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.
| Original language | English |
|---|---|
| Article number | 4092 |
| Journal | International Journal of Molecular Sciences |
| Volume | 20 |
| Issue number | 17 |
| Number of pages | 18 |
| ISSN | 1661-6596 |
| DOIs | |
| Publication status | Published - 2019 |
Keywords
- Dual-agonism
- Gastric inhibitory peptide
- Glucagon
- Glucagon-like peptide 1
- Glucose-dependent insulinotropic polypeptide
- Incretins
- Obesity
- Type 2 diabetes
