Hypoglycemia-associated autonomic failure (HAAF) is a maladaptive failure in glucose counterregulation in persons with diabetes (PWD) that is caused by recurrent exposure to hypoglycemia. The adipokine leptin is known to regulate glucose homeostasis, and leptin levels fall following exposure to recurrent hypoglycemia. Yet, little is known regarding how reduced leptin levels influence glucose counterregulation, or if low leptin levels are involved in the development of HAAF. The purpose of this study was to determine the effect of hypoleptinemia on the neuroendocrine responses to hypoglycemia. We utilized two separate experimental paradigms known to induce a hypoleptinemic state: 60% caloric restriction (CR) in mice and three days of recurrent hypoglycemia (3dRH) in rats. A sub-set of animals were also treated with leptin (0.5–1.0 μg/g) during the CR or 3dRH periods. Neuroendocrine responses to hypoglycemia were assessed 60 min following an IP insulin injection on the terminal day of the paradigms. CR mice displayed defects in hypoglycemic counterregulation, indicated by significantly lower glucagon levels relative to controls, 13.5 pmol/L (SD 10.7) versus 64.7 pmol/L (SD 45) (p = 0.002). 3dRH rats displayed reduced epinephrine levels relative to controls, 1900 pg/mL (SD 1052) versus 3670 pg/mL (SD 780) (p = 0.030). Remarkably, leptin treatment during either paradigm completely reversed this effect by normalizing glucagon levels in CR mice, 78.0 pmol/L (SD 47.3) (p = 0.764), and epinephrine levels in 3dRH rats, 2910 pg/mL (SD 1680) (p = 0.522). These findings suggest that hypoleptinemia may be a key signaling event driving the development of HAAF and that leptin treatment may prevent the development of HAAF in PWD.

低血糖相关自主神经衰竭 (HAAF) 是糖尿病 (PWD) 患者因反复暴露于低血糖而导致的葡萄糖反调节的不适应失败。已知脂肪因子瘦素可调节葡萄糖稳态，并且瘦素水平在暴露于复发性低血糖后下降。然而，关于瘦素水平降低如何影响葡萄糖反调节，或者低瘦素水平是否参与 HAAF 的发展，我们知之甚少。本研究的目的是确定低瘦素血症对神经内分泌对低血糖反应的影响。我们利用了两个独立的实验范例，已知它们会诱发低瘦素血症状态：小鼠 60% 热量限制 (CR) 和大鼠三天反复低血糖 (3dRH)。一组动物也用瘦素（0.5-1. 0 μg/g）在 CR 或 3dRH 期间。在范式的最后一天，在 IP 胰岛素注射后 60 分钟评估对低血糖的神经内分泌反应。CR 小鼠表现出低血糖反调节缺陷，表现为胰高血糖素水平相对于对照组显着降低，分别为 13.5 pmol/L (SD 10.7) 和 64.7 pmol/L (SD 45) (p  = 0.002)。与对照组相比，3dRH 大鼠的肾上腺素水平降低，分别为 1900 pg/mL (SD 1052) 和 3670 pg/mL (SD 780) ( p  = 0.030)。值得注意的是，瘦素治疗在任一范例中通过使 CR 小鼠的胰高血糖素水平正常化，78.0 pmol/L (SD 47.3) ( p  = 0.764) 和 3dRH 大鼠的肾上腺素水平，2910 pg/mL (SD 1680) ( p  = 0.522）。这些发现表明，低瘦素血症可能是推动 HAAF 发展的关键信号事件，瘦素治疗可能会阻止 PWD 中 HAAF 的发展。