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Cholesterol Efflux Assay
Published on: March 6, 2012
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Glucagon receptor antagonism induces increased cholesterol absorption
Hong-Ping Guan1, Xiaodong Yang1, Ku Lu1
1Departments of Cardiometabolic Disease, Merck Research Laboratories, Kenilworth, NJ 07033.
Journal of Lipid Research
|September 17, 2015
Summary
Glucagon receptor antagonists lower blood sugar in type 2 diabetes but raise LDL cholesterol. This study links this side effect to increased cholesterol absorption, suggesting a new mechanism for managing cholesterol metabolism.
Area of Science:
- Endocrinology
- Metabolic Diseases
- Pharmacology
Background:
- Elevated plasma glucagon contributes to hyperglycemia in type 2 diabetes mellitus (T2DM).
- Glucagon receptor (GCGR) antagonism is a therapeutic strategy for T2DM.
- Small-molecule GCGR antagonists (GRAs) reduce hyperglycemia but increase LDL-cholesterol (LDL-c).
Purpose of the Study:
- Investigate the mechanism behind GRA-induced LDL-c elevation.
- Identify potential therapeutic strategies to mitigate this side effect.
Main Methods:
- Administered MK-0893, a small-molecule GCGR antagonist, to T2DM models.
- Measured plasma glucagon-like peptide 2 and cholesterol absorption markers.
- Assessed cholesterol synthesis pathways.
- Co-administered ezetimibe with GRAs in mice.
Main Results:
- MK-0893 treatment increased glucagon-like peptide 2 and cholesterol absorption.
- No GRA-related modulation of cholesterol synthesis was observed.
- Structurally diverse GRAs replicated these findings.
- Ezetimibe coadministration abrogated GRA-associated LDL-c increase in mice.
Conclusions:
- GCGR antagonism in T2DM is linked to increased cholesterol absorption, not synthesis.
- This provides a novel insight into glucagon's role in cholesterol metabolism.
- Targeting cholesterol absorption may mitigate GRA-induced LDL-c elevation.
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