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

30% of people in the United States have diabetes or pre-diabetes. Many of these individuals will develop diabetic neuropathy as a comorbidity, which is often treated with exogenous opioids like morphine, oxycodone, or tramadol. Although these opioids are effective analgesics, growing evidence indicates that they may directly impact the endocrine pancreas function in human and preclinical models. One common feature of these exogenous opioid ligands is their preference for the mu opioid receptor (MOPR), so we aimed to determine if 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 enriched in human islet -cells, but downregulated in T2D islet donors, suggesting a link between metabolism and MOPR expression. Conditional genetic knockout of MOPRs in murine -cells increases glucagon secretion in 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. Finally, we show that MOPR-mediated changes in glucagon secretion are driven, in part, by KATP channel activity. Together, these results demonstrate a direct mechanism of action for endogenous opioid regulation of endocrine pancreas.