Abstract

Due to a high occurrence of diabetes mellitus (DM) and its complications, insulin-positive cells detected in different organs are of great interest as they can probably partially compensate for insulin deficiency in DM. The development of pancreatic β-cells is regulated by the consecutive expression of transcription factors, among which Pdx1, MafA and Ngn3 are most extensively explored. Specifically, these factors have been reported to be able to transdifferentiate a broad variety of cell types into insulin-positive cells. The goal of this study was to characterize insulin-positive (insulin⁺) cells in the liver and to evaluate the expression of transcription factors Pdx1, MafA and Ngn3 involved in their differentiation in an alloxan-induced rat model of type 1 DM (T1DM) and streptozotocin-nicotinamide-induced rat model of type 2 DM (T2DM). Experiments were carried out on male Wistar rats. In experimental animals, plasma levels of glucose, glycosylated hemoglobin and insulin were determined. The oral glucose tolerance test was performed and the insulin resistance index (HOMA-IR) was calculated. The expression of Pdx1⁺, MafA⁺ and Ngn3⁺ was investigated immunohistochemically. Insulin⁺, Pdx1⁺, MafA⁺ and Ngn3⁺ cells were detected in the liver both of healthy animals and those with experimental models of T1DM and T2DM. The largest number of insulin⁺ cells was found in animals with streptozotocin-nicotinamide-induced T2DM, wherein cells were localized throughout the hepatic lobule. In an alloxan-induced model of T1DM, these cells were detected mainly at the periphery of the hepatic lobule. The number of Pdx1⁺, Mafa⁺ and Ngn3⁺ hepatic cells was different in intact animals vs. those with experimental DM. A correlation was established between the number of Ngn3⁺ cells and insulin⁺ cells in alloxan-induced DM, as well as between the number of MafA⁺ cells and insulin⁺ cells in both types of experimental DM. Thus, in rats with both experimental models of DM, the number of insulin⁺, Pdx1⁺ and MafA⁺ cells in the liver increases compared to intact animals. Localization and the number of insulin⁺ cells varies depending on the experimental model of DM. At the same time, the number of Pdx1⁺ and MafA⁺ cells increases in an alloxan-induced model of T1DM compared to a streptozotocin-nicotinamide-induced model of T2DM. There is a correlation between the number of insulin⁺ and MafA⁺ cells both in T1DM and T2DM models and between the number of insulin⁺ and Ngn3⁺ cells in a T1DM model only.

中文翻译：

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1 型和 2 型糖尿病大鼠模型中的肝胰岛素阳性细胞和主要转录因子（PDX1、MAFA、NGN3）

摘要

由于糖尿病 (DM) 及其并发症的发生率很高，因此在不同器官中检测到的胰岛素阳性细胞很受关注，因为它们可能可以部分补偿 DM 中的胰岛素缺乏。胰腺 β 细胞的发育受转录因子的连续表达调控，其中 Pdx1、MafA 和 Ngn3 的研究最为广泛。具体而言，据报道这些因子能够将多种细胞类型转分化为胰岛素阳性细胞。本研究的目的是表征胰岛素阳性（胰岛素⁺) 肝脏中的细胞，并评估转录因子 Pdx1、MafA 和 Ngn3 在四氧嘧啶诱导的 1 型 DM (T1DM) 大鼠模型和链脲佐菌素-烟酰胺诱导的 2 型 DM (T2DM) 大鼠模型中的表达）。实验是在雄性 Wistar 大鼠上进行的。在实验动物中，测定了葡萄糖、糖化血红蛋白和胰岛素的血浆水平。进行口服葡萄糖耐量试验并计算胰岛素抵抗指数（HOMA-IR）。免疫组化研究了Pdx1 ⁺、MafA ⁺和Ngn3 ⁺的表达。胰岛素⁺ , Pdx1 ⁺ , MafA ⁺和 Ngn3 ⁺在健康动物和具有 T1DM 和 T2DM 实验模型的肝脏中检测到细胞。在链脲佐菌素-烟酰胺诱导的 T2DM 动物中发现的胰岛素⁺细胞数量最多，其中细胞位于整个肝小叶。在四氧嘧啶诱导的 T1DM 模型中，这些细胞主要在肝小叶的外围被检测到。Pdx1 ⁺、Mafa ⁺和Ngn3 ⁺肝细胞的数量在完整动物与实验性糖尿病的动物中不同。Ngn3的数量之间建立的相关性⁺细胞和胰岛素⁺细胞在四氧嘧啶诱导的DM，以及之间的MafA的数量⁺两种类型的实验性糖尿病中的细胞和胰岛素⁺细胞。因此，在具有两种 DM 实验模型的大鼠中，与完整动物相比，肝脏中胰岛素⁺、Pdx1 ⁺和 MafA ⁺细胞的数量增加。胰岛素⁺细胞的定位和数量取决于 DM 的实验模型。同时，与链脲佐菌素-烟酰胺诱导的 T2DM 模型相比，四氧嘧啶诱导的 T1DM 模型中 Pdx1 ⁺和 MafA ⁺细胞的数量增加。T1DM 和 T2DM 模型中胰岛素⁺和 MafA ⁺细胞数量之间以及胰岛素数量之间存在相关性⁺和 Ngn3 ⁺细胞仅在 T1DM 模型中。