Hepato-incretin function of GLP-1: novel concept and target in type 1 diabetes.

Abstract

The liver is a key player in glucose regulation, and several factors are involved in this regulation (1). Glucagon, autonomic nerves, and the adrenals stimulate hepatic glucose production to allow sufficient brain glucose delivery. Insulin inhibits hepatic glucose production, preventing excess hepatic glucose release. This is of particular importance after meals, as is evident from the negative correlation between early insulin response after meals and postprandial glucose (2). Therefore, low insulin and high glucagon levels—such as observed in type 1 and type 2 diabetes—sustain liver glucose production, thereby resulting in postprandial and fasting hyperglycemia. Thus, reducing hepatic glucose production is an important target in the treatment of diabetes (3). The incretin hormone GLP-1 inhibits hepatic glucose production through its ability to stimulate insulin secretion and inhibit glucagon secretion (4). As GLP-1 is released after meal ingestion in proportion to meal size (5), this effect allows meal-dependent inhibition of hepatic glucose production. However, GLP-1 may also inhibit endogenous glucose production through an islet-independent mechanism (6–9). This allows not only a rapid shutoff of endogenous glucose production after meal ingestion but also incretin therapy to be potent in insulin-deficient diabetes. A study in the current issue of Diabetes presents convincing evidence for such an islet-independent inhibition of endogenous glucose production by GLP-1 (10). The study by Jun et al. (10) leveraged the unique glucagon receptor …