Division of Endocrinology, Diabetes and Clinical Nutrition, Department of Medicine 1, University of Kiel, Kiel, Germany.
Department of General, Visceral, Thoracic, Transplantation, and Pediatric Surgery, University of Kiel, Kiel, Germany.
J Clin Endocrinol Metab. 2021 Jan 23;106(2):e592-e601. doi: 10.1210/clinem/dgaa758.
Dipeptidylpeptidase (DPP)-4 is a key regulator of the incretin system. It exists in a membrane-bound form and a soluble form (sDPP-4). Initial human studies suggested sDPP-4 to be an adipokine involved in metabolic inflammation. However, recent mechanistic data in genetically modified mice has questioned these findings.
We examined circulating sDPP-4 in a cohort of n = 451 humans with different metabolic phenotypes and during 3 different weight loss interventions (n = 101) to further clarify its role in human physiology and metabolic diseases.
sDPP-4 serum concentrations were measured by enzyme-linked immunosorbent assay and related to several phenotyping data including gut microbiome analysis.
sDPP-4 increased with age and body weight and was positively associated with insulin resistance and hypertriglyceridemia but was reduced in manifest type 2 diabetes. In addition, we found reduced serum concentrations of sDPP-4 in subjects with arterial hypertension. In contrast to earlier reports, we did not identify an association with systemic markers of inflammation. Impaired kidney and liver functions significantly altered sDPP-4 concentrations while no relation to biomarkers for heart failure was observed. Having found increased levels of sDPP-4 in obesity, we studied surgical (gastric bypass and sleeve gastrectomy) and nonsurgical interventions, revealing a significant association of sDPP-4 with improvement of liver function tests but not with changes in body weight.
Our data suggest that sDPP-4 is related to hepatic abnormalities in obesity rather than primarily functioning as an adipokine and that sDPP-4 is implicated both in glucose and in lipid metabolism, but not fundamentally in systemic inflammation.
二肽基肽酶-4（DPP-4）是肠降血糖素系统的关键调节因子。它以膜结合形式和可溶性形式（sDPP-4）存在。最初的人体研究表明，sDPP-4 是一种参与代谢炎症的脂肪因子。然而，最近在基因修饰小鼠中的机制数据对这些发现提出了质疑。
我们在不同代谢表型的 451 名人类队列中检查了循环 sDPP-4，并在 3 种不同的减肥干预中（n=101）进行了检查，以进一步阐明其在人体生理学和代谢疾病中的作用。
通过酶联免疫吸附试验测量 sDPP-4 的血清浓度，并将其与包括肠道微生物组分析在内的多种表型数据相关联。
sDPP-4 随年龄和体重增加而增加，与胰岛素抵抗和高三酰甘油血症呈正相关，但在显性 2 型糖尿病中降低。此外，我们发现动脉高血压患者的血清 sDPP-4 浓度降低。与早期报告相反，我们没有发现与全身性炎症标志物之间存在关联。受损的肾功能和肝功能显著改变了 sDPP-4 浓度，而与心力衰竭的生物标志物无关。我们发现肥胖症患者的 sDPP-4 水平升高，因此研究了手术（胃旁路和袖状胃切除术）和非手术干预，结果表明 sDPP-4 与肝功能测试的改善显著相关，但与体重变化无关。
我们的数据表明，sDPP-4 与肥胖症中的肝异常有关，而不是主要作为脂肪因子发挥作用，并且 sDPP-4 既参与葡萄糖代谢，也参与脂质代谢，但不是系统性炎症的根本原因。
