Relationship between Immunological Abnormalities in Rat Models of Diabetes Mellitus and the Amplification Circuits for Diabetes

Abstract

A better understanding of pathogenic mechanisms is required in order to treat diseases. However, the mechanisms of diabetes mellitus and diabetic complications are extremely complex. Immune reactions are involved in the pathogenesis of diabetes and its complications, while diabetes influences immune reactions. Furthermore, both diabetes and immune reactions are influenced by genetic and environmental factors. To address these issues, animal models are useful tools. So far, various animal models of diabetes have been developed in rats, which have advantages over mice models in terms of the larger volume of tissue samples and the variety of type 2 diabetes models. In this review, we introduce rat models of diabetes and summarize the immune reactions in diabetic rat models. Finally, we speculate on the relationship between immune reactions and diabetic episodes. For example, diabetes-prone Biobreeding rats, type 1 diabetes model rats, exhibit increased autoreactive cellular and inflammatory immune reactions, while Goto-Kakizaki rats, type 2 diabetes model rats, exhibit increased Th2 reactions and attenuation of phagocytic activity. Investigation of immunological abnormalities in various diabetic rat models is useful for elucidating complicated mechanisms in the pathophysiology of diabetes. Studying immunological alterations, such as predominance of Th1/17 or Th2 cells, humoral immunity, and innate immune reactions, may improve understanding the structure of amplification circuits for diabetes in future studies.

Figure 1

Relationships between phagocytosis and CD11b/c and between body weight and CD3 in the G-K/Wistar strains and Zucker strains. (a) Relationship between phagocytic ability and CD11b/c expression levels in G-K/Wistar and Zucker strain rats. (b) Relationship between body weight and CD3 ratio in lymphocytes in G-K/Wistar and Zucker strain rats. Bubble size indicates standard error, and bubble color shows each rat strain as follows: deep blue, ZL; light blue, ZF; green, ZDF; yellow, Wistar; red, G-K. The bubble charts were drawn using Graph-R software, version 2.19.

Figure 2

Pathogenesis of diabetes mellitus in rat models. Dash lines and gray squares indicate the pathogenesis of diabetes in each rat model. DM, diabetes mellitus; Ig, immunoglobulin; TCR, T cell receptor.

Figure 3

Difference in phosphorylation of signal transducers (NF-κB and ERK) in monocytes dependent on diabetes status. The phosphorylation levels of NF-κB and ERK in peripheral blood monocytes were measured by flow cytometry. Peripheral blood was collected from Zucker lean (ZL), Zucker fatty (ZF), Zucker diabetic fatty (ZDF), Wister, or G-K and stimulated with lipopolysaccharide (1 μg/mL). After stimulation for 0 or 10 min, the blood was immediately fixed in Lyse/Fix Buffer (BD Biosciences) and treated with methanol at −20°C for membrane-permeabilization. Next, whole leukocytes in blood were stained with specific antibodies (anti-NF-κB-p60 Abs and anti-ERK Abs from Cell Signaling Technologies). The cells were measured by flow cytometry, and the levels of total or phosphorylated signal transducers in monocytes were analyzed by monocyte-gating. The ratio of phosphorylation to the total was calculated based on the mean of fluorescence intensity. Changes in the phosphorylation levels of NF-κB or ERK are shown in (a) or (b), respectively. Data are the mean ± SE (n = 3). ^∗p < 0.05;  ^∗∗p < 0.01;  ^∗∗∗p < 0.001 (one-way ANOVA with post hoc test using Bonferroni).