Rapid alteration of pancreatic proinsulin and preproinsulin messenger ribonucleic acid in rats treated with cyproheptadine.
Cyproheptadine (CPH) appears to be unique among islet beta-cell toxicants by virtue of its ability to rapidly and reversibly inhibit insulin biosynthesis in rats. These studies examined the mechanism of CPH-induced insulin depletion by determining the time course for CPH-induced changes in pancreatic preproinsulin mRNA, proinsulin, and insulin levels. A single oral dose of CPH decreased proinsulin levels to 35% of the control value by 3 h. Proinsulin stayed depressed for up to 24 h. Preproinsulin mRNA declined more slowly, reaching 35% of the control value at 6 h, and increased more rapidly, returning to the control value by 24 h. Pancreatic insulin levels did not decrease significantly until 24 h. Exposure of isolated rat islets to CPH for 30 min in vitro selectively inhibited proinsulin synthesis by 62%, without affecting preproinsulin mRNA levels. The dissociation between changes in proinsulin and preproinsulin mRNA levels suggests that the decrease in preproinsulin mRNA in vivo is associated with but does not cause CPH-induced changes in insulin biosynthesis.
Miller
C P
CP
Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824.
Giddings
S J
SJ
Chatterjee
A K
AK
Fischer
L J
LJ
D000199:Actins / Q000235:genetics; D000818:Animals; D002850:Chromatography, Gel; D003533:Cyproheptadine / Q000494:pharmacology*; D005215:Fasting; D066298:In Vitro Techniques; D007328:Insulin; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D010179:Pancreas / Q000378:metabolism*; D011384:Proinsulin / Q000235:genetics*; D011498:Protein Precursors / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats
D000199:Actins; D007328:Insulin; D011498:Protein Precursors; D012333:RNA, Messenger; D003533:Cyproheptadine; C013737:preproinsulin; D011384:Proinsulin