Individual Variation in Conditional β Cell Ablation Mice Contributes Significant Biases in Evaluating β Cell Functional Recovery.

Song Lu,Kathy O Lui,Jiatao Li

doi:10.3389/fendo.2017.00242

Song Lu, Kathy O Lui + Show 1 more

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https://doi.org/10.3389/fendo.2017.00242

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Abstract

Despite the βDTA (Ins2-rtTA; Tet-DTA) mice have been developed as a valuable tool to study β cell regeneration, their individual variation in therapeutic efficacy has not been characterized. Here, we demonstrated that the βDTA mice exhibited significant variations in both spontaneous and acquired β cell regeneration. We found that doxycycline (DOX)-induced β cell death was sufficient to cause polydipsia, translating even subtle difference in drinking habit into large variations in actual DOX intake among individuals within the same group. Accumulating evidence shows that transient expression of VEGFA enhances β cell functional recovery after injury. Therefore, we utilized the chemically modified mRNA (modRNA) technology to enable transient yet efficient VEGFA expression in the pancreas after DOX-induced β cell death. Surprisingly, under optimized DOX dose permissive of β cell regeneration, VEGFA modRNA only demonstrated marginal benefits on β cell functional recovery with large individual variations. We also revealed that the therapeutic efficacy of VEGFA modRNA on β cell regeneration was dependent on the degree of β cell loss induced by the accumulated DOX intake. Therefore, our results highlight a significant contribution of individual variation in the βDTA model and call for attention in evaluating potential efficacy of therapeutic agents in β cell regeneration studies.

Highlights

Pancreatic islets are highly vascularized; pancreatic β cells and microvascular endothelial cells (ECs) have an interdependent physical and functional relationship [1]
Because Human VEGFA (hVEGFA) modRNA demonstrated some improvement in glucose tolerance following DOX-induced β cell death; yet there was large variation in β cell mass among individuals within the same group (Figure 4), and we found that the difference in accumulated DOX intake contributed to variation in spontaneous β cell recovery (Figure 5), we hypothesized that the effect of hVEGFA modRNA treatment might be dependent on the accumulated DOX intake
We aimed to establish a model for evaluating the therapeutic potential of VEGFA modRNA in promoting β cell functional recovery after DOX-induced β cell death using the βDTA mice

Summary

Introduction

Pancreatic islets are highly vascularized; pancreatic β cells and microvascular endothelial cells (ECs) have an interdependent physical and functional relationship [1]. Β cells secrete angiogenic factors such as VEGFA to maintain survival and growth of the adjacent pancreatic ECs that facilitate efficient glucose sensing by and transport of secreted insulin from β cells [1, 2]. Membrane proteins, such as laminins [3, 4], collagen [5] and integrins [4, 5] of the vascular basement membrane between pancreatic ECs and β cells, have been shown to stimulate β cell replication and insulin gene expression. Harnessing EC-mediated β cell regeneration may shed light on development of novel therapeutics for treatment of diabetes

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