Diabetes is characterized by rising levels in blood glucose and is often associated with a progressive loss of insulin producing beta cells. Recent studies have demonstrated that it is possible to regenerate new beta cells through proliferation of existing beta cells or trans-differentiation of other cell types into beta cells, raising hope that diabetes can be cured through restoration of functional beta cell mass. Efficient quantification of beta cell mass and islet characteristics is needed to enhance drug discovery for diabetes. Here we report a 3D quantitative imaging platform for unbiased evaluation of changes in islets in mouse models of type I and II diabetes. To determine if the method can detect pharmacologically induced changes in beta cell volume, mice were dosed for 14 days with either vehicle or the insulin receptor antagonist S961 (2.4 nmol/day) using osmotic minipumps. Mice dosed with S961 displayed increased blood glucose and insulin levels. Light sheet imaging of insulin and Ki67-immunostained pancreata revealed a 43% increase in beta cell volume and 21% increase in islet number. S961 treatment resulted in an increase of islets positive for cell proliferation marker Ki-67, suggesting that proliferation of existing beta cells underlies the expansion of total beta cell volume. Using light sheet imaging of non-obese diabetic (NOD) mouse model of type I diabetes we also characterized the infiltration of CD45-labelled leukocytes in islets. At 14 weeks 40% of small islet volume, but more than 80% of large islet show leukocyte infiltration. These results demonstrate how quantitative light sheet imaging can capture changes in individual islets to help pharmacological research in diabetes.

中文翻译：

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I 型和 II 型糖尿病小鼠模型中胰岛变化的 3D 量化。


糖尿病的特点是血糖水平升高，并且通常与产生胰岛素的β细胞的逐渐丧失有关。最近的研究表明，可以通过现有β细胞的增殖或其他细胞类型转分化为β细胞来再生新的β细胞，这增加了通过恢复功能性β细胞团来治愈糖尿病的希望。需要对 β 细胞质量和胰岛特征进行有效量化，以增强糖尿病药物的发现。在这里，我们报告了一个 3D 定量成像平台，用于公正评估 I 型和 II 型糖尿病小鼠模型中胰岛的变化。为了确定该方法是否可以检测药理学诱导的 β 细胞体积变化，使用渗透微型泵给小鼠注射媒介物或胰岛素受体拮抗剂 S961（2.4 nmol/天）14 天。服用 S961 的小鼠表现出血糖和胰岛素水平升高。胰岛素和 Ki67 免疫染色胰腺的光片成像显示，β 细胞体积增加了 43%，胰岛数量增加了 21%。 S961 处理导致细胞增殖标记物 Ki-67 呈阳性的胰岛增加，表明现有 β 细胞的增殖是总 β 细胞体积扩张的基础。利用 I 型糖尿病非肥胖糖尿病 (NOD) 小鼠模型的光片成像，我们还表征了胰岛中 CD45 标记的白细胞的浸润。 14周时，40%的小胰岛体积出现白细胞浸润，但80%以上的大胰岛出现白细胞浸润。这些结果证明了定量光片成像如何捕获单个胰岛的变化，以帮助糖尿病的药理学研究。