The effects of dual GLP-1/GIP receptor agonism on glucagon secretion: a review

TY - JOUR

T1 - The effects of dual GLP-1/GIP receptor agonism on glucagon secretion

T2 - a review

AU - Mathiesen, David S.

AU - Bagger, Jonatan I.

AU - Bergmann, Natasha C.

AU - Lund, Asger

AU - Christensen, Mikkel B.

AU - Vilsbøll, Tina

AU - Knop, Filip K.

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - Dual-agonism

KW - Gastric inhibitory peptide

KW - Glucagon

KW - Glucagon-like peptide 1

KW - Glucose-dependent insulinotropic polypeptide

KW - Incretins

KW - Obesity

KW - Type 2 diabetes

U2 - 10.3390/ijms20174092

DO - 10.3390/ijms20174092

M3 - Review

C2 - 31443356

AN - SCOPUS:85071507284

SN - 1424-6783

VL - 20

JO - International Journal of Molecular Sciences (CD-ROM)

JF - International Journal of Molecular Sciences (CD-ROM)

IS - 17

M1 - 4092

ER -