Mediating effect of leptin levels between insulin resistance and nonalcoholic fatty liver disease in obese children
-
摘要:
目的 小儿非酒精性脂肪肝(NAFLD)是儿童中最常见的慢性肝病,其患病率随着超重和肥胖率的增加而上升,瘦素是第一个被分离和鉴定的脂肪因子,本研究探讨瘦素水平在肥胖儿童胰岛素抵抗与NAFLD间的中介作用。 方法 将舟山市妇女儿童医院2022年1月—2023年3月收治的肥胖儿童80例作为研究对象,根据是否存在NAFLD分为NAFLD组(32例)和非NAFLD组(48例)。收集所有研究对象一般资料、体格资料、胰岛素抵抗指数、瘦素水平及肝功能等,同时采用Pearson相关分析上述变量间的相关性;采用中介效应分析瘦素水平在肥胖儿童胰岛素抵抗与非酒精性脂肪肝间的作用。 结果 NAFLD组稳态模型胰岛素抵抗指数(HOMA-IR)、瘦素、谷丙转氨酶(ALT)、谷草转氨酶(AST)、肝内脂肪(IHL)水平均较非NAFLD组高(均P < 0.05);Pearson相关性分析显示:HOMA-IR与瘦素、IHL具有较强的正相关关系(r=0.573,P < 0.001;r=0.577,P < 0.001);瘦素与肝内脂肪IHL具有较强的正相关关系(r=0.557,P < 0.001);中介效应分析显示:HOMA-IR作为直接效应占总效应的56.48%(0.340),脂肪因子作为中介效应占总效应的43.52%(0.262)。 结论 肥胖儿童的胰岛素抵抗与非酒精性脂肪肝有关,这种关系可由脂肪因子介导。 Abstract:Objective Paediatric non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in children and its prevalence is increasing with the rise in overweight and obesity. Leptin was the first adipokine to be isolated and identified. Therefore, the mediating role of leptin levels between insulin resistance and NAFLD in obese children is discussed. Methods Eighty obese children admitted to Zhoushan Women's and Children's Hospital from January 2022 to March 2023 were selected as research objects, and divided into NAFLD group (32 cases) and non-NAFLD group (48 cases) according to the presence or absence of NAFLD. General data, physical data, insulin resistance index, leptin level and liver function of all subjects were collected, and Pearson correlation was used to analyze the correlation between the above variables. Mediation effects were used to analyze the effects of leptin levels on insulin resistance and non-alcoholic fatty liver disease in obese children. Results Homeostasis model assessment forinsulin resistance (HOMA-IR), leptin, alanine transaminase (ALT), aspartate transaminase (AST) and intrahepatic lipiol (IHL) levels in the NAFLD group were higher than those in the non-NAFLD group (all P < 0.05). Pearson correlation showed that HOMA-IR was positively correlated with leptin and IHL (r=0.573, P < 0.001; r=0.577, P < 0.001); leptin was positively correlated with IHL (r=0.557, P < 0.001). Mediation effect analysis showed that HOMA-IR as a direct effect accounted for 56.48% (0.340) of the total effect and adipokines as a mediating effect accounted for 43.52% (0.262). Conclusion Insulin resistance in obese children is associated with non-alcoholic fatty liver disease, which may be mediated by adipokines. -
Key words:
- Leptin /
- Obesity /
- Insulin resistance /
- Non-alcoholic fatty liver disease
-
表 1 2组肥胖儿童一般资料比较
Table 1. General data analysis of the two groups in obese children
项目 NAFLD组
(n=32)非NAFLD组
(n=48)统计量 P值 性别(男/女,例) 20/12 28/20 0.139a 0.709 年龄(x±s,岁) 10.26±3.16 10.38±3.31 0.163b 0.871 BMI(x±s) 28.26±1.26 27.79±1.19 1.671b 0.100 腰围(x±s,cm) 87.36±10.23 86.26±10.16 0.472b 0.638 臀围(x±s,cm) 93.26±10.69 90.69±10.98 1.042b 0.301 代谢参数 FPG(x±s,mmol/L) 6.25±0.98 4.94±1.02 1.702b 0.094 HOMA-IR(x±s) 4.56±1.16 4.02±1.01 2.146b 0.036 瘦素(x±s,μg/L) 13.96±2.11 12.11±2.40 3.643b 0.001 ALT(x±s,U/L) 55.27±6.56 31.76±7.84 14.510b < 0.001 AST(x±s,U/L) 53.15±7.65 30.42±7.62 13.040b < 0.001 IHL(x±s,%) 10.57±2.58 4.58±0.90 12.631b < 0.001 注:a为χ2值,b为t值。 表 2 瘦素水平在肥胖儿童胰岛素抵抗与非酒精性脂肪肝间的相关性分析
Table 2. Correlating leptin levels with insulin resistance and nonalcoholic fatty liver disease in obese children
变量 HOMA-IR 瘦素 ALT AST 肝内脂肪IHL HOMA-IR 1 瘦素 0.573a 1 ALT 0.143 0.358 1 AST 0.190 1.359 0.894a 1 肝内脂肪IHL 0.577a 0.557a 0.810a 0.818a 1 注:aP < 0.001。 -
[1] POWELL E E, WONG V W, RINELLA M. Non-alcoholic fatty liver disease[J]. Lancet, 2021, 397(10290): 2212-2224. doi: 10.1016/S0140-6736(20)32511-3 [2] BRUNNER K T, HENNEBERG C J, WILECHANSKY R M, et al. Nonalcoholic fatty liver disease and obesity treatment[J]. Curr Obes Rep, 2019, 8(3): 220-228. doi: 10.1007/s13679-019-00345-1 [3] FRIEDMAN S L, NEUSCHWANDER-TETRI B A, RINELLA M, et al. Mechanisms of NAFLD development and therapeutic strategies[J]. Nat Med, 2018, 24(7): 908-922. doi: 10.1038/s41591-018-0104-9 [4] PEREIRA S, CLINE D L, GLAVAS M M, et al. Tissue-specific effects of leptin on glucose and lipid metabolism[J]. Endocr Rev, 2021, 42(1): 1-28. doi: 10.1210/endrev/bnaa027 [5] SETH M, BISWAS R, GANGULY S, et al. Leptin and obesity[J]. Physiol Int, 2020, 107(4): 455-468. [6] GUZZARDI M A, GUIDUCCI L, CAMPANI D, et al. Leptin resistance before and after obesity: evidence that tissue glucose uptake underlies adipocyte enlargement and liver steatosis/steatohepatitis in Zucker rats from early-life stages[J]. Int J Obes (Lond), 2022, 46(1): 50-58. doi: 10.1038/s41366-021-00941-z [7] PETRESCU M, VLAICU S I, CIUMǍRNEAN L, et al. Chronic inflammation-a link between nonalcoholic fatty liver disease (NAFLD) and dysfunctional adipose tissue[J]. Medicina (Kaunas), 2022, 58(5): 641. doi: 10.3390/medicina58050641 [8] 中国肥胖问题工作组. 中国学龄儿童青少年超重、肥胖筛查体重指数值分类标准[J]. 中华流行病学杂志, 2004, 25(2): 97-102. doi: 10.3760/j.issn:0254-6450.2004.02.003China Working Group on Obesity. Body mass index reference norm for screening overweight and obesity in Chinese children and adolescents[J]. Chinese Journal of Epidemiology, 2004, 25(2): 97-102. doi: 10.3760/j.issn:0254-6450.2004.02.003 [9] 中华医学会儿科分会内分泌遗传代谢学组. 儿童非酒精性脂肪肝病诊断与治疗专家共识[J]. 中国实用儿科杂志, 2018, 33(7): 487-491.Endocrinology, Genetics and Metabolism Group, Pefiatric Society, Chinese Medical Association. Expert consensus on the diagnosis and treatment of nonalcoholic fatty liver disease in children[J]. Chinese Journal of Practical Pediatrics, 2018, 33(7): 487-491. [10] CHAO H W, CHAO S W, LIN H, et al. Homeostasis of glucose and lipid in non-alcoholic fatty liver disease[J]. Int J Mol Sci, 2019, 20(2): 298. doi: 10.3390/ijms20020298 [11] 王声翰, 杨菊红, 郑妙艳, 等. 可溶性CD36与2型糖尿病及其并发症的关系[J]. 中华全科医学, 2020, 18(11): 1921-1924. doi: 10.16766/j.cnki.issn.1674-4152.001654WANG S H, YANG J H, ZHENG M Y, et al. Association of soluble CD36 with type 2 diabetes and its complications[J]. Chinese Journal of General Practice, 2020, 18(11): 1921-1924. doi: 10.16766/j.cnki.issn.1674-4152.001654 [12] LEWIS G F, CARPENTIER A C, PEREIRA S, et al. Direct and indirect control of hepatic glucose production by insulin[J]. Cell Metab, 2021, 33(4): 709-720. doi: 10.1016/j.cmet.2021.03.007 [13] SHEKA A C, ADEYI O, THOMPSON J, et al. Nonalcoholic steatohepatitis: a review[J]. JAMA, 2020, 323(12): 1175-1183. doi: 10.1001/jama.2020.2298 [14] SCHWIMMER J B, JOHNSON J S, ANGELES J E, et al. Microbiome signatures associated with steatohepatitis and moderate to severe fibrosis in children with nonalcoholic fatty liver disease[J]. Gastroenterology, 2019, 157(4): 1109-1122. doi: 10.1053/j.gastro.2019.06.028 [15] BERNDT N, HUDERT C A, ECKSTEIN J, et al. Alterations of central liver metabolism of pediatric patients with non-alcoholic fatty liver disease[J]. Int J Mol Sci, 2022, 23(19): 11072. doi: 10.3390/ijms231911072 [16] 李婧, 李小凤, 闫妮, 等. 评估肥胖相关指标对非酒精性脂肪肝的筛查价值[J]. 中华全科医学, 2023, 21(2): 195-198. doi: 10.16766/j.cnki.issn.1674-4152.002843LI J, LI X F, YAN N, et al. Evaluation the screening value of obesity-related indices for non-alcoholic fatty liver disease[J]. Chinese Journal of General Practice, 2023, 21(2): 195-198. doi: 10.16766/j.cnki.issn.1674-4152.002843 [17] VATIER C, JÉRU I, FELLAHI S, et al. Leptin, adiponectin, lipodystrophic and severe insulin resistance syndromes[J]. Ann Biol Clin (Paris), 2020, 78(3): 261-264. [18] BRAND C, GAYA A, DIAS A F, et al. Relationship between insulin resistance and adipocytokines: the mediator role of adiposity in children[J]. Ann Hum Biol, 2020, 47(3): 244-249. doi: 10.1080/03014460.2020.1740320 [19] KADO T, NAWAZ A, TAKIKAWA A, et al. Linkage of CD8+ T cell exhaustion with high-fat diet-induced tumourigenesis[J]. Sci Rep, 2019, 9(1): 12284. doi: 10.1038/s41598-019-48678-0 [20] MICU E S, AMZOLINI A M, BARǍU ABU-ALHIJA A, et al. Systemic and adipose tissue inflammation in NASH: correlations with histopathological aspects[J]. Rom J Morphol Embryol, 2021, 62(2): 509-515. [21] DUDEK M, PFISTER D, DONAKONDA S, et al. Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH[J]. Nature, 2021, 592(7854): 444-449. doi: 10.1038/s41586-021-03233-8 [22] LEE J K, HA J H, KIM D K, et al. Depletion of zinc causes osteoblast apoptosis with elevation of leptin secretion and phosphorylation of JAK2/STAT3[J]. Nutrients, 2022, 15(1): 77. doi: 10.3390/nu15010077 [23] OSINSKI V, BAUKNIGHT D K, DASA S, et al. In vivo liposomal delivery of PPARα/γ dual agonist tesaglitazar in a model of obesity enriches macrophage targeting and limits liver and kidney drug effects[J]. Theranostics, 2020, 10(2): 585-601. doi: 10.7150/thno.36572 -