N-terminal glycation of cholecystokinin-8 abolishes its insulinotropic action on clonal pancreatic B-cells

YHA Abdel-Wahab*, FPM O'Harte, MH Mooney, JM Conlon, PR Flatt

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)

Abstract

Monoglycated cholecystokinin octapeptide (Asp(1)-glucitol CCK-X) was prepared under hyperglycaemic reducing conditions and purified by reverse phase-high performance liquid chromatography. Electrospray ionisation mass spectrometry and automated Edman degradation demonstrated that CCK-8 was glycated specifically at the amino-terminal Asp(1) residue. Effects of Asp(1)-glucitol CCK-8 and CCK-8 on insulin secretion were examined using glucose-responsive clonal BRIN-BD11 cells. In acute (20 min) incubations, 10(-10) mol/l CCK-8 enhanced insulin release by 1.2-1.5-fold at 5.6-11.1 mmol/l glucose. The stimulatory effect induced by 10(-10) mom CCK-8 was abolished following glycation. At 5.6 mmol/l glucose, CCK-8 at concentrations ranging from 10(-11) to 10(-7) mol/l induced a significant 1.6-1.9-fold increase in insulin secretion. Insulin output in the presence of Asp(1)-glucitol CCK-8 over the concentration range 10(-11)-10(-7) mol/l was decreased by 21-35% compared with CCK-8, and its insulinotropic action was effectively abolished. Asp(1)-glucitol CCK-8 at 10(-8) mol/l also completely blocked the stimulatory effects of 10(-11)-10(-8) mol/l CCK-8. These data indicate that structural modification by glycation at the amino-terminal Asp(1) residue effectively abolishes and/or antagonises the insulinotropic activity of CCK-8. (C) 1999 Elsevier Science B.V. All rights reserved.

Original languageEnglish
Pages (from-to)60-67
Number of pages8
JournalBiochimica et Biophysica Acta (BBA)-Molecular Cell Research
Volume1452
Issue number1
Publication statusPublished - 13 Oct 1999

Keywords

  • cholecystokinin-8
  • glycation
  • insulin secretion
  • BRIN-BD11 cell
  • GLUCAGON-LIKE PEPTIDE-1
  • BIOLOGICAL-ACTIVITY
  • ENDOCRINE PANCREAS
  • SECRETING CELLS
  • HUMAN-PLASMA
  • RAT ISLETS
  • GLUCOSE
  • RECEPTOR
  • CCK
  • DEGRADATION

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