Post-prandial insulin sensitization. new perspectives for gastrointestinal endocrinology

Eating a meal has been found to activate a parasympathetic reflex in the liver that through the release of a hepatic insulin sensitizing substance (HISS) into the circulation sensitizes peripheral tissues to the hypoglycaemic effect of insulin. Partial hepatic sensory denervation (PHSD) was achieved by a 3-day perineurial treatment with 2% capsaicin solution around the anterior hepatic plexus in male guinea-pigs, rats or rabbits to confirm the sensory nature of the HISS mechanism in these species. One week later, hyperinsulinaemic (100µU/ml) euglycaemic (5.5 mmol/l) glucose clamp were performed to estimate whole body insulin sensitivity in anaesthetized animals. Calcitonin gene-related peptide (CGRP), substance P, somatostatin and insulin were determined by means of RIA. The HISS effect was characterized by insulin-stimulated uptake of 2-deoxy-D [l-14C] glucose in cardiac and gastrocnemius muscle and percentage suppression of endogenous glucose production. PHSB decreased post-prandial insulin sensitivity characterized by a decrease in glucose infusion rate from 19±2.4 to 7.9±1.5mg/kg/min to maintain euglycaemia at clamped hyperinsulinaemia. Inhibition of hepatic NO synthesis by either intraportal nitro L-arginine (10mg/kg) or 7-nitro indazole (5mg/kg) attained similar inhibition. Both intraportal and systemic atropine (1mg/kg) was without effect in each species. Post-prandial insulin sensitization (65±7.2% vs. the fasted state) was accompanied by a significant increase in plasma somatostatin immunoreactivity with no change with respect to the other peptides measured. Cysteamine (200mg/kg/s.c.) completely blocked post-prandial insulin sensitization. PHSB decreased post-prandial cardiac 2-deoxy-D [l-14C] glucose uptake by 37±4.6% with no significant effect on hepatic glucose production. The results shed light on a novel hepatic sensory nitrergic endogenous insulin sensitizing mechanism that is mediated by a circulating substance showing somatostatin-like immunoreactivity in three species.