipid metabolic process,small molecule metabolic process,cellular response to growth factor stimulus,etc.The main enriched cellular components include endoplasmic reticulum,endoplasmic reticulum membrane,etc.The main enriched molecular functions include enzyme binding,lysophospholipid acyltransferase activity,calcium-release channel activity,etc.The IGF1 had important biological roles in these processes.iii)Analysis using the KEGG database revealed that the differentially expressed genes were enriched in fatty acid metabolism,growth hormone synthesis,secretion and action,PI3K/Akt signaling pathway.The IGF1 is expressed in fibroblasts of adipose tissue in patients with acromegaly.Conclusions:(1)Patients with acromegaly have diverse clinical symptoms,most have comorbidities such as hypertension or glucose abnormalities,and preoperative impairment of anterior pituitary function is often present.Preoperative growth hormone levels and elevated IGF-1index affect the postoperative outcome of patients with acromegaly.(2)IGF-1 level is independently associated with the risk of IVS thickening,and the risk of IVS thickening increases with the increase of IGF-1,and there is a certain linear dose relationship between them.IGF-1 is an important risk factor for the risk of IVS thickening.(3)IGF-1gene may be a key regulatory gene in the adipose tissue of patients with acromegaly,mediating multiple biological processes involved in the development of acromegaly through multiple signaling pathways.