DIFFERENTIAL EXPRESSION OF RAT INSULIN-I AND INSULIN-II MESSENGER-RIBONUCLEIC-ACID AFTER PROLONGED EXPOSURE OF ISLET BETA-CELLS TO ELEVATEDGLUCOSE-LEVELS

Prolonged exposure of rat islet beta-cells to 10 mmol/liter glucose ha s been previously shown to activate more cells into a glucose-responsi ve state (>90%) than has exposure to 6 mmol/liter glucose (50%). The p resent study demonstrates that this recruitment of more activated cell s results in 4- to B-fold higher levels of proinsulin I and proinsulin II messenger RNA (mRNA). However, only the rate of proinsulin I synth esis is increased. Failure to increase the rate of proinsulin II synth esis in the glucose-activated cells results in cellular depletion of t he insulin II isoform, which can be responsible for degranulation of b eta-cells cultured at 10 mmol/liter glucose. Higher glucose levels (20 mmol/liter) during culture did not correct this dissociation between the stimulated insulin I formation and the nonstimulated insulin II fo rmation. On the contrary, the rise from 10 to 20 mmol/liter glucose re sulted in a 2-fold reduction in the levels of proinsulin II mRNA, but not of proinsulin I mRNA; this process further increased the ratio of insulin I over insulin II to B-fold higher values than those in freshl y isolated beta-cells. The present data suggest that an elevated insul in I over insulin II ratio in pancreatic tissue is a marker for a prol onged exposure to elevated glucose levels. The increased ratio in this condition results from a transcriptional and/or a posttranscriptional failure in elevating insulin a formation while insulin I production i s stimulated in the glucose-activated beta-cells.