Comparative medical characteristics of ZDF-T2DM rats during the course of development to late stage disease

Abstract

Background: There are few reports on the comparative medical characteristics of type 2 diabetes models in late stage. An analysis of comparative medical characteristics of Zucker diabetic fatty type 2 diabetes mellitus (ZDF-T2DM) rats during the course of development to late stage disease was performed.

Methods: In this study, ZDF rats were fed with high-sugar and high-fat diets to raise the fasting blood glucose, and develop of type 2 diabetes. At the late stage of T2DM, the preliminary comparative medical characteristics of the T2DM model were analyzed through the detection of clinical indicators, histopathology, related cytokine levels, and insulin-related signaling molecule expression levels.

Results: In the T2DM group, the fasting blood glucose was higher than 6.8 mmol/L, the serum insulin, leptin, and adiponectin levels were significantly decreased, and glucose intolerance and insulin resistance were measured as clinical indicators. Regarding pathological indicators, a large number of pancreatic islet cells showed the reduction of insulin secretion, resulting in damaged glycogen synthesis and liver steatosis. At the molecular level, the insulin signal transduction pathway was inhibited by decreasing the insulin receptor substrate 1 (IRS1), insulin receptor substrate 2 (IRS2), phosphatidylinositol 3 kinase (PI3K), and glycogen synthesis kinase 3β (GSK-3β) expression levels.

Conclusion: The results show that the ZDF/T2DM rats have typical clinical, histopathological, and molecular characteristics of human T2DM and thus can be used as an effective model for T2DM drug development and treatment of advanced T2DM.

Keywords: Zucker diabetic fatty rats; clinical indicators; histopathology; molecular expression; type 2 diabetes mellitus.

Figure 1

The partial clinical index of each group of rats. A, the daily food intake, daily drinking water consumption and body weight of the T2DM group of rats were higher than that of the control group. B, curves for fasting blood glucose (upper), glucose tolerance test (middle), and insulin tolerance test (bottom) and the AUC analysis. C, serum insulin levels (upper left), insulin resistance index (right upper) and HOMA‐β index (lower left). D, levels of total cholesterol (TC), triglyceride (TG), high‐density lipoprotein (HDL) and low‐density lipoprotein (LDL) in each group of rats. All data are presented as means ± SEM (*P < 0.05; **P < 0.01; ***P < 0.001)

Figure 2

The partial histopathological diagnosis of each group of rats. A, analysis of HE staining in pancreas, liver, and kidney tissues. B, oil red O staining of liver tissue. C, immunohistochemical results showing insulin level of pancreatic tissue. All data are presented as means ± SEM (*P < 0.05; **P < 0.01; ***P < 0.001)

Figure 3

The leptin and adiponectin levels in each group of rats. A, levels of serum leptin. B, expression of plasma adiponnectin. All data are presented as means ± SEM (*P < 0.05; **P < 0.01; ***P < 0.001)

Figure 4

The glycogen contents of liver and muscle tissues were decreased in the T2DM group of rats. The PAS staining analysis demonstrated that the liver glycogen (A) and muscle glycogen (B) contents of the T2DM group were decreased. All data are presented as means ± SEM (*P < 0.05; **P < 0.01; ***P < 0.001)

Figure 5

The expression levels of proteins related to glucose metabolism in the liver and muscle tissues. A, expression levels of IRS1, IRS2, PI3K, and GSK3β were decreased in the liver tissues of T2DM group of rats. B, similarly, the expression levels of IRS1, IRS2, PI3K, and GSK3β were decreased in the muscle tissues of the T2DM group. All data are presented as means ± SEM (*P < 0.05; **P < 0.01; ***P < 0.001)