ABSTRACT
Objective: In obesity and type 2 diabetes, hyperglucagonaemia may be caused by elevated levels of glucagonotropic amino acids due to hepatic glucagon resistance at the level of amino acid turnover. Here, we investigated the effect of exogenous glucagon on circulating amino acids in obese and non-obese individuals with and without type 2 diabetes. Design: This was a post hoc analysis in a glucagon infusion study performed in individuals with type 2 diabetes (n = 16) and in age, sex, and body mass index-matched control individuals without diabetes (n = 16). Each group comprised two subgroups of eight individuals with and without obesity, respectively. Methods: All participants received a 1-h glucagon infusion (4 ng/kg/min) in the overnight fasted state. Plasma amino acid concentrations were measured with frequent intervals. Results: Compared to the control subgroup without obesity, baseline total amino acid levels were elevated in the control subgroup with obesity and in the type 2 diabetes subgroup without obesity. In all subgroups, amino acid levels decreased by up to 20% in response to glucagon infusion, which resulted in high physiological steady-state glucagon levels (mean concentration: 74 pmol/L, 95% CI [68;79] pmol/L). Following correction for multiple testing, no intergroup differences in changes in amino acid levels reached significance. Conclusion: Obesity and type 2 diabetes status was associated with elevated fasting levels of total amino acids. The glucagon infusion decreased circulating amino acid levels similarly in all subgroups, without significant differences in the response to exogenous glucagon between individuals with and without obesity and type 2 diabetes. Significance statement: The hormone glucagon stimulates glucose production from the liver, which may promote hyperglycaemia if glucagon levels are abnormally elevated, as is often seen in type 2 diabetes and obesity. Glucagon levels are closely linked to, and influenced by, the levels of circulating amino acids. To further investigate this link, we measured amino acid levels in individuals with and without obesity and type 2 diabetes before and during an infusion of glucagon. We found that circulating amino acid levels were higher in type 2 diabetes and obesity, and that glucagon infusion decreased amino acid levels in both individuals with and without type 2 diabetes and obesity. The study adds novel information to the link between circulating levels of glucagon and amino acids.
ABSTRACT
PURPOSE: Cardiovascular-safety studies assessing glucagon-like peptide (GLP)-1 receptor agonists and dipeptidyl peptidase 4 inhibitors have provided inconsistent data on the risk for developing heart failure. Animal studies have shown that GLP-1 is a vasodilator; if confirmed in humans, this may ameliorate heart failure symptoms. METHODS: In a single-center, observational pilot study, we recruited 10 patients with advanced heart failure undergoing right heart catheterization, and we recorded pulmonary hemodynamic measures, including cardiac output calculated by thermodilution and the indirect Fick method before and after a 15-minute continuous infusion of native GLP-1 (7-36) NH2. FINDINGS: There was a neutral effect of GLP-1 on all pressure and hemodynamics indices as derived by cardiac output calculated by thermodilution. However, there was a small but consistent reduction in cardiac output as calculated by the indirect Fick method after GLP-1 infusion (baseline, 4.0 [1.1] L/min vs GLP-1, 3.6 [0.9] L/min; P = 0.003), driven by a consistent reduction in mixed venous oxygen saturation after GLP-1 infusion (baseline, 62.2% [7.0%] vs GLP-1, 59.3% [6.8%]; P < 0.001), whereas arterial saturation remained constant (baseline, 96.8% [3.3%] vs GLP-1, 97.0% [3.2%]; P = 0.34). This resulted in an increase in systemic vascular resistance by Fick (baseline, 1285 [228] dyn · s/cm5 vs GLP-1, 1562 [247] dyn · s/cm5; P = 0.001). IMPLICATIONS: Acute infusion of GLP-1 has a neutral hemodynamic effect, when assessed by thermodilution, in patients with heart failure. However, GLP-1 reduces mixed venous oxygen saturation. ClinicalTrials.gov identifier: NCT02129179.
