Abstract
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.
Highlights
The discovery of insulin in the dawn of the 20th century [1] led to the discovery of a hyperglycemic substance originating from the pancreas [2]
This review provides insights into the mechanisms by which glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) modulate glucagon secretion and discusses findings on glucagon in the context of GLP-1 and GIP co-infusion studies as well as studies with novel unimolecular dual GIP/GLP-1 receptor agonists
Hyperglucagonemia is a common phenomenon in type 2 diabetes and—via glucagon’s stimulatory effect on endogenous glucose production—it contributes to the core pathophysiological trait of these patients namely hyperglycemia
Summary
The discovery of insulin in the dawn of the 20th century [1] led to the discovery of a hyperglycemic substance originating from the pancreas [2] This substance was named glucagon, short for glucose agonist, 30 years before it was crystallized and its amino acid sequence was determined [3,4]. Insulin and somatostatin exert inhibitory effects on alpha cell secretion of glucagon, whereas hypoglycemia and amino acids are known to stimulate the secretion of glucagon. The gut-derived incretin hormones glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), best known for their potent insulinotropic effects, modulate glucagon secretion and they may play a role in the dysregulation of glucagon secretion observed in patients with type 2 diabetes [16]. This review provides insights into the mechanisms by which GLP-1 and GIP modulate glucagon secretion and discusses findings on glucagon in the context of GLP-1 and GIP co-infusion studies as well as studies with novel unimolecular dual GIP/GLP-1 receptor agonists
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
