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Impact of glucagon‐like peptide‐1 (7‐36) amide, isosteviol and 5‐aminoimidazole‐4‐carboxamide 1‐ β ‐ d ‐ribofuranoside on leucine‐mediated α ‐cell dysfunction
Author(s) -
Chen X.,
Hermansen K.,
Jeppesen P. B.
Publication year - 2012
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/j.1463-1326.2012.01633.x
Subject(s) - medicine , endocrinology , glucagon , leucine , insulin , triglyceride , chemistry , biology , biochemistry , cholesterol , amino acid
Aim To investigate the acute and chronic effects of l ‐leucine on pancreatic α ‐cell function in vitro . Furthermore, we wanted to explore if glucagon‐like peptide‐1 ( GLP ‐1), isosteviol ( ISV ) and 5‐aminoimidazole‐4‐carboxamide 1‐ β ‐ d ‐ribofuranoside ( AICAR ) counteract changes in α ‐cell function induced by chronic exposure to leucine. Methods Isolated mice islets were incubated with 10 mM leucine for 2 or 72 h. We investigated glucagon and insulin secretion at 2 mM and 16.7 mM glucose. In addition, we cultured clonal α ‐ TC1 ‐6 cells with 5 mM leucine, 5 mM leucine plus GLP ‐1 (10 −6 M ), or ISV (10 −6 M ) or AICAR (10 −5 M ) at high glucose for 72 h. We measured the glucagon secretion, cholesterol ( CHO ) and triglyceride ( TG ) content, cell proliferation as well as gene expression. Results Ten millimolar of leucine for 2 h significantly stimulated glucagon and insulin secretion both at 2 and 16.7 mM glucose in mice islets. After 72 h incubation with 10 mM leucine the glucagon secretion was enhanced at both 2 and 16.7 mM glucose, whereas the glucose‐stimulated insulin secretion (16.7 mM glucose) was inhibited. Chronic exposure to 5 mM leucine increased glucagon secretion, CHO and TG content, cell proliferation and Pcsk2 (p < 0.001), MafB (p < 0.05), Gcg (p < 0.001), Prkaa1 (p < 0.01), Hmgcr (p < 0.001), Srebf 2 (p < 0.001), Acaca (p < 0.001), Mtor (p < 0.05) mRNA expression in clonal α ‐ TC1 ‐6 cells. While GLP ‐1 was cable of reducing glucagon hypersecretion and Pcsk 2 (p < 0.05) mRNA expression. ISV and AICAR had no effect on leucine‐induced glucagon hypersecretion. Conclusions Long‐term exposure to leucine induces hypersecretion of glucagon secretion, that is, aminoacidotoxicity and influences some key genes of pancreatic α ‐cells. Interestingly, GLP ‐1 counteracts the leucine‐induced α ‐cell dysfunction.