The effect of lipids on glucoregulatory hormone actions

Abstract

Glucoregulatory hormones tightly control glucose production and uptake by their direct actions on glucose metabolism and indirect actions on both lipid and protein metabolism. Our laboratory and others have shown that the main substrate responsible for the indirect actions of glucoregulatory hormones on hepatic glucose production (HGP) is free fatty acids (FFA). The antilipolytic effects of insulin mediate its ability to suppress HGP by reducing gluconeogenesis; whereas the lipolytic action of epinephrine influences its ability to stimulate HGP by limiting glycogenolysis and augmenting gluconeogenesis. Although glucagon has little to no effect on adipose tissue in vivo, elevated levels of FFA and glucagon are observed postprandially in individuals with type 2 diabetes. Part of this work determined how FFA interact with glucagon to acutely regulate HGP. Our findings indicate that elevated FFA inhibit the glycogenolytic effects of glucagon, as they do the glycogenolytic effect of epinephrine. However, this effect is short-lived compared to epinephrine. In contrast to epinephrine, an increase in FFA does not augment glucagon-stimulated hepatic gluconeogenesis. A dysregulation of lipid metabolism, or an elevation of lipids, could possibly interact with glucoregulatory hormones to cause harmful metabolic effects. There is strong evidence for elevated fasting and postprandial FFA levels in type 2 diabetes and those at risk for the disease. Both acute and chronic elevations of FFA have been shown to induce insulin resistance. Additionally, accumulation of intracellular triglycerides in liver and skeletal muscle have also been strongly implicated in the development of insulin resistance; however to date, their putative role is based solely upon correlative results. This work shows for the first time that repeated brief daily elevations of FFA induce insulin resistance in liver, skeletal muscle, and adipose tissue. This finding suggests that recurring elevations of FFA, such as might occur during the postprandial period in type 2 diabetes, could progressively lead to chronic insulin resistance. In addition, we show that accumulation of hepatic triglycerides does not worsen the effects of repeated elevations of FFA. Furthermore, this work shows that repeated brief elevations of FFA also alter mechanisms of basal HGP.