Warner Shana O, Wadian Abby M, Smith Marta, Farmer Ben, Dai Yufei, Sheanon Nicole, Edgerton Dale S, Winnick Jason J
Department of Internal Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Cincinnati College of Medicine, Cincinnati, Ohio.
Vanderbilt University School of Medicine, Nashville, Tennessee.
Am J Physiol Endocrinol Metab. 2021 May 1;320(5):E914-E924. doi: 10.1152/ajpendo.00501.2020. Epub 2021 Mar 29.
Iatrogenic hypoglycemia is a prominent barrier to achieving optimal glycemic control in patients with diabetes, in part due to dampened counterregulatory hormone responses. It has been demonstrated that elevated liver glycogen content can enhance these hormonal responses through signaling to the brain via afferent nerves, but the role that hypoglycemia in the brain plays in this liver glycogen effect remains unclear. During the first 4 h of each study, the liver glycogen content of dogs was increased by using an intraportal infusion of fructose to stimulate hepatic glucose uptake (HG; = 13), or glycogen was maintained near fasting levels with a saline infusion (NG; = 6). After a 2-h control period, during which the fructose/saline infusion was discontinued, insulin was infused intravenously for an additional 2 h to bring about systemic hypoglycemia in all animals, whereas brain euglycemia was maintained in a subset of the HG group by infusing glucose bilaterally into the carotid and vertebral arteries (HG-HeadEu; = 7). Liver glycogen content was markedly elevated in the two HG groups (43 ± 4, 73 ± 3, and 75 ± 7 mg/g in NG, HG, and HG-HeadEu, respectively). During the hypoglycemic period, arterial plasma glucose levels were indistinguishable between groups (53 ± 2, 52 ± 1, and 51 ± 1 mg/dL, respectively), but jugular vein glucose levels were kept euglycemic (88 ± 5 mg/dL) only in the HG-HeadEu group. Glucagon and epinephrine responses to hypoglycemia were higher in HG compared with NG, whereas despite the increase in liver glycogen, neither increased above basal in HG-HeadEu. These data demonstrate that the enhanced counterregulatory hormone secretion that accompanies increased liver glycogen content requires hypoglycemia in the brain. It is well known that iatrogenic hypoglycemia is a barrier to optimal glycemic regulation in patients with diabetes. Our data confirm that increasing liver glycogen content 75% above fasting levels enhances hormonal responses to insulin-induced hypoglycemia and demonstrate that this enhanced hormonal response does not occur in the absence of hypoglycemia in the brain. These data demonstrate that information from the liver regarding glycogen availability is integrated in the brain to optimize the counterregulatory response.
医源性低血糖是糖尿病患者实现最佳血糖控制的一个突出障碍，部分原因是反调节激素反应受到抑制。已经证明，肝脏糖原含量升高可通过传入神经向大脑发出信号来增强这些激素反应，但大脑中的低血糖在这种肝脏糖原效应中所起的作用仍不清楚。在每项研究的前4小时，通过门静脉输注果糖以刺激肝脏葡萄糖摄取（HG组；n = 13）来增加犬的肝脏糖原含量，或者通过输注生理盐水使糖原维持在接近空腹的水平（NG组；n = 6）。在2小时的对照期（在此期间停止果糖/生理盐水输注）之后，对所有动物静脉输注胰岛素额外2小时以引起全身性低血糖，而通过双侧颈内动脉和椎动脉输注葡萄糖，在HG组的一个亚组中维持大脑血糖正常（HG-HeadEu组；n = 7）。两个HG组的肝脏糖原含量均显著升高（NG组、HG组和HG-HeadEu组分别为43±4、73±3和75±7 mg/g）。在低血糖期，各组之间动脉血浆葡萄糖水平无差异（分别为53±2、52±1和51±1 mg/dL），但仅HG-HeadEu组的颈静脉葡萄糖水平维持在血糖正常水平（88±5 mg/dL）。与NG组相比，HG组对低血糖的胰高血糖素和肾上腺素反应更高，而尽管肝脏糖原增加，但HG-HeadEu组两者均未高于基础水平。这些数据表明，伴随肝脏糖原含量增加的反调节激素分泌增强需要大脑中的低血糖。众所周知，医源性低血糖是糖尿病患者最佳血糖调节的一个障碍。我们的数据证实，将肝脏糖原含量提高到比空腹水平高75%可增强对胰岛素诱导的低血糖的激素反应，并表明在大脑无低血糖的情况下不会出现这种增强的激素反应。这些数据表明，来自肝脏的关于糖原可用性的信息在大脑中整合，以优化反调节反应。
