Sympathetic Denervation of the Common Hepatic Artery Lessens Glucose Intolerance in the Fat- and Fructose-Fed Dog

Abstract

This study assessed the effectiveness of surgical sympathetic denervation of the common hepatic artery (CHADN) in improving glucose tolerance. CHADN eliminated norepinephrine content in the liver and partially decreased it in the pancreas and the upper gut. We assessed oral glucose tolerance at baseline and after 4 weeks of high-fat high-fructose (HFHF) feeding. Dogs were then randomized to sham surgery (SHAM) (n = 9) or CHADN surgery (n = 11) and retested 2.5 or 3.5 weeks later while still on the HFHF diet. CHADN improved glucose tolerance by ∼60% in part because of enhanced insulin secretion, as indicated by an increase in the insulinogenic index. In a subset of dogs (SHAM, n = 5; CHADN, n = 6), a hyperinsulinemic-hyperglycemic clamp was used to assess whether CHADN could improve hepatic glucose metabolism independent of a change in insulin release. CHADN reduced the diet-induced defect in net hepatic glucose balance by 37%. In another subset of dogs (SHAM, n = 4; CHADN, n = 5) the HFHF diet was continued for 3 months postsurgery and the improvement in glucose tolerance caused by CHADN continued. In conclusion, CHADN has the potential to enhance postprandial glucose clearance in states of diet-induced glucose intolerance.

Safety of surgical denervation of the common hepatic artery in insulin‐resistant dogs

“…The HFHF-fed dog model has been used widely to study glucose intolerance. Our goal here was to take dogs which had developed this defect and examine the impact of CHADN versus SHAM to improve glucose metabolism (Kraft et al, 2019), and at the same time examine the impact of CHADN versus SHAM on the response to hypoglycemia. However, the present study did not investigate the effect of HFHF on the hypoglycemic response compared to animals fed chow.…”

“…glucose tolerance test in dogs with diet-induced glucose intolerance (Kraft et al, 2019). The success of CHADN and other metabolic surgeries in improving glucose intolerance, however, raises the question of whether eliminating sympathetic nervous input to the liver alters hepatic responsiveness to insulin or predisposes to low blood sugar leading to a greater risk of iatrogenic hypoglycemia.…”

“…The success of CHADN and other metabolic surgeries in improving glucose intolerance, however, raises the question of whether eliminating sympathetic nervous input to the liver alters hepatic responsiveness to insulin or predisposes to low blood sugar leading to a greater risk of iatrogenic hypoglycemia. The data in this paper come from a study that assessed efficacy and safety, the former was already published (Kraft et al, 2019). Given the ability of the procedure to reverse glucose intolerance caused by high-fat high-fructose (HFHF) feeding, it is essential to show that the procedure is also safe.…”

“…Further, the release of key counterregulatory hormones is also under the control of the central nervous system (CNS). When the common hepatic artery is surgically denervated, the sympathetic tone to the liver is decreased, but as we recently showed sympathetic tone to the pancreas is also partially decreased (as evident by the lower norepinephrine (NE) content in the pancreas) (Kraft et al, 2019). It remains unclear what effect CHADN has on the response of the α cell, the CNS, and the liver in response to a hypoglycemic challenge.…”

“…We studied the efficacy and safety of the technique in parallel, thereby reducing the number of dogs required. The efficacy data have been published (Kraft et al, 2019) and the safety data are presented here.…”