Hepatic insulin-sensitizing substance pathway (HISS pathway) (HISS pathway)

The Hepatic Insulin-Sensitizing Substance (HISS) pathway is a physiological mechanism that accounts for approximately 50% of the total glucose disposal effect of insulin following a meal (Lautt, 2005). This pathway is activated when insulin reaches the liver in the presence of a feeding-induced parasympathetic signal, which involves the release of acetylcholine and the subsequent production of nitric oxide (Macedo et al., 2008). These signals trigger the liver to release HISS, a putative hormone that enters the systemic circulation and acts on skeletal muscle to stimulate glucose uptake (Lautt, 2004). Dysfunction of this pathway, termed HISS-dependent insulin resistance (HDIR), is a primary defect in early-stage type 2 diabetes, obesity, and metabolic syndrome (Lautt, 2005). Pharmacological strategies to target this pathway include the use of muscarinic agonists like bethanechol or nitric oxide donors to restore HISS release and improve glycemic control (SciMar, 2023). Despite its physiological significance, the specific chemical identity of the HISS molecule remains uncharacterized, presenting a challenge for direct therapeutic development (Lautt, 2004).

Other names

HISSHISS-dependent insulin actionHIDAParasympathetic-dependent insulin actionHepatic insulin-sensitizing substance

The HISS pathway operates through a "feed-forward" mechanism where insulin and parasympathetic signals (acetylcholine and nitric oxide) act on the liver to trigger the release of HISS, which then enhances glucose uptake in skeletal muscle (Lautt, 2005).