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Int J Mol Sci. 2019 Aug 22;20(17). pii: E4092. doi: 10.3390/ijms20174092.

The Effects of Dual GLP-1/GIP Receptor Agonism on Glucagon Secretion-A Review.

Author information

1
Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark.
2
Steno Diabetes Center Copenhagen, 2820 Gentofte, Denmark.
3
Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, 2400 Copenhagen, Denmark.
4
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.
5
Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, 2900 Hellerup, Denmark. filip.krag.knop.01@regionh.dk.
6
Steno Diabetes Center Copenhagen, 2820 Gentofte, Denmark. filip.krag.knop.01@regionh.dk.
7
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark. filip.krag.knop.01@regionh.dk.
8
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark. filip.krag.knop.01@regionh.dk.

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.

KEYWORDS:

dual-agonism; gastric inhibitory peptide; glucagon; glucagon-like peptide 1; glucose-dependent insulinotropic polypeptide; incretins; obesity; type 2 diabetes

PMID:
31443356
DOI:
10.3390/ijms20174092
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