Naloxone, but Not Valsartan, Preserves Responses to Hypoglycemia After Antecedent Hypoglycemia
Naloxone, but Not Valsartan, Preserves Responses to Hypoglycemia After Antecedent Hypoglycemia
复制标题
纳洛酮（而非缬沙坦）在既往低血糖后保留对低血糖的反应
作者：
M. Poplawski;J. Mastaitis;C. Mobbs
目的低血糖相关的自主神经衰竭(Haaf)是影响1型糖尿病最佳治疗的主要临床障碍之一。下丘脑腹内侧的神经元被认为介导了对低血糖的反调节反应。我们先前假设低血糖诱导的下丘脑血管紧张素可能参与HAAF的发生，提示血管紧张素阻滞剂valsartan可能预防HAAF。另一方面，临床研究表明，阿片受体阻滞剂纳洛酮可改善HAAF。这项研究的目的是产生新的下丘脑低血糖标志物，并使用它们来评估介导HAAF及其逆转的机制。研究设计与方法利用定量聚合酶链式反应验证一组新的受低血糖调节的下丘脑基因。小鼠被暴露于一次或五次胰岛素诱导的低血糖，同时或不同时暴露于valsartan或纳洛酮。在低血糖最后一次发作后，评估皮质酮、胰升糖素、肾上腺素和下丘脑基因的表达。结果反复低血糖后，下丘脑中受低血糖强烈调控的基因亚群没有反应。纳洛酮保留了这些基因的一部分的反应性，而valsartan则没有。值得注意的是，包括丙酮酸脱氢酶4和甘油3-磷酸脱氢酶1在内的四个基因在下丘脑中的表达可由单次低血糖引起，但不能在先前的低血糖后诱导；纳洛酮治疗可阻止这一失败。同样，肉碱棕榈酰转移酶-1在反复低血糖后被抑制，这种抑制可被纳洛酮阻止。反复低血糖还导致低血糖引起的糖皮质激素分泌增加，纳洛酮可预防这一失败，但valsartan不能预防。结论根据这些观察结果，我们推测急性低血糖导致下丘脑代谢从糖酵解向β氧化的重编程，HAF与这种重编程的逆转有关，而纳洛酮通过阻止这种逆转而保留了对低血糖的一些反应。
OBJECTIVE Hypoglycemia-associated autonomic failure (HAAF) constitutes one of the main clinical obstacles to optimum treatment of type 1 diabetes. Neurons in the ventromedial hypothalamus are thought to mediate counterregulatory responses to hypoglycemia. We have previously hypothesized that hypoglycemia-induced hypothalamic angiotensin might contribute to HAAF, suggesting that the angiotensin blocker valsartan might prevent HAAF. On the other hand, clinical studies have demonstrated that the opioid receptor blocker naloxone ameliorates HAAF. The goal of this study was to generate novel hypothalamic markers of hypoglycemia and use them to assess mechanisms mediating HAAF and its reversal. RESEARCH DESIGN AND METHODS Quantitative PCR was used to validate a novel panel of hypothalamic genes regulated by hypoglycemia. Mice were exposed to one or five episodes of insulin-induced hypoglycemia, with or without concurrent exposure to valsartan or naloxone. Corticosterone, glucagon, epinephrine, and hypothalamic gene expression were assessed after the final episode of hypoglycemia. RESULTS A subset of hypothalamic genes regulated acutely by hypoglycemia failed to respond after repetitive hypoglycemia. Responsiveness of a subset of these genes was preserved by naloxone but not valsartan. Notably, hypothalamic expression of four genes, including pyruvate dehydrogenase kinase 4 and glycerol 3-phosphate dehydrogenase 1, was acutely induced by a single episode of hypoglycemia, but not after antecedent hypoglycemia; naloxone treatment prevented this failure. Similarly, carnitine palmitoyltransferase-1 was inhibited after repetitive hypoglycemia, and this inhibition was prevented by naloxone. Repetitive hypoglycemia also caused a loss of hypoglycemia-induced elevation of glucocorticoid secretion, a failure prevented by naloxone but not valsartan. CONCLUSIONS Based on these observations we speculate that acute hypoglycemia induces reprogramming of hypothalamic metabolism away from glycolysis toward β-oxidation, HAAF is associated with a reversal of this reprogramming, and naloxone preserves some responses to hypoglycemia by preventing this reversal.
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影响因子：
21.1
作者：
M. Gasparo;K. Catt;T. Inagami;J. Wright;T. Unger
通讯作者：
M. Gasparo;K. Catt;T. Inagami;J. Wright;T. Unger
影响因子：
15.9
作者：
Borg, MA;Sherwin, RS;Shulman, GI
通讯作者：
Shulman, GI
影响因子：
15.9
作者：
Wang, Jun;Ho, Lap;Pasinetti, Giulio Maria
通讯作者：
Pasinetti, Giulio Maria
影响因子：
7.7
作者：
Sandoval, DA;Ertl, AC;Davis, SN
通讯作者：
Davis, SN
影响因子：
15.9
作者：
BORG, WP;DURING, MJ;SHULMAN, GI
通讯作者：
SHULMAN, GI