Abstract：
Signaling through prostaglandin E2 EP3 receptor (EP3) actively contributes to the β-cell dysfunction of type 2 diabetes (T2D). In T2D models, full-body EP3 knockout mice have a significantly worse metabolic phenotype than wild-type controls due to hyperphagia and severe insulin resistance resulting from loss of EP3 in extra-pancreatic tissues, masking any potential beneficial effects of EP3 loss in the β cell. We hypothesized β-cell-specific EP3 knockout (EP3 βKO) mice would be protected from high-fat diet (HFD)-induced glucose intolerance, phenocopying mice lacking the EP3 effector, Gαz, which is much more limited in its tissue distribution. When fed a HFD for 16 wk, though, EP3 βKO mice were partially, but not fully, protected from glucose intolerance. In addition, exendin-4, an analog of the incretin hormone, glucagon-like peptide 1, more strongly potentiated glucose-stimulated insulin secretion in islets from both control diet- and HFD-fed EP3 βKO mice as compared with wild-type controls, with no effect of β-cell-specific EP3 loss on islet insulin content or markers of replication and survival. However, after 26 wk of diet feeding, islets from both control diet- and HFD-fed EP3 βKO mice secreted significantly less insulin as a percent of content in response to stimulatory glucose, with or without exendin-4, with elevated total insulin content unrelated to markers of β-cell replication and survival, revealing severe β-cell dysfunction. Our results suggest that EP3 serves a critical role in temporally regulating β-cell function along the progression to T2D and that there exist Gαz-independent mechanisms behind its effects.NEW & NOTEWORTHY The EP3 receptor is a strong inhibitor of β-cell function and replication, suggesting it as a potential therapeutic target for the disease. Yet, EP3 has protective roles in extrapancreatic tissues. To address this, we designed β-cell-specific EP3 knockout mice and subjected them to high-fat diet feeding to induce glucose intolerance. The negative metabolic phenotype of full-body knockout mice was ablated, and EP3 loss improved glucose tolerance, with converse effects on islet insulin secretion and content.
摘要：
通过前列腺素E2EP3受体（EP3）的信号传导积极促进2型糖尿病（T2D）的β细胞功能障碍。在T2D模型中，由于胰腺外组织中EP3缺失导致的饮食过多和严重的胰岛素抵抗，全身EP3敲除小鼠的代谢表型比野生型对照明显更差。掩盖β细胞中EP3损失的任何潜在有益作用。我们假设β细胞特异性EP3基因敲除（EP3βKO）小鼠将被保护免受高脂饮食（HFD）诱导的葡萄糖不耐受，缺乏EP3效应子的表型小鼠，Gαz,其组织分布更为有限。当喂HFD16周时，虽然,EP3βKO小鼠部分，但不完全,免受葡萄糖不耐受。此外,exendin-4是肠促胰岛素激素的类似物,胰高血糖素样肽1，与野生型对照相比，对照饮食和HFD喂养的EP3βKO小鼠胰岛中葡萄糖刺激的胰岛素分泌更强，β细胞特异性EP3损失对胰岛胰岛素含量或复制和存活标志物没有影响。然而,经过26周的饮食喂养，来自对照饮食和HFD喂养的EP3βKO小鼠的胰岛分泌的胰岛素含量百分比显着减少，有或没有exendin-4，与β细胞复制和存活标记无关的总胰岛素含量升高，显示严重的β细胞功能障碍。我们的结果表明，EP3在T2D进展过程中在时间上调节β细胞功能中起关键作用，并且其作用背后存在不依赖Gαz的机制。EP3受体是β细胞功能和复制的强抑制剂，表明它是该疾病的潜在治疗靶点。然而，EP3在胰腺外组织中具有保护作用。为了解决这个问题，我们设计了β细胞特异性EP3基因敲除小鼠，并对其进行高脂饮食喂养以诱导葡萄糖不耐受。全身基因敲除小鼠的负代谢表型被消融,和EP3损失改善葡萄糖耐量，对胰岛胰岛素分泌和含量有相反的影响。
