Coadministration of Glucagon-Like Peptide-1 During Glucagon Infusion in Humans Results in Increased Energy Expenditure and Amelioration of Hyperglycemia

Abstract

Glucagon and glucagon-like peptide (GLP)-1 are the primary products of proglucagon processing from the pancreas and gut, respectively. Giving dual agonists with glucagon and GLP-1 activity to diabetic, obese mice causes enhanced weight loss and improves glucose tolerance by reduction of food intake and by increase in energy expenditure (EE). We aimed to observe the effect of a combination of glucagon and GLP-1 on resting EE and glycemia in healthy human volunteers. In a randomized, double-blinded crossover study, 10 overweight or obese volunteers without diabetes received placebo infusion, GLP-1 alone, glucagon alone, and GLP-1 plus glucagon simultaneously. Resting EE—measured using indirect calorimetry—was not affected by GLP-1 infusion but rose significantly with glucagon alone and to a similar degree with glucagon and GLP-1 together. Glucagon infusion was accompanied by a rise in plasma glucose levels, but addition of GLP-1 to glucagon rapidly reduced this excursion, due to a synergistic insulinotropic effect. The data indicate that drugs with glucagon and GLP-1 agonist activity may represent a useful treatment for type 2 diabetes and obesity. Long-term studies are required to demonstrate that this combination will reduce weight and improve glycemia in patients.

Glucagon increases energy expenditure independently of brown adipose tissue activation in humans

“…The baseline respiratory quotients (respiratory quotient: Vco 2 /Vo 2 ) in each group were not significantly different from one another [0.797 ± 0.016 (cold); 0.788 ± 0.017 (vehicle); and 0.765 ± 0.021 (glucagon)] but rose significantly with glucagon infusion [change from baseline in respiratory quotient by end of intervention: −0.012 ± 0.009 (cold), −0.003 ± 0.001 (vehicle), and +0.055 ± 0.016 (glucagon, p < 0.01)], which was indicative of the expected rise in rate of carbohydrate oxidation with glucagon, in line with its glucose-liberating effects and hence the relative substrate availabilities of glucose versus free fatty acid, and consistent with our previous data [7,8]. Plasma levels of glucagon rose only during the glucagon infusion, which is shown in Figure S2 alongside plasma glucose and insulin levels.…”

“…Glucagon infusion acutely increases EE in humans [7,8], but the mechanism by which this occurs is not known. Rodents can increase their EE via activation of brown adipose tissue (BAT), which consumes fuel for thermogenesis using uncoupling protein-1 (UCP-1), and do so in response to both cold exposure and caloric excess [9].…”

Neuronal GLP1R mediates liraglutide’s anorectic but not glucose-lowering effect

“…This could be a result of inherent measurement inaccuracy in the food intake; however, we cannot exclude small differences in energy expenditure. Additionally, recent clinical literature demonstrates that weight loss secondary to GLP1R agonists can be explained via alterations in energy intake without effects on energy expenditure (28,29). Regardless of their limited role in normal body weight, these data do point to an important role for CNS GLP1Rs in mediating food intake, body weight, and body fat responses to a long-acting GLP1R agonist.…”

Glucagon receptor signalling – backwards and forwards

“…Moreover, GCGr is also expressed in numerous extrahepatic tissues, including the brain, heart, kidney, gastrointestinal tract, and adipose tissue. Stimulation of GCGr in the hypothalamus may suppress appetite directly, while peripheral administration of glucagon increases energy expenditure in humans [16].…”