GLUCAGON-LIKE PEPTIDE-1 AFFECTS GENE-TRANSCRIPTION AND MESSENGER-RIBONUCLEIC-ACID STABILITY OF COMPONENTS OF THE INSULIN SECRETORY SYSTEM IN RIN-1046-38 CELLS

It has been previously demonstrated that the enteric hormone glucagon- like peptide-1 (7-36 amide) (GLP-1) has acute effects on glucose-induc ed insulin secretion by RIN 1046-38 cells. In this study, we investiga ted the effects of extended exposure of RIN 1046-38 cells to GLP-1 and examine the mechanism by which GLP-1 synergizes with glucose in stimu lating insulin secretion. Compared with cells cultured with glucose al one, incubation of cells with glucose plus 1 or 10 nM GLP-1 for 12 or 24 h significantly increased insulin release by about 3-fold, intracel lular insulin content by 1.5-fold, and insulin messenger RNA (mRNA) by almost 2.5-fold. The insulinotropic effects of GLP-1 on RIN 1046-38 c ells were accompanied by an up-regulation of both glucose transporter- 1 (GLUT-1) and hexokinase I mRNA by about 2-fold. mRNA levels of GLUT- 2 and glucokinase, which were low in controls, were unchanged by GLP-1 treatment. Treatment of cells with a transcription inhibitor, actinom ycin D, demonstrated that elevated insulin mRNA levels after a GLP-1 e xposure are mainly due to stabilization of the mRNA. In contrast, the elevated mRNA levels of GLUT-1 and hexokinase I are the result of incr eased transcription stimulated by GLP-1 exposure. Actinomycin D blunte d the GLP-1 effect on insulin release but did not affect GLP-1-mediate d elevation of insulin mRNA. This suggests that actinomycin D inhibits the transcription of the proteins necessary for insulin biosynthesis and insulin release, such as GLUT-1 and hexokinase I. Our study sugges ts that the mechanisms by which extended exposure of RIN 1046-38 cells to GLP-1 increases glucose-stimulated insulin secretion include signi ficant up-regulation of glucose-sensing elements.