The vagus nerve, part of the parasympathetic nervous system, is a mixed nerve composed of both sensory afferents and motor efferents. Vagal afferents relay information from peripheral tissues such as the stomach and intestine to the nucleus of the solitary tract (NTS). Neurons from the NTS descend in a topographical manner into the dorsal motor nucleus of the vagus (DMV). At the onset of, and during food ingestion, descending pre-ganglionic vagal efferent neurons from the DMV are activated and stimulate post-ganglionic neurons which release acetylcholine on target tissues including the pancreas and liver, two tissues critically involved in the regulation of blood glucose (). In the pancreas, the vagal efferents terminate on intrapancreatic neurons which release acetylcholine as well as other peptides such as vasointestinal peptide. To elicit insulin secretion (113
), acetylcholine binds to M3
muscarinic receptors and activates phospholipase C resulting in hydrolysis of phosphoinositides (114
). This intracellular pathway is activated by acetylcholine and carbachol, a muscarinic agonist and inhibited by atropine, the muscarinic antagonist. Acetylcholine enhances insulin secretion to glucose (113
) and conditions leading to desensitization of insulin release to glucose have been associated with increased sensitivity to acetylcholine in pancreatic islets (116
). Conversely, elevated free fatty acids postulated in the etiology of insulin resistance, can inhibit the stimulatory effect of acetylcholine on insulin release from pancreatic islets (118
). Olanzapine and clozapine have been shown to inhibit inositol phosphate accumulation and insulin secretion to carbachol in pancreatic islets, demonstrating functionally significant consequences of M3
binding by the AAPs (119
Role of the Vagus Nerve in Glucose Homeostasis.
In healthy humans, vagal efferent activation only takes place during food ingestion as the sensory properties of food stimulate receptors in the oral cavity. The sensory properties of food can elicit a small insulin response, termed the cephalic phase insulin response, that is dependent on vagal efferent activation, and occurs prior to nutrient absorption in the first 10 minutes of food ingestion or just by tasting and chewing food (120
). Increases in cephalic phase insulin release (CPIR) indicate that vagal efferent activation has occurred. When glucose is administered directly into the stomach via a nasogastric tube, there is no CPIR since vagal efferent stimulation of insulin release does not take place (122
). Under these conditions, post-prandial glucose levels are 30% greater than when food is tasted simultaneously to gastric administration alone. Similarly, when glucose is administered intravenously (IV), there is no vagal efferent contribution to insulin secretion as demonstrated by a lack of effect of administration of the muscarinic antagonist atropine on insulin secretion (123
). Understanding the conditions by which vagal efferent activation takes place, is crucial for interpreting the results of experiments assessing the vagal contribution to various physiological responses. For example, trying to reveal the effect of an intervention (i.e. AAP administration) on a vagally-mediated response such as insulin release will be ineffective using the established methodologies for assessing insulin secretion and insulin sensitivity which involve IV glucose administration. A vagal efferent contribution to insulin secretion after IV glucose only takes place during conditions requiring compensatory insulin secretion such as would occur during over-feeding or as we have shown during prolonged stimulation of the pancreatic b-cell with a 48-h glucose infusion (123
). Under these conditions, there is an induction of vagal efferent activity which contributes to the increase in insulin required to maintain glucose homeostasis.
The vagus nerve also plays a role in the regulation of hepatic glucose production. In studies published more than 30 years ago, Shimazu demonstrated that electrical stimulation of the vagus inhibits glycogenolysis (125
) and increases activity of enzymes involved in glycogen synthesis (126
). When acetylcholine is administered directly into the portal vein of dogs (127
) and streptozotocin-diabetic rats, net hepatic glucose uptake is increased (128
). Furthermore, both vagotomy and atropine increase hepatic glucose output (129
). The importance of vagal mediation of hepatic glucose production has been elegantly verified by the demonstration that activation of ATP-dependent potassium channels in the hypothalamus lowers peripheral blood glucose levels by inhibition of hepatic glucose output (130
). This effect can be blocked by surgical resection of the hepatic branch of the vagus nerve, resulting in an increase in hepatic glucose production. In humans, administration of the muscarinic agonist, bethanechol decreases hepatic glucose production, confirming the functionality of muscarinic activation in mediating hepatic glucose production (131
). While these many physiological experiments support an important role for vagal innervation of the liver, it is still not clear where the neurons terminate and which receptors mediate the reported effects.
Inhibition of vagally-mediated responses such as the enhancement of insulin secretion and inhibition of endogenous glucose production by an AAP with a high muscarinic antagonism would contribute to a pre-diabetic profile of impaired post-prandial insulin release and increased endogenous glucose production, two hallmarks of diabetes. While these outcomes may be the ultimate consequence of chronic AAP administration on a background of increased weight gain and body adiposity as well as increased levels of circulating lipids, we postulate that short-term administration of some of the AAPs, such as olanzapine may initially result in an increase in vagally-mediated insulin release due to two factors: 1) increased food intake which would repetitively stimulate vagal efferent activity and 2) a compensatory increase in central vagal efferent activity due to peripheral blockade of muscarinic receptors (). Preliminary data from our laboratory indicates that short-term administration of olanzapine to healthy men results in significant increases in cephalic phase insulin release as well as post-prandial hyperinsulinemia. The hyperinsulinemia occurs independent of weight gain and accompanied by only very modest insulin resistance such has been reported previously (132
). To date, only two studies have examined the effect of olanzapine or other AAPs such as risperidone on post-prandial hormonal release. In one study, blood sampling only took place every 2 hours which was insufficient to document changes in post-prandial responses (65
) while in another, where short and long-acting olanzapine were compared, the effects of the drugs on insulin were not reported although no significant differences in other hormones such as glucagon-like peptide were found (133
). As discussed above, only meal ingestion could reveal whether there was an enhancement or deficit in vagally-mediated responses. We postulate that the increase in post-prandial insulin will drive the deposition of nutrients thereby contributing to weight gain. In addition to a direct effect on the pancreatic b-cell, the AAPs may target hepatic lipid synthesis and storage. Early changes in plasma lipids and modest insulin resistance have been reported after short periods of AAP administration, primarily olanzapine, to healthy individuals (68
). The magnitude of decrease in insulin sensitivity is relatively small after a 9–14 day period of administration and it is unlikely that this is mediated through muscle insulin resistance. A more plausible hypothesis is that there are direct effects of the AAPs on hepatic glucose and lipid metabolism as well as on the pancreas.
Acute Effects of Atypical Antipsychotic Administration to Humans
As body adiposity accumulates, the known effects of weight gain are manifested: elevated triglycerides, increased free fatty acids, elevated levels of plasma glucose and insulin. Thus, chronic AAP treatment is now being administered on a background of the metabolic syndrome phenotype. Many of the diagnostic components of the metabolic syndrome overlap with those potentially induced by AAP administration. Thus, weight gain will exacerbate the acute AAP-induced metabolic impairments and in some individuals, may eventually result in overt diabetes. Long term administration of the AAP may eventually result in down-regulation of receptors or desensitization to the antagonist effects of the drugs. It is not know whether the stimulatory effect of food intake is maintained over long term treatment. Clinical data seems to suggest that rapid weight gain occurs primarily at the onset of treatment. We would postulate that the compensatory vagally-mediated responses such as the increase in post-prandial insulin release and suppression of endogenous glucose production may be down-regulated or in the case of insulin secretion, may be inhibited by the presence of elevated free fatty acids binding to muscarinic receptors as has been demonstrated in vitro
). Loss of the compensatory responses would contribute to impaired glucose tolerance (3