Interindividual Heterogeneity of SGLT2 Expression and Function in Human Pancreatic Islets
Interindividual Heterogeneity of SGLT2 Expression and Function in Human Pancreatic Islets
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DOI：
10.2337/db19-0888
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发表时间：
2020-05-01
期刊：
影响因子：
7.7
通讯作者：
Bonner, Caroline
中科院分区：
文献类型：
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作者：
Saponaro, Chiara;Muhlemann, Markus;Bonner, Caroline
涉及钠-葡萄糖协同转运蛋白2（SGLT 2）抑制剂影响胰腺α细胞胰高血糖素分泌的研究报告了有争议的结果。我们假设SGLT 2表达和调节的个体间异质性可能影响人α细胞对SGLT 2抑制剂的胰高血糖素分泌。对207名供体的无偏RNA测序分析显示，SLC 5A 2表达的异质性达到了前所未有的水平。为了在蛋白质水平上确定SGLT 2表达的异质性，首先严格评估抗SGLT 2抗体的特异性，然后分别对10名和12名供体的胰岛进行Western印迹和免疫荧光分析。结果显示，SGLT 2蛋白表达的供体间变异性较高。对665个人胰岛的定量分析显示，SGLT 2蛋白与胰高血糖素显著共定位，但与胰岛素或生长抑素不共定位。此外，在低葡萄糖（1 mmol/L）下，31名供体胰岛的胰高血糖素分泌也是异质性的，并且与6 mmol/L葡萄糖下达格列净诱导的胰高血糖素分泌相关。有趣的是，来自3名供体的胰岛对1 mmol/L葡萄糖或达格列净均不分泌胰高血糖素，表明这些供体的胰岛对葡萄糖感知和SGLT 2抑制的功能受损。总的来说，这些数据表明SGLT 2蛋白的异质性表达和胰高血糖素分泌反应的变异性有助于对SGLT 2抑制剂反应的个体间差异。
Studies implicating sodium-glucose cotransporter 2 (SGLT2) inhibitors in glucagon secretion by pancreatic alpha-cells reported controversial results. We hypothesized that interindividual heterogeneity in SGLT2 expression and regulation may affect glucagon secretion by human alpha-cells in response to SGLT2 inhibitors. An unbiased RNA-sequencing analysis of 207 donors revealed an unprecedented level of heterogeneity of SLC5A2 expression. To determine heterogeneity of SGLT2 expression at the protein level, the anti-SGLT2 antibody was first rigorously evaluated for specificity, followed by Western blot and immunofluorescence analysis on islets from 10 and 12 donors, respectively. The results revealed a high interdonor variability of SGLT2 protein expression. Quantitative analysis of 665 human islets showed a significant SGLT2 protein colocalization with glucagon but not with insulin or somatostatin. Moreover, glucagon secretion by islets from 31 donors at low glucose (1 mmol/L) was also heterogeneous and correlated with dapagliflozin-induced glucagon secretion at 6 mmol/L glucose. Intriguingly, islets from three donors did not secrete glucagon in response to either 1 mmol/L glucose or dapagliflozin, indicating a functional impairment of the islets of these donors to glucose sensing and SGLT2 inhibition. Collectively, these data suggest that heterogeneous expression of SGLT2 protein and variability in glucagon secretory responses contribute to interindividual differences in response to SGLT2 inhibitors.