Centre for Biomolecular Interactions Bremen, University of Bremen, Bremen, Germany.
Department of Bioinformatics and Biochemistry and Braunschweig Integrated Center of Systems Biology (BRICS), Technische Universität Braunschweig, Braunschweig, Germany.
Front Endocrinol (Lausanne). 2021 Jul 5;12:697120. doi: 10.3389/fendo.2021.697120. eCollection 2021.
Glucagon-like peptide-1 (GLP-1) shows robust protective effects on β-cell survival and function and GLP-1 based therapies are successfully applied for type-2 diabetes (T2D) and obesity. Another cleavage product of pro-glucagon, Glucagon-like peptide-2 (GLP-2; both GLP-1 and GLP-2 are inactivated by DPP-4) has received little attention in its action inside pancreatic islets. In this study, we investigated GLP-2 production, GLP-2 receptor (GLP-2R) expression and the effect of GLP-2R activation in human islets. Isolated human islets from non-diabetic donors were exposed to diabetogenic conditions: high glucose, palmitate, cytokine mix (IL-1β/IFN-γ) or Lipopolysaccharide (LPS) in the presence or absence of the DPP4-inhibitor linagliptin, the TLR4 inhibitor TAK-242, the GLP-2R agonist teduglutide and/or its antagonist GLP-2(3-33). Human islets under control conditions secreted active GLP-2 (full-length, non-cleaved by DPP4) into the culture media, which was increased by combined high glucose/palmitate, the cytokine mix and LPS and highly potentiated by linagliptin. Low but reproducible GLP-2R mRNA expression was found in all analyzed human islet isolations from 10 donors, which was reduced by pro-inflammatory stimuli: the cytokine mix and LPS. GLP-2R activation by teduglutide neither affected acute or glucose stimulated insulin secretion nor insulin content. Also, teduglutide had no effect on high glucose/palmitate- or LPS-induced dysfunction in cultured human islets but dampened LPS-induced macrophage-dependent expression, while its antagonist GLP-2(3-33) abolished such reduction. In contrast, the expression of islet macrophage-independent cytokines , and was not affected by teduglutide. Medium conditioned by teduglutide-exposed human islets attenuated M1-like polarization of human monocyte-derived macrophages, evidenced by a lower mRNA expression of pro-inflammatory cytokines, compared to vehicle treated islets, and a reduced production of itaconate and succinate, marker metabolites of pro-inflammatory macrophages. Our results reveal intra-islet production of GLP-2 and GLP-2R expression in human islets. Despite no impact on β-cell function, local GLP-2R activation reduced islet inflammation which might be mediated by a crosstalk between endocrine cells and macrophages.
胰高血糖素样肽-1 (GLP-1) 对β细胞的存活和功能具有强大的保护作用，基于 GLP-1 的疗法已成功应用于 2 型糖尿病 (T2D) 和肥胖症。前胰高血糖素的另一种切割产物，胰高血糖素样肽-2 (GLP-2；GLP-1 和 GLP-2 均被 DPP-4 失活) 在胰岛内的作用很少受到关注。在这项研究中，我们研究了 GLP-2 的产生、GLP-2 受体 (GLP-2R) 的表达以及 GLP-2R 激活对人胰岛的影响。从非糖尿病供体中分离的人胰岛暴露于致糖尿病条件下：高葡萄糖、棕榈酸、细胞因子混合物 (IL-1β/IFN-γ) 或脂多糖 (LPS)，存在或不存在 DPP4 抑制剂 linagliptin、TLR4 抑制剂 TAK-242、GLP-2 激动剂 teduglutide 和/或其拮抗剂 GLP-2(3-33)。在对照条件下，人胰岛分泌有活性的 GLP-2(全长，不受 DPP4 切割)进入培养基，高葡萄糖/棕榈酸、细胞因子混合物和 LPS 增加了 GLP-2 的分泌，并被 linagliptin 高度增强。在来自 10 个供体的所有分析的人胰岛分离物中均发现低但可重复的 GLP-2R mRNA 表达，其被促炎刺激物：细胞因子混合物和 LPS 降低。GLP-2R 激活剂 teduglutide 既不影响急性或葡萄糖刺激的胰岛素分泌，也不影响胰岛素含量。此外，teduglutide 对高葡萄糖/棕榈酸或 LPS 诱导的人胰岛功能障碍没有影响，但减轻了 LPS 诱导的巨噬细胞依赖性表达，而其拮抗剂 GLP-2(3-33)则消除了这种减少。相反，teduglutide 不影响胰岛巨噬细胞独立细胞因子 、 和 的表达。与用载体处理的胰岛相比，用 teduglutide 暴露的人胰岛条件培养基降低了人单核细胞衍生巨噬细胞的 M1 样极化，表现为促炎细胞因子的 mRNA 表达降低，并且产生的异丁酸盐和琥珀酸盐减少，这是促炎巨噬细胞的标记代谢物。我们的结果揭示了人胰岛内 GLP-2 的产生和 GLP-2R 的表达。尽管对β细胞功能没有影响，但局部 GLP-2R 激活减少了胰岛炎症，这可能是内分泌细胞与巨噬细胞之间的串扰介导的。
