دورية أكاديمية
Leucine suppresses α-cell cAMP and glucagon secretion via a combination of cell-intrinsic and islet paracrine signaling.
| العنوان: | Leucine suppresses α-cell cAMP and glucagon secretion via a combination of cell-intrinsic and islet paracrine signaling. |
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| المؤلفون: | Knuth ER; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, WI 53705, USA., Foster HR; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, WI 53705, USA., Jin E; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, WI 53705, USA., Ekstrand MH; Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark., Knudsen JG; Section for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark., Merrins MJ; Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Wisconsin-Madison, Madison, WI 53705, USA.; William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA. |
| المصدر: | Diabetes [Diabetes] 2024 Jun 13. Date of Electronic Publication: 2024 Jun 13. |
| Publication Model: | Ahead of Print |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Diabetes Association Country of Publication: United States NLM ID: 0372763 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1939-327X (Electronic) Linking ISSN: 00121797 NLM ISO Abbreviation: Diabetes Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Alexandria, VA : American Diabetes Association Original Publication: [New York, American Diabetes Association] |
| مستخلص: | Glucagon is critical for the maintenance of blood glucose, however nutrient regulation of pancreatic α-cells remains poorly understood. Here, we identified a role for leucine, a well-known β-cell fuel, in the α-cell intrinsic regulation of glucagon release. In islet perifusion assays, physiological concentrations of leucine strongly inhibited alanine and arginine-stimulated glucagon secretion from human and mouse islets under hypoglycemic conditions. Mechanistically, leucine dose-dependently reduced α-cell cAMP, independently of Ca2+, ATP/ADP, or fatty acid oxidation. Leucine also reduced α-cell cAMP in islets treated with Sstr2 antagonists or diazoxide, compounds that limit paracrine signaling from β/δ-cells. Studies in dispersed mouse islets confirmed an α-cell intrinsic effect. The inhibitory effect of leucine on cAMP was mimicked by glucose, α-ketoisocaproate, succinate, and the glutamate dehydrogenase activator BCH, and blocked by cyanide, indicating a mechanism dependent on mitochondrial metabolism. Glucose dose-dependently reduced the impact of leucine on α-cell cAMP, indicating an overlap in function, however leucine was still effective at suppressing glucagon secretion in the presence of elevated glucose, amino acids, and the incretin GIP. Taken together, these findings show that leucine plays an intrinsic role in limiting α-cell secretory tone across the physiological range of glucose levels, complementing the inhibitory paracrine actions of β/δ-cells. (© 2024 by the American Diabetes Association.) |
| تواريخ الأحداث: | Date Created: 20240613 Latest Revision: 20240613 |
| رمز التحديث: | 20240614 |
| DOI: | 10.2337/db23-1013 |
| PMID: | 38870025 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1939-327X |
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| DOI: | 10.2337/db23-1013 |