Hepatic Insulin-Positive Cells and Major Transcription Factors (PDX1, MAFA, NGN3) in Rat Models of Type 1 and Type 2 Diabetes Mellitus

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.