1. Intra-islet GLP-1, but not CCK, is necessary for β-cell function in mouse and human islets
- Author
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Jiayin Tang, Matthew J. Merrins, Carly R. Kibbe, Dawn Belt Davis, Arnaldo H. de Souza, Samuel T. Saghafi, Amanjot Kaur Yadev, and Amelia K. Linnemann
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,endocrine system ,medicine.medical_treatment ,lcsh:Medicine ,030209 endocrinology & metabolism ,Peptide hormone ,digestive system ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Glucagon-Like Peptide 1 ,Internal medicine ,Insulin-Secreting Cells ,Insulin Secretion ,medicine ,Animals ,Humans ,Homeostasis ,Secretion ,Obesity ,Receptor ,lcsh:Science ,Cholecystokinin ,2. Zero hunger ,geography ,Multidisciplinary ,geography.geographical_feature_category ,Chemistry ,Insulin ,Pancreatic islets ,Diabetes ,digestive, oral, and skin physiology ,lcsh:R ,Islet ,Mice, Inbred C57BL ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,lcsh:Q ,Pancreas ,hormones, hormone substitutes, and hormone antagonists - 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.
- Published
- 2020