Risk of postprandial insulin resistance: the liver/vagus rapport

Abstract

Ingestion of a meal is the greatest challenge faced by glucose homeostasis. The surge of nutrients has to be disposed quickly, as high concentrations in the bloodstream may have pathophysiological effects, and also properly, as misplaced reserves may induce problems in affected tissues. Thus, loss of the ability to adequately dispose of ingested nutrients can be expected to lead to glucose intolerance, and favor the development of pathologies. Achieving interplay of several organs is of upmost importance to maintain effectively postprandial glucose clearance, with the liver being responsible of orchestrating global glycemic control. This dogmatic role of the liver in postprandial insulin sensitivity is tightly associated with the vagus nerve. Herein, we uncover the behaviour of metabolic pathways determined by hepatic parasympathetic function status, in physiology and in pathophysiology. Likewise, the inquiry expands to address the impact of a modern lifestyle, especially one's feeding habits, on the hepatic parasympathetic nerve control of glucose metabolism.

Figure 1

The postprandial livercentric hypothesis interplays the relationship of organs and how the liver acts as a maestro for the regulation of plasma glucose levels and of insulin sensitivity. The gut responds to a meal by realizing hormones and by activating the vagus to the hypothalamus. Thereafter, efferent vagus nerve signalling can be triggered by sensing metabolic alterations in the brainstem and the hypothalamus regulating hepatic glucose production glycogen synthesis as well as pancreatic endocrine function (insulin). The liver is subsequently responsible for insulin clearance, regulating the levels of the hormone that reaches the periphery. Vagal activation to the liver in the postprandial state allows hormonal communications from the liver to skeletal muscle, heart, and kidney to increment glucose clearance by these organs.

Figure 2

This figure depicts the postprandial percentage of glucose clearance in whole-body tissue distribution. (A) The total amount of glucose cleared by tissues after a meal in control animals and after hepatic parasympathetic denervation. In control-animal skeletal muscle glucose clearance, adipose tissue and liver accounts for 69% and 7%, respectively. The parasympathetic hepatic denervation major effect was on skeletal muscle, decreasing glucose clearance to 38%. Other tissues, almost certainly the brain, account for 16% of postprandial glucose clearance and remained unchanged after hepatic parasympathetic denervation. (B) Hepatic parasympathetic nerves affect postprandial glucose disposal at kidney, heart, and skeletal muscle, accounting for 67%, 35%, and 45% of glucose clearance, respectively.

Figure 3

Proposed mechanism for the increment of insulin-dependent glucose disposal following a mixed meal. Intestinal absorption of glucose and amino acids, following ingestion of a mixed meal containing carbohydrates and proteins, leads to pancreatic insulin secretion, which acts in peripheral tissues—skeletal muscle—to promote glucose uptake. Additionally, absorbed glucose and amino acids also induce the release of serotonin (5-HT) from enterochromaffin cells, which activates parasympathetic afferent terminals and triggers a centrally-mediated parasympathetic reflex that results in nitric oxide (NO) production in hepatocytes. Finally, this efferent hepatic parasympathetic-dependent NO, along with increased hepatic glutathione (GSH) synthesis resulting from amino-acid absorption, potentiate insulin action in peripheral tissues, resulting in higher glucose uptake and concomitant reduction of postprandial glucose excursion. GI, gastrointestinal; 5-HT, serotonin; CNS, central nervous system; Cys, cysteine.