Intra-islet GLP-1, but not CCK, is necessary for β-cell function in mouse and human islets

Arnaldo Henrique de Souza, Jiayin Tang, Amanjot Kaur Yadev, Samuel T. Saghafi, Carly R. Kibbe, Amelia K. Linnemann, Matthew J. Merrins, Dawn Belt Davis

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Abstract

Glucagon-like peptide 1 (GLP-1) and cholecystokinin (CCK) are gut-derived peptide hormones known to play important roles in the regulation of gastrointestinal motility and secretion, appetite, and food intake. We have previously demonstrated that both GLP-1 and CCK are produced in the endocrine pancreas of obese mice. Interestingly, while GLP-1 is well known to stimulate insulin secretion by the pancreatic β-cells, direct evidence of CCK promoting insulin release in human islets remains to be determined. Here, we tested whether islet-derived GLP-1 or CCK is necessary for the full stimulation of insulin secretion. We confirm that mouse pancreatic islets secrete GLP-1 and CCK, but only GLP-1 acts locally within the islet to promote insulin release ex vivo. GLP-1 is exclusively produced in approximately 50% of α-cells in lean mouse islets and 70% of α-cells in human islets, suggesting a paracrine α to β-cell signaling through the β-cell GLP-1 receptor. Additionally, we provide evidence that islet CCK expression is regulated by glucose, but its receptor signaling is not required during glucose-stimulated insulin secretion (GSIS). We also see no increase in GSIS in response to CCK peptides. Importantly, all these findings were confirmed in islets from non-diabetic human donors. In summary, our data suggest no direct role for CCK in stimulating insulin secretion and highlight the critical role of intra-islet GLP-1 signaling in the regulation of human β-cell function.

Original languageEnglish (US)
Article number2823
JournalScientific reports
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2020

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de Souza, A. H., Tang, J., Yadev, A. K., Saghafi, S. T., Kibbe, C. R., Linnemann, A. K., Merrins, M. J., & Davis, D. B. (2020). Intra-islet GLP-1, but not CCK, is necessary for β-cell function in mouse and human islets. Scientific reports, 10(1), [2823]. https://doi.org/10.1038/s41598-020-59799-2