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

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@article{73e1818390af438b9af8f62371c9316e,
title = "The Effects of Dual GLP-1/GIP Receptor Agonism on Glucagon Secretion - A Review",
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",
author = "Mathiesen, {David S} and Bagger, {Jonatan I} and Bergmann, {Natasha C} and Asger Lund and Christensen, {Mikkel B} and Tina Vilsb{\o}ll and Knop, {Filip K}",
year = "2019",
month = "8",
day = "22",
doi = "10.3390/ijms20174092",
language = "English",
volume = "20",
journal = "International Journal of Molecular Sciences",
issn = "1661-6596",
publisher = "Molecular Diversity Preservation International (M D P I)",
number = "17",

}

RIS

TY - JOUR

T1 - The Effects of Dual GLP-1/GIP Receptor Agonism on Glucagon Secretion - 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 - 2019/8/22

Y1 - 2019/8/22

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

UR - http://www.scopus.com/inward/record.url?scp=85071507284&partnerID=8YFLogxK

U2 - 10.3390/ijms20174092

DO - 10.3390/ijms20174092

M3 - Review

VL - 20

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

SN - 1661-6596

IS - 17

M1 - 4092

ER -

ID: 57856582