Loss of function of renal Glut2 reverses hyperglycaemia and normalises body weight in mouse models of diabetes and obesity.
Loss of function of renal Glut2 reverses hyperglycaemia and normalises body weight in mouse models of diabetes and obesity.
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DOI：
10.1007/s00125-022-05676-8
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发表时间：
2022-06
期刊：
影响因子：
8.2
通讯作者：
Chhabra, Kavaljit H.
中科院分区：
文献类型：
--
作者：
Cordeiro, Leticia Maria de Souza;Bainbridge, Lauren;Devisetty, Nagavardhini;McDougal, David H.;Peters, Dorien J. M.;Chhabra, Kavaljit H.
糖尿病患者的肾脏GLUT 2增加，从而增强葡萄糖重吸收并加重高血糖症。在这里，我们确定了在糖尿病和肥胖小鼠模型中，肾脏中特异性Glut 2（也称为Slc 2a 2）的丢失是否会逆转高血糖症并使体重正常化。我们在小鼠中使用他莫昔芬诱导的CreERT 2-Lox系统特异性敲除肾脏中的Glut 2（Ks-Glut 2 KO），以确定肾脏GLUT 2对健康和胰岛素依赖性以及非胰岛素依赖性糖尿病中全身葡萄糖稳态的贡献。我们在不同的实验条件下，在Ks-Glut 2 KO及其对照小鼠中测量了响应于OGTT或IVGTT的循环葡萄糖和胰岛素水平。此外，我们定量尿糖水平来解释小鼠的表型独立于胰岛素作用。我们还使用了转录因子阵列来确定肾脏GLUT 2和钠-葡萄糖协同转运蛋白2（SGLT 2）之间串扰的潜在机制。Ks-Glut 2 KO小鼠表现出改善的葡萄糖耐量和大量糖尿。有趣的是，当我们敲除肝脏和肾脏中的Glut 2时，血糖控制的这种改善被消除，这表明这种改善可归因于肾脏GLUT 2的缺乏。值得注意的是，在糖尿病和肥胖的小鼠模型中，诱导肾Glut 2缺乏逆转了高血糖症和正常体重。肾脏葡萄糖转运蛋白的纵向监测显示，Sglt 2（也称为Slc 5a 2）的表达几乎取消后3周诱导肾Glut 2缺乏。为了确定这种串扰的分子基础，我们筛选了在Ks-Glut 2 KO小鼠中下调的肾转录因子。Hnf 1 α（也称为Hnf 1a）是下调最多的基因之一，其恢复恢复了从Ks-Glut 2 KO小鼠分离的原代肾近端小管细胞中的Sglt 2表达。总之，这些结果证明了肾脏GLUT 2和SGLT 2之间通过葡萄糖重吸收调节全身葡萄糖稳态的新串扰。我们的研究结果还表明，抑制肾脏GLUT 2是糖尿病和肥胖症的潜在治疗方法。
Renal GLUT2 is increased in diabetes, thereby enhancing glucose reabsorption and worsening hyperglycaemia. Here, we determined whether loss of Glut2 (also known as Slc2a2) specifically in the kidneys would reverse hyperglycaemia and normalise body weight in mouse models of diabetes and obesity. We used the tamoxifen-inducible CreERT2-Lox system in mice to knockout Glut2 specifically in the kidneys (Ks-Glut2 KO) to establish the contribution of renal GLUT2 to systemic glucose homeostasis in health and in insulin-dependent as well as non-insulin-dependent diabetes. We measured circulating glucose and insulin levels in response to OGTT or IVGTT under different experimental conditions in the Ks-Glut2 KO and their control mice. Moreover, we quantified urine glucose levels to explain the phenotype of the mice independently of insulin actions. We also used a transcription factor array to identify mechanisms underlying the crosstalk between renal GLUT2 and sodium–glucose cotransporter 2 (SGLT2). The Ks-Glut2 KO mice exhibited improved glucose tolerance and massive glucosuria. Interestingly, this improvement in blood glucose control was eliminated when we knocked out Glut2 in the liver in addition to the kidneys, suggesting that the improvement is attributable to the lack of renal GLUT2. Remarkably, induction of renal Glut2 deficiency reversed hyperglycaemia and normalised body weight in mouse models of diabetes and obesity. Longitudinal monitoring of renal glucose transporters revealed that Sglt2 (also known as Slc5a2) expression was almost abolished 3 weeks after inducing renal Glut2 deficiency. To identify a molecular basis for this crosstalk, we screened for renal transcription factors that were downregulated in the Ks-Glut2 KO mice. Hnf1α (also known as Hnf1a) was among the genes most downregulated and its recovery restored Sglt2 expression in primary renal proximal tubular cells isolated from the Ks-Glut2 KO mice. Altogether, these results demonstrate a novel crosstalk between renal GLUT2 and SGLT2 in regulating systemic glucose homeostasis via glucose reabsorption. Our findings also indicate that inhibiting renal GLUT2 is a potential therapy for diabetes and obesity.
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影响因子：
3.7
作者：
Hohendorff J;Szopa M;Skupien J;Kapusta M;Zapala B;Platek T;Mrozinska S;Parpan T;Glodzik W;Ludwig-Galezowska A;Kiec-Wilk B;Klupa T;Malecki MT
通讯作者：
Malecki MT
DOI：
10.3791/57718
发表时间：
2018-06-20
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Ding W;Yousefi K;Shehadeh LA
通讯作者：
Shehadeh LA
影响因子：
4.1
作者：
Freitas, H. S.;Schaan, B. D.;Machado, U. F.
通讯作者：
Machado, U. F.
影响因子：
4.8
作者：
Chin, E;Zamah, AM;Bondy, CA
通讯作者：
Bondy, CA
影响因子：
--
作者：
DOMINGUEZ, JH;CAMP, K;GARVEY, WT
通讯作者：
GARVEY, WT