Pathophysiological Mechanisms That Alter the Autonomic Brain-Liver Communication in Metabolic Diseases

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  Figure 1.. Potential mechanisms contributing to hepatic diabetic neuropathy. A, The SAR pathway and oxidative stress. Hyperglycemia can promote sorbitol accumulation in cells, leading to oxidative stress. This in turn can lead to microvascular damages and neuropathy. B, Hyperglycemia-induced glycation. Glycation of proteins can alter their structure and function, leading to the production of AGEs. Through their action on RAGE, AGEs contribute to oxidative stress and inflammation. This results in alterations in neuronal functions and peripheral neuropathy. C, Inflammation. Neuropathy has been associated with increased pro-inflammatory cytokines. Abbreviations: AGEs, advanced glycation end products; RAGE, receptor for AGEs; SAR, sorbitol-aldose reductase; SORD, sorbitol dehydrogenase; TNFα, tumor necrosis factor α.

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  Figure 2.. Bimodal hypothesis of the autonomic control of liver during metabolic diseases. We hypothesize that obesity and type 2 diabetes may first lead to increased sympathetic outflow to the liver, followed by a progressive decrease in the number of hepatic sympathetic fibers and ultimately the development of hepatic neuropathy. Therefore, autonomic control of liver during metabolic diseases is a “moving target” and a better understanding the chronology of autonomic dysfunctions in the liver may help applying the right strategy at the right time. Preventing sympathetic overactivity early on may be a viable strategy to prevent the development of metabolic complications.