Acid Loading Unmasks Glucose Homeostatic Instability in Proximal-Tubule-Targeted Insulin/Insulin-Like-Growth-Factor-1 Receptor Dual Knockout Mice.
Acid Loading Unmasks Glucose Homeostatic Instability in Proximal-Tubule-Targeted Insulin/Insulin-Like-Growth-Factor-1 Receptor Dual Knockout Mice.
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DOI：
10.33594/000000248
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发表时间：
2020-07-18
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影响因子：
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通讯作者：
Ecelbarger, Carolyn M
中科院分区：
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作者：
Aljaylani, Abdullah;Fluitt, Maurice;Ecelbarger, Carolyn M
背景/目的：代谢综合征和2型糖尿病与一定程度的酸中毒有关。酸中毒也被证明可以上调肾脏的新生血管。受损的胰岛素或胰岛素样生长因子1受体（IGF 1）信号传导是否改变了这种关系尚不清楚。我们的目的是确定从肾近端小管（PT）中删除胰岛素和IGF 1受体（Insr和Igf 1 r）对酸中毒的致炎性反应的影响。方法：我们通过用γ-谷氨酰转移酶（gGT）启动子驱动Cre重组酶，建立了PT靶向Insr/Igf 1 r双敲除（KO）的小鼠模型。雄性和雌性小鼠作为对照组或酸中毒的治疗NH 4Cl在饮用水1 week.RESULTS：酸中毒在两种基因型增加磷酸烯醇式丙酮酸羧激酶（PEPCK）和果糖-1-二磷酸酶（FBP 1），但不是葡萄糖-6-磷酸酶催化亚基（G6 PC），这表明显着降低表达的KO，无论治疗。KO和WT之间的几个差异表明，胰岛素/IGF 1受体信号传导在面对酸中毒时维持相对正常的保护作用。首先，在KO中，FBP 1随酸的增加更大（显著相互作用项）。其次，近端小管相关的FOXO 1和AKT总蛋白水平被KO中的酸负荷抑制，但在WT中没有。需要稳健的完整胰岛素信号传导来减少PT中的胰岛素生成。第三，KO PT中的磷酸化FOXO 1（pS256）水平因酸负荷而显着降低，但WT中则不然。这种减少将支持更大的再生。第四，钠-葡萄糖协同转运蛋白（SGLT 1）在KO肾脏中因酸负荷而增加，但WT没有。虽然这不一定会影响肾脏再生，但可能会通过肾脏重吸收导致循环葡萄糖增加。WT中对葡萄糖稳态失调的敏感性降低可能与肾脏sirtuin-1（SIRT 1）水平的急剧（超过50%）降低有关，SIRT 1可使许多基因脱乙酰化并调节转录。结论：肾脏的胰岛素抵抗可能增加全身葡萄糖不稳定性，这是糖尿病发病的主要危险因素。高膳食酸负荷为肾脏提供了一个困境，因为氨生成释放α-酮戊二酸，这是一种代谢的底物。我们证明了胰岛素和/或IGF 1受体信号在PT中的重要作用，以促进这一过程并减少血糖波动。因此，改善肾脏胰岛素敏感性的药物和生活方式的改变也可能为2型糖尿病提供额外的益处，特别是当与代谢性酸中毒相结合时。
BACKGROUND/AIMS: Metabolic syndrome and type 2 diabetes are associated with some degree of acidosis. Acidosis has also been shown to upregulate renal gluconeogenesis. Whether impaired insulin or insulin-like-growth factor 1 receptor (IGF1) signaling alter this relationship is not known. Our aim was to determine the effects of deletion of insulin and IGF1 receptors (Insr and Igf1r) from renal proximal tubule (PT) on the gluconeogenic response to acidosis.METHODS: We developed a mouse model with PT-targeted dual knockout (KO) of the Insr/Igf1r by driving Cre-recombinase with the gamma-glutamyl transferase (gGT) promoter. Male and female mice were maintained as control or acidotic by treatment with NH4Cl in the drinking water for 1-week.RESULTS: Acidosis in both genotypes increased renal expression of phosphoenolpyruvate carboxykinase (PEPCK) and fructose-1-bisphosphatase (FBP1), but not glucose-6-phosphatase catalytic subunit (G6PC), which showed significantly lower expression in the KO regardless of treatment. Several differences between KO and WT suggested a protective role for insulin/IGF1 receptor signaling in maintaining relative euglycemia in the face of acidosis. First, the increase in FBP1 with acid was greater in the KO (significant interactive term). Secondly, proximal-tubule-associated FOXO1 and AKT overall protein levels were suppressed by acid loading in the KO, but not in the WT. Robust intact insulin signaling would be needed to reduce gluconeogenesis in PT. Third, phosphorylated FOXO1 (pS256) levels were markedly reduced by acid loading in the KO PT, but not in the WT. This reduction would support greater gluconeogenesis. Fourth, the sodium-glucose cotransporter (SGLT1) was increased by acid loading in the KO kidney, but not the WT. While this would not necessarily affect gluconeogenesis, it could result in increased circulatory glucose via renal reabsorption. Reduced susceptibility to glucose-homeostatic dysregulation in the WT could potentially relate to the sharp (over 50%) reduction in renal levels of sirtuin-1 (SIRT1), which deacetylates and regulates transcription of a number of genes. This reduction was absent in the KO.CONCLUSION: Insulin resistance of the kidney may increase whole-body glucose instability a major risk factor for morbidity in diabetes. High dietary acid loads provide a dilemma for the kidney, as ammoniagenesis liberates alpha-ketoglutarate, which is a substrate for gluconeogenesis. We demonstrate an important role for insulin and/or IGF1 receptor signaling in the PT to facilitate this process and reduce excursions in blood glucose. Thus, medications and lifestyle changes that improve renal insulin sensitivity may also provide added benefit in type 2 diabetes especially when coupled with metabolic acidosis.