Kraft Guillaume, Scott Melanie, Allen Eric, Edgerton Dale S, Farmer Ben, Azamian Bobak R, Cherrington Alan D
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, TN, USA.
Hormone Assay and Analytical Services Core, Vanderbilt University Medical Center, Nashville, TN, USA.
Physiol Rep. 2021 Mar;9(6):e14805. doi: 10.14814/phy2.14805.
The objective of this study was to assess the safety of surgical common hepatic artery denervation (CHADN). This procedure has previously been shown to improve glucose tolerance in dogs fed a high-fat high-fructose (HFHF) diet. We assessed the hypoglycemic response of dogs by infusing insulin at a constant rate (1.5 mU/kg/min) for 3 h and monitoring glucose and the counterregulatory hormones (glucagon, catecholamine, and cortisol). After an initial hypoglycemic study, the dogs were randomly assigned to a SHAM surgery (n = 4) or hepatic sympathetic denervation (CHADN, n = 5) and three follow-up studies were performed every month up to 3 months after the surgery. The level of norepinephrine (NE) in the liver and the pancreas was significantly reduced in the CHADN dogs, showing a decrease in sympathetic tone to the splanchnic organs. There was no evidence of any defect of the response to hypoglycemia after the CHADN surgery. Indeed, the extent of hypoglycemia was similar in the SHAM and CHADN groups (45 mg/dl) for the same amount of circulating insulin (50 µU/ml) regardless of time or surgery. Moreover the responses of the counterregulatory hormones were similar in extent and pattern during the 3 h of hypoglycemic challenge. Circulating lactate, glycerol, free fatty acids, and beta-hydroxybutyrate were also unaffected by CHADN during fasting conditions or during the hypoglycemia. There were no other notable surgery-induced changes over time in nutrients, minerals, and hormones clinically measured in the dogs nor in the blood pressure and heart rate of the animals. The data suggest that the ablation of the sympathetic nerve connected to the splanchnic bed is not required for a normal counterregulatory response to insulin-induced hypoglycemia and that CHADN could be a safe new therapeutic intervention to improve glycemic control in individuals with metabolic syndrome or type 2 diabetes.
本研究的目的是评估外科手术性肝总动脉去神经支配（CHADN）的安全性。此前已证明该手术可改善高脂高果糖（HFHF）饮食喂养的犬的糖耐量。我们通过以恒定速率（1.5 mU/kg/分钟）输注胰岛素3小时并监测血糖和反调节激素（胰高血糖素、儿茶酚胺和皮质醇）来评估犬的低血糖反应。在进行初步的低血糖研究后，将犬随机分为假手术组（n = 4）或肝交感神经去神经支配组（CHADN，n = 5），并在手术后每月进行三次随访研究，直至术后3个月。CHADN犬肝脏和胰腺中的去甲肾上腺素（NE）水平显著降低，表明内脏器官的交感神经张力降低。CHADN手术后没有证据表明对低血糖的反应存在任何缺陷。实际上，无论时间或手术情况如何，对于相同量的循环胰岛素（约50 μU/ml），假手术组和CHADN组的低血糖程度相似（约45 mg/dl）。此外，在3小时的低血糖挑战期间，反调节激素的反应在程度和模式上相似。在禁食状态或低血糖期间，循环中的乳酸、甘油、游离脂肪酸和β-羟基丁酸也不受CHADN的影响。随着时间的推移，在犬临床测量的营养物质、矿物质和激素方面，以及动物的血压和心率方面，没有其他明显的手术诱导变化。数据表明，对于胰岛素诱导的低血糖的正常反调节反应，不需要切断与内脏床相连的交感神经，并且CHADN可能是一种安全的新治疗干预措施，可改善代谢综合征或2型糖尿病患者的血糖控制。
