The regulation of glucose effectiveness: how glucose modulates its own production

Abstract

'Glucose effectiveness' refers to the ability of glucose per se to suppress endogenous glucose production and stimulate glucose uptake. In addition to the inhibitory effects of insulin on endogenous glucose production, rising glucose levels have important direct effects on glucose homeostasis. The loss of glucose effectiveness in type 2 diabetes mellitus contributes importantly to hyperglycemia in those individuals. Given the rapidly increasing incidence and serious complications of type 2 diabetes mellitus, understanding the regulation of glucose effectiveness has great potential therapeutic benefits. The loss of this important regulation appears to be secondary to the chronic 'diabetic milieu' in type 2 diabetes mellitus, which includes elevated plasma glucose and free fatty acid levels. Glucose effectiveness is completely restored by normalizing plasma free fatty acid levels. Increased free fatty acid availability stimulates gluconeogenesis and alters flux through key hepatic enzymes. It is likely that at least part of this regulation is through central pathways. In addition, hormones that may exert important effects on hepatic glucose effectiveness include cortisol, insulin and glucagon-like peptide 1. The effectiveness of glucose to stimulate glucose uptake is impaired by elevated free fatty acid levels and may be enhanced by glucagon-like peptide 1. The regulation of glucose effectiveness involves a complex interplay of hormonal and metabolic factors, with free fatty acid and glucoregulatory hormones playing key roles. The loss of this regulation in type 2 diabetes mellitus contributes importantly to hyperglycemia, and may largely be caused by increased free fatty acid levels.