%0 Journal Article
%T The Effects of Dual GLP-1/GIP Receptor Agonism on Glucagon Secretion-A Review.
%A Mathiesen DS
%A Bagger JI
%A Bergmann NC
%A Lund A
%A Christensen MB
%A Vilsbøll T
%A Knop FK
%J Int J Mol Sci
%V 20
%N 17
%D Aug 2019 22
%M 31443356
%F 6.208
%R 10.3390/ijms20174092
%X The gut-derived incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted after meal ingestion and work in concert to promote postprandial insulin secretion. Furthermore, GLP-1 inhibits glucagon secretion when plasma glucose concentrations are above normal fasting concentrations while GIP acts glucagonotropically at low glucose levels. A dual incretin receptor agonist designed to co-activate GLP-1 and GIP receptors was recently shown to elicit robust improvements of glycemic control (mean haemoglobin A1c reduction of 1.94%) and massive body weight loss (mean weight loss of 11.3 kg) after 26 weeks of treatment with the highest dose (15 mg once weekly) in a clinical trial including overweight/obese patients with type 2 diabetes. Here, we describe the mechanisms by which the two incretins modulate alpha cell secretion of glucagon, review the effects of co-administration of GLP-1 and GIP on glucagon secretion, and discuss the potential role of glucagon in the therapeutic effects observed with novel unimolecular dual GLP-1/GIP receptor agonists. For clinicians and researchers, this manuscript offers an understanding of incretin physiology and pharmacology, and provides mechanistic insight into future antidiabetic and obesity treatments.