Reduction in SGLT1 mRNA Expression in the Ventromedial Hypothalamus Improves the Counterregulatory Responses to Hypoglycemia in Recurrently Hypoglycemic and Diabetic Rats
Reduction in SGLT1 mRNA Expression in the Ventromedial Hypothalamus Improves the Counterregulatory Responses to Hypoglycemia in Recurrently Hypoglycemic and Diabetic Rats
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DOI：
10.2337/db15-0022
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发表时间：
2015-10-01
期刊：
影响因子：
7.7
通讯作者：
Sherwin, Robert
中科院分区：
文献类型：
--
作者：
Fan, Xiaoning;Chan, Owen;Sherwin, Robert
本研究的目的是确定下丘脑腹内侧（VMH）中的钠-葡萄糖转运蛋白SGLT 1是否在葡萄糖感知和调节低血糖的反调节反应中发挥作用，如果是这样，在VMH中敲低SGLT 1是否可以改善糖尿病大鼠或暴露于反复发作的低血糖（RH）的大鼠对低血糖的反调节反应。正常Sprague-Dawley大鼠以及RH或链脲佐菌素（STZ）糖尿病大鼠接受双侧VMH显微注射的腺相关病毒载体含有SGLT 1短发夹RNA（shRNA）或乱序RNA序列。随后，对这些大鼠进行低血糖钳夹以评估激素反应。在一组大鼠中，使用氚化葡萄糖测定葡萄糖动力学。在非糖尿病大鼠中，shRNA使VMH SGLT 1的表达降低了53%，这增强了低血糖期间胰高血糖素和肾上腺素的反应以及肝脏葡萄糖的产生。同样，SGLT 1敲低可改善RH大鼠的胰高血糖素和肾上腺素反应，并恢复STZ糖尿病动物对低血糖的受损肾上腺素反应。这些发现表明，VMH中的SGLT 1在检测和激活低血糖的反调节反应中发挥重要作用。抑制SGLT 1可能提供一个潜在的治疗靶点，以降低糖尿病低血糖的风险。
The objective of this study was to determine whether the sodium-glucose transporter SGLT1 in the ventromedial hypothalamus (VMH) plays a role in glucose sensing and in regulating the counterregulatory response to hypoglycemia, and if so, whether knockdown of in the VMH can improve counterregulatory responses to hypoglycemia in diabetic rats or rats exposed to recurrent bouts of hypoglycemia (RH). Normal Sprague-Dawley rats as well as RH or streptozotocin (STZ)-diabetic rats received bilateral VMH microinjections of an adenoassociated viral vector containing either the SGLT1 short hairpin RNA (shRNA) or a scrambled RNA sequence. Subsequently, these rats underwent a hypoglycemic clamp to assess hormone responses. In a subgroup of rats, glucose kinetics was determined using tritiated glucose. The shRNA reduced VMH SGLT1 expression by 53% in nondiabetic rats, and this augmented glucagon and epinephrine responses and hepatic glucose production during hypoglycemia. Similarly, SGLT1 knockdown improved the glucagon and epinephrine responses in RH rats and restored the impaired epinephrine response to hypoglycemia in STZ-diabetic animals. These findings suggest that SGLT1 in the VMH plays a significant role in the detection and activation of counterregulatory responses to hypoglycemia. Inhibition of SGLT1 may offer a potential therapeutic target to diminish the risk of hypoglycemia in diabetes.