The HISS story overview: a novel hepatic neurohumoral regulation of peripheral insulin sensitivity in health and diabetes

Data are reviewed that are consistent with the following working hypothesis that proposes a novel mechanism regulating insulin sensitivity, which when nonfunctional, leads to severe insulin resistance. Postprandial elevation in insulin levels activates a hepatic parasympathetic reflex release of a p utative hepatic insulin-sensitizing substance (HISS), which activates gluco se uptake at skeletal muscle. Insulin causes HISS release in fed but not fa sted animals. The reflex is mediated by acetylcholine and involves release of nitric oxide in the liver. Interruption of the release of HISS is achiev ed by surgical denervation of the anterior hepatic nerve plexus, muscarinic receptor blockade, or nitric oxide synthase antagonism and leads to immedi ate severe insulin resistance. The nitric oxide donor, SIN-1, reverses L-NA ME-induced insulin resistance. Denervation-induced insulin resistance is re versed by intraportal but not intravenous administration of acetylcholine o r SIN-1. Liver disease is often associated with insulin resistance; the bil e duct ligation model of liver disease results in parasympathetic neuropath y and insulin resistance that is reversed by intraportal acetylcholine. Pos sible relevance of this HISS-dependent control of insulin action to insulin resistance in diabetes, liver disease, and obesity is discussed.