The role of mu-opioid receptors in pancreatic islet α-cells

in Journal of Molecular Endocrinology
Authors:
Chen Kong Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, Missouri, USA

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Daniel C Castro Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, USA

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https://orcid.org/0000-0001-8036-1313
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Jeongmin Lee Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, Missouri, USA

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David W Piston Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, Missouri, USA

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Correspondence should be addressed to D C Castro: castro.d@wustl.edu or to D W Piston: piston@wustl.edu

(C Kong and D C Castro contributed equally to this work)

DOI:
https://doi.org/10.1530/JME-24-0060
Volume/Issue:
Volume 74: Issue 1
Article Type:
Research Article
Article ID:
e240060
Online Publication Date:
20 Dec 2024
Copyright:
© the author(s) 2024
Restricted access
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Diabetes is a complex disease that impacts more than 500 million people across the world. Many of these individuals will develop diabetic neuropathy as a comorbidity, which is historically treated with exogenous opioids, such as morphine, oxycodone, or tramadol. Although these opioids are effective analgesics, growing evidence indicates that they may directly impact the endocrine pancreas function in patients. One common feature of these exogenous opioid ligands is their preference for the mu-opioid receptor (MOPR), so we aimed to determine whether endogenous MOPRs directly regulate pancreatic islet metabolism and hormone secretion. We show that pharmacological antagonism of MOPRs enhances glucagon secretion, but not insulin secretion, from human islets under high-glucose conditions. This increased secretion is accompanied by increased cAMP signaling. mRNA expression of MOPRs is robust in nondiabetic human islets but downregulated in islets from T2D donors, suggesting a link between metabolism and MOPR expression. Conditional genetic knockout of MOPRs in murine α-cells increases glucagon secretion under high-glucose conditions without increasing glucagon content. Consistent with downregulation of MOPRs during metabolic disease, conditional MOPR knockout mice treated with a high-fat diet show impaired glucose tolerance, increased glucagon secretion, increased insulin content, and increased islet size. Together, these results demonstrate a direct mechanism of action for endogenous opioid regulation of endocrine pancreas.

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Online ISSN:
1479-6813
Print ISSN:
0952-5041
Copyright:
© the author(s) 2024
Article ID:
e240060
Article Type:
Research Article
Received Date:
25 Jun 2024
Rev-recd:
23 Oct 2024
Accepted Date:
29 Oct 2024
Print Publication Date:
01 Jan 2025
Online Publication Date:
20 Dec 2024
Keywords:
human islets; OPRM1; MOPR; glucagon secretion; alpha-cell; beta-cell

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