ANGPTL8與肥胖和糖尿病病人腎功能惡化相關性與致病機轉之探討

Abstract

背景與研究目的 肥胖與第2型糖尿病、心血管疾病和較低預期壽命相關。研究指出內臟脂肪堆積與胰島素阻抗、動脈粥樣硬化的脂質與糖尿病的發生之間相關聯。探究不同脂肪組織特定基因的表現與肥胖之間的關聯可以提供更多治療方向。而肥胖和脂毒性在糖尿病患者的慢性腎臟疾病中也有著重要作用，部分研究指出慢性腎臟疾病與血清ANGPTL8有關，關於ANGPTL8在合併糖尿病和慢性腎臟疾病患者上的調節機制仍需進一步研究。 Angiopoietin-like protein 8（ANGPTL8）是脂質代謝的重要調節因子。我們的研究目的其一是探討肥胖和非肥胖個體之間不同脂肪組織中ANGPTL8表現量的差異，以及其在合併糖尿病和慢性腎臟疾病族群中的調節機制。 方法 我們收集了330位接受肥胖手術或腹內手術患者的皮下脂肪組織和內臟脂肪組織。使用即時定量聚合酶連鎖反應測定ANGPTL8的表現量。分析ANGPTL8表現量與各種代謝指標間的相關性。另外我們從臺大醫院收集了846位第2型糖尿病的患者，收集其血液樣本，使用酵素連結免疫吸附分析測定空腹血漿中的ANGPTL8數值，從2010年至2022年進行長期追蹤。其中慢性腎臟疾病定義為UACR ≥ 30mg/g或eGFR < 60 ml/min/1.73m2 。 結果 肥胖者內臟脂肪中ANGPTL8的表現量較高，且與身體質量指數呈正相關。術前血漿 ANGPTL8濃度最高的患者在減肥手術後6個月體重減少的百分比最低。而在血清中的ANGPTL8與腎功能惡化追蹤研究中，發現三酸甘油脂、身體質量指數、年齡、罹病時間長短、糖化血色素、收縮壓是糖尿病患者發生慢性腎臟疾病的危險因子，但與血漿中ANGPTL8濃度並無顯著相關。而且在12年的追蹤期內，血漿中ANGPTL8濃度高低並不影響慢性腎病變的發生率。 結論 肥胖者內臟脂肪組織中ANGPTL8的表現量較高，並且與身體質量指數呈正相關。而手術前血漿中ANGPTL8值越高者，其肥胖手術後的體重降幅越小，表示ANGPTL8在肥胖的病理生理過程中可能扮演重要角色。在第2型糖尿病人的世代研究中，雖然血漿ANGPTL8濃度在有或無慢性腎病變患者中並無顯著差異。但分析指出三酸甘油脂和身體質量指數是慢性腎臟疾病的危險因子，可能與脂毒性造成的腎功能異常相關。

Background and objective Obesity is associated with type 2 diabetes, cardiovascular disease, and lower life expectancy. Obesity contributes to the development of insulin resistance related to type 2 diabetes, study had reported that visceral adipose tissue (VAT) was associated with insulin resistance, more atherogenic lipid profiles, prevalent diabetes, investigating the association between expression levels of specific genes in different depots of adipose tissue with obesity can yield more functional information. Obesity and lipotoxicity also play crucial role on chronic kidney disease (CKD) on diabetic patients. The relationship between serum levels of angiopoietin-like protein 8 (ANGPTL8) and lipid metabolism had been studied extensively, and few studies had indicated that CKD is associated with serum ANGPTL8, in which may be due to lipotoxicity, but specific mechanisms for the regulation of ANGPTL8 on diabetes with CKD still need more investigation. Angiopoietin-like protein 8 (ANGPTL8) is an important regulator of lipid metabolism. We aimed to investigate the difference of ANGPTL8 expression in different depots of adipose tissues between individuals with and without obesity, and its specific mechanisms for the regulation of ANGPTL8 on diabetes with CKD. Methods Subcutaneous (SAT) and visceral adipose tissue (VAT) samples were collected from patients who underwent bariatric or intra-abdominal surgery. Expression levels of ANGPTL8, monoglyceride lipase (MGL), N-alpha-acetyltransferase 10 (NAA10), monocyte chemoattractant protein-1 (MCP-1), leptin and adiponectin (APM1) were determined using real-time qPCR. The correlation of ANGPTL8 expression with various metabolic parameters and other gene expression levels was analyzed using Pearson’s correlation analysis. Logistic regression was used to establish a prediction model of obesity and CKD. We also enrolled 846 patients form National Taiwan University Hospital (NTUH) with type 2 diabetes since 2010, baseline serum sample were collected, fasting serum ANGPTL8 levels were assessed using ELISA kits. Longitudinal follow up during 2010-2022. CKD is defined as UACR ≥ 30mg/g or eGFR < 60 ml/min/1.73m2, and progression to CKD is defined as sustained eGFR < 60 ml/min/1.73m2 in the following years. Results ANGPTL8 expression levels in VAT were higher in subjects with obesity, and positively correlated with BMI (O.R: 1.246, P = 0.038). On the other hand, the patients with the highest tertiles of pre-operative plasma ANGPTL8 level had the lowest percentage of BW reduction 6 months after bariatric surgery. The analysis on diabetes and renal function revealed baseline serum ANGPTL8 showed no significant difference on cross sectional and longitudinal follow up. In the longitudinal follow-up study of type 2 diabetes patients at NUTH, it was found that plasma triglyceride levels, body mass index, age, diabetes duration, HbA1c, and systolic blood pressure are risk factors for chronic kidney disease in diabetic patients. Plasma ANGPTL8 concentrations were not significantly correlated with CKD in diabetic patients. Moreover, during the 12-year follow-up period, the level of plasma ANGPTL8 did not affect the incidence of chronic kidney disease. Conclusion The expression of ANGPTL8 in visceral adipose tissue of obese people is higher, and it is positively correlated with body mass index. The higher the pre-operative plasma ANGPTL8 level, the lesser the weight loss after obesity surgery, indicating that ANGPTL8 may play an important role in the pathophysiological process of obesity. In a cohort study of people with type 2 diabetes, although serum ANGPTL8 concentrations were not significantly different in patients with or without CKD, triglycerides and body mass index are positive risk factors for chronic kidney disease, which may be associated with abnormal renal function caused by lipotoxicity.