Hepatic glycogen can regulate hypoglycemic counterregulation via a liver-brain axis
Jason J. Winnick, … , Eric Allen, Alan D. Cherrington
Jason J. Winnick, … , Eric Allen, Alan D. Cherrington
Published May 3, 2016
Citation Information: J Clin Invest. 2016;126(6):2236-2248. https://doi.org/10.1172/JCI79895.
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Research Article Metabolism

Hepatic glycogen can regulate hypoglycemic counterregulation via a liver-brain axis

Abstract

Liver glycogen is important for the counterregulation of hypoglycemia and is reduced in individuals with type 1 diabetes (T1D). Here, we examined the effect of varying hepatic glycogen content on the counterregulatory response to low blood sugar in dogs. During the first 4 hours of each study, hepatic glycogen was increased by augmenting hepatic glucose uptake using hyperglycemia and a low-dose intraportal fructose infusion. After hepatic glycogen levels were increased, animals underwent a 2-hour control period with no fructose infusion followed by a 2-hour hyperinsulinemic/hypoglycemic clamp. Compared with control treatment, fructose infusion caused a large increase in liver glycogen that markedly elevated the response of epinephrine and glucagon to a given hypoglycemia and increased net hepatic glucose output (NHGO). Moreover, prior denervation of the liver abolished the improved counterregulatory responses that resulted from increased liver glycogen content. When hepatic glycogen content was lowered, glucagon and NHGO responses to insulin-induced hypoglycemia were reduced. We conclude that there is a liver-brain counterregulatory axis that is responsive to liver glycogen content. It remains to be determined whether the risk of iatrogenic hypoglycemia in T1D humans could be lessened by targeting metabolic pathway(s) associated with hepatic glycogen repletion.

Authors

Jason J. Winnick, Guillaume Kraft, Justin M. Gregory, Dale S. Edgerton, Phillip Williams, Ian A. Hajizadeh, Maahum Z. Kamal, Marta Smith, Ben Farmer, Melanie Scott, Doss Neal, E. Patrick Donahue, Eric Allen, Alan D. Cherrington

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Figure 1

Schematic representation of the study.

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Schematic representation of the study. During the glycogen-manipulation ...
During the glycogen-manipulation period, most (see explanation below) animals underwent a hyperglycemic-pancreatic clamp where both insulin and glucagon were replaced at basal levels with an intraportal (Po) infusion of the hormones and glucose was clamped using a peripheral (Pe) infusion of dextrose. One group received an intraportal infusion of saline (Gly), and a second group received an intraportal infusion of fructose to increase liver glycogen content (Gly++). The glycogen-loading period (pd) was followed by a 2-hour control period where the respective infusions of either saline or fructose were discontinued and then a 2-hour hypoglycemic/hyperinsulinemic experimental period during which counterregulatory responses were assessed. The GlyMatch group did not have increased liver glycogen content, but glucagon and epinephrine were infused during the hypoglycemic period to match those seen in the Gly++ group. The role of hepatic afferent nerves in the increased counterregulatory hormone levels seen as a result of increased liver glycogen content was assessed in the Gly++DEN group. To determine the effect of a decrease in liver glycogen on hypoglycemic counterregulation, another group of animals received a variable intraportal glucagon infusion during the glycogen-manipulation period (Gly– –). Finally, to determine the role of fructose per se on the responses to insulin-induced hypoglycemia, the sugar was infused into either the carotid and vertebral arteries of the head (GlyHeadFru), or it was infused intraportally under euglycemic conditions (GlyPoFru).