Insulin Impairment Disrupts Central Serotonin Synthesis: Implications for Stress Resilience

Abstract

This chapter reviews the important neurophysiological mechanisms that drive symptoms characteristic of comorbid depression and metabolic disease. It outlines how insulin impairment in the periphery1 interferes with central 5-hydroxyindole metabolism and ultimately restricts central2 serotonin synthesis. More specifically, peripheral insulin impairment disrupts i) peripheral and central tryptophan stores, ii) tryptophan uptake into the brain, and iii) tryptophan hydroxylase-2 function. Central serotonin availability appears to be increasingly restricted by higher degree and duration of insulin impairment, which can lead to both physiological and behavioral positive feedback loops experienced by individuals as a spiral of deteriorating mental health and tryptophan metabolism. Serotonin and its metabolites are fundamentally homeostatic regulators that serve to enhance adaptive response to stress in all organisms. Considering this essential trait, this review proposes that: disruptions in normal 5-hydroxyindole metabolism of tryptophan during impaired insulin function will disrupt homeostatic adaptive capacity of central serotonin, thereby increasing vulnerability to emotional and energy disturbances, and limiting recovery from such disturbances.