The Effects of Dual GLP-1/GIP Receptor Agonism on Glucagon Secretion-A Review.
David S MathiesenJonatan I BaggerNatasha Chidekel BergmannAsger LundMikkel B ChristensenTina VilsbøllFilip K Krag KnopPublished in: International journal of molecular sciences (2019)
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.
Keyphrases
- weight loss
- glycemic control
- blood glucose
- bariatric surgery
- roux en y gastric bypass
- type diabetes
- gastric bypass
- clinical trial
- metabolic syndrome
- insulin resistance
- weight gain
- obese patients
- stem cells
- open label
- palliative care
- current status
- physical activity
- bone marrow
- study protocol
- phase ii
- binding protein
- risk assessment
- preterm birth