Copper binding to glucagon and glucagon-like peptide 1: Relevance to diabetes
Abstract
Glucagon (GCG) and glucagon-like peptide 1 (GLP1) are hormones involved in maintaining glucose homeostasis. Diabetic patients display a chronic dysfunction of these hormones along with an increase in copper levels in the bloodstream. Although GCG(1–29) and GLP1(1–37) harbour Cu2+-anchoring groups at their N-terminal regions, their metal-binding properties have not been assesed, nor their implications in metal homeostasis/hormone function. In this study, spectroscopic tools (circular dichroism, electron paramagnetic resonance and X-ray absorption spectroscopy) were used to elucidate the Cu2+-binding properties of GCG and GLP1, and to assay the ability of these hormones to compete for the metal ion with the extracellular Cu2+-binding site of the Copper transporter 1 (CTR1)–the major source of copper uptake in mammalian cells–and Metformin–the Cu2+-binding drug used as first-line treatment for Type 2 diabetes. Our results show that Cu2+-binding to GCG(1–29) and GLP1(1–37) is highly dependent on metal-to-hormone ratio, yielding at least two different Cu2+ complexes (Modes I and II) depending on the metal-to-hormone ratio. Mode I, favoured at low metal-tohormone ratio, can efficiently transfer Cu2+ to the metal-binding site of CTR1, while Mode II can only do a partially transfer, suggesting that Cu2+-hormone speciation could impact metal homeostasis. Metformin can deliver Cu2+ to GCG and GLP1, indicating that this drug could buffer Cu2+ accumulation in the bloodstream in diabetes, without preventing Cu2+-hormone interactions. Altogether, this study elucidates metal-hormone interactions that are crucial to understand the role of Cu2+ in the pathophysiology of diabetes and paves the way for evaluating the potential of Metformin, and other drugs, as regulators of Cu2+-hormone interactions in diabetes.
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BibTeX
@misc{posadas2026copper,
title = {{Copper binding to glucagon and glucagon-like peptide 1: Relevance to diabetes}},
author = {Yanahi Posadas and Carolina Sánchez-López and Victor E. López-Guerrero and Christophe Den Auwer and José Segovia and Liliana Quintanar},
howpublished = {ChemRxiv},
year = {2026},
month = oct,
doi = {10.26434/chemrxiv.15010094/v1},
url = {https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010094/v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Copper binding to glucagon and glucagon-like peptide 1: Relevance to diabetes
AU - Yanahi Posadas
AU - Carolina Sánchez-López
AU - Victor E. López-Guerrero
AU - Christophe Den Auwer
AU - José Segovia
AU - Liliana Quintanar
PY - 2026
DA - 2026/10/08
PB - ChemRxiv
DO - 10.26434/chemrxiv.15010094/v1
UR - https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010094/v1
AB - Glucagon (GCG) and glucagon-like peptide 1 (GLP1) are hormones involved in maintaining glucose homeostasis. Diabetic patients display a chronic dysfunction of these hormones along with an increase in copper levels in the bloodstream. Although GCG(1–29) and GLP1(1–37) harbour Cu2+-anchoring groups at their N-terminal regions, their metal-binding properties have not been assesed, nor their implications in metal homeostasis/hormone function. In this study, spectroscopic tools (circular dichroism, electron paramagnetic resonance and X-ray absorption spectroscopy) were used to elucidate the Cu2+-binding properties of GCG and GLP1, and to assay the ability of these hormones to compete for the metal ion with the extracellular Cu2+-binding site of the Copper transporter 1 (CTR1)–the major source of copper uptake in mammalian cells–and Metformin–the Cu2+-binding drug used as first-line treatment for Type 2 diabetes. Our results show that Cu2+-binding to GCG(1–29) and GLP1(1–37) is highly dependent on metal-to-hormone ratio, yielding at least two different Cu2+ complexes (Modes I and II) depending on the metal-to-hormone ratio. Mode I, favoured at low metal-tohormone ratio, can efficiently transfer Cu2+ to the metal-binding site of CTR1, while Mode II can only do a partially transfer, suggesting that Cu2+-hormone speciation could impact metal homeostasis. Metformin can deliver Cu2+ to GCG and GLP1, indicating that this drug could buffer Cu2+ accumulation in the bloodstream in diabetes, without preventing Cu2+-hormone interactions. Altogether, this study elucidates metal-hormone interactions that are crucial to understand the role of Cu2+ in the pathophysiology of diabetes and paves the way for evaluating the potential of Metformin, and other drugs, as regulators of Cu2+-hormone interactions in diabetes.
ER -