Glycation of glucagon-like peptide-1(7-36)amide: characterization and impaired action on rat insulin secreting cells

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Abstract

Glucagon-like peptide-1 (7-36) amide (truncated GLP-1, tGLP-1) is a potent insulin releasing hormone of the enteroinsular axis. This study has examined glycation of tGLP-1 and effects of such structural modification on insulin secretion. Monoglycated tGLP-1 (M-r 3463.8, determined by plasma desorption mass spectrometry) was prepared by incubation with glucose under reducing conditions and purified by reversed-phase high performance liquid chromatography. Automated Edman degradation indicated that tGLP-1 was specifically glycated at the amino terminal His(7) site. In extracts from mouse small intestine, glycated tGLP-1 represented approximately 14 % of the total tGLP-1 content. Effects of glycated and non-glycated tGLP-1 on insulin secretion were examined using glucose-responsive clonal BRIN-BD11 cells. In acute (20 min) incubations, 10(-9) mol/l tGLP-1 enhanced insulin release by 2.2-fold and 1.5-fold at 5.6 and 11.1 mmol/l glucose, respectively. In contrast, 10(-9) mol/l glycated tGLP-1 failed to stimulate secretion and insulin output was decreased by 34-73 % following glycation. At 5.6 mmol/l glucose, non-glycated tGLP-1 (3 x 10(-10) mol/l-10(-8) mol/l) exerted a 2.3-fold to 3.2-fold increase in insulin secretion compared with controls. The effect of glycated tGLP-1 at 10(-9) mol/l and 3 x 10(-9) mol/l was reduced by 51-55 % compared with non-glycated peptide, and its insulinotropic action was effectively abolished. These data indicate that when tGLP-1 is glycated at the amino terminal His7, this modification substantially reduces the glucose-dependent insulinotropic action of the peptide.
Original languageEnglish
Pages (from-to)1187-1193
JournalDiabetologia
Volume41
Issue number10
Publication statusPublished - Oct 1998

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