Glucose-Dependent Effects of Exogenous Glucagon-Like Peptide-2 on Circulating Glucagon Levels in Healthy Men

CONTEXT: Despite evidence of possible glucagonotropic effects, the role of the gut hormone glucagon-like peptide 2 (GLP-2) in glucose metabolism is unclear.

OBJECTIVE: This work aimed to evaluate the effect of exogenous GLP-2 on plasma glucagon levels during hypoglycemia, euglycemia, and hyperglycemia in healthy male volunteers.

METHODS: A randomized, double-blind, placebo-controlled, crossover study was conducted with supportive ex vivo human islet experiments. Participants included 10 lean, healthy men, median (interquartile range) aged 22 (21-23) years, with body mass index of 23.5 (23.3-23.8) and glycated hemoglobin A1c of 4.8 (4.6-5.1)% (29 (26.5-32.5) mmol/mol). During 6 separate study days, GLP-2 (6 pmol/kg/min for 10 minutes and 2 pmol/kg/min for the following 90 minutes) and placebo (saline), respectively, were infused intravenously during insulin-induced hypoglycemia (∼2.5 mmol/L), euglycemia (∼5 mmol/L), or hyperglycemia (∼10 mmol/L). Primary outcome was baseline-subtracted area under the curve for plasma glucagon, and secondary outcomes were serum insulin and C-peptide concentrations. Exploratory outcomes included norepinephrine, growth hormone, and bone homeostatic markers carboxy-terminal collagen crosslinks (CTX) and procollagen type I amino-terminal propeptide (PINP).

RESULTS: During GLP-2 infusions, steady-state plasma GLP-2 concentrations were 50-fold higher than during placebo. Compared to placebo, GLP-2 increased glucagon secretion slightly during euglycemia, and not during insulin-induced hypoglycemia or hyperglycemia. Ex vivo, GLP-2 did not affect glucagon secretion from isolated human islets. GLP-2 did not affect circulating concentrations of insulin, C-peptide, growth hormone, norepinephrine, or CTX during hypoglycemia, euglycemia, or hyperglycemia. GLP-2 decreased PINP during euglycemia and hyperglycemia.

CONCLUSION: Exogenous GLP-2 increased glucagon secretion slightly during euglycemia and not during insulin-induced hypoglycemia or hyperglycemia in healthy young men.