Prolonged exposure of human beta-cells to high glucose increases their release of proinsulin during acute stimulation with glucose or arginine

The disproportionate hyperproinsulinemia in type 2 diabetes has been attrib uted to either a primary beta-cell defector a secondary dysregulation of be ta cells under sustained hyperglycemia. This study examines the effect of a 10- to 13-day exposure to 20 mmol/L glucose on subsequent proinsulin and i nsulin release by human islets isolated from nondiabetic donors. Compared t o control preparations kept at 6 mmol/L glucose, the high glucose cultured beta-cells released more proinsulin and less insulin during perifusion at 5 , 10, or 20 mmol/L glucose. The lower amounts of secreted insulin resulted from a marked reduction in cellular insulin content (5-fold lower than in c ontrols). The higher amount of secreted proinsulin is attributed to the sus tained state of cellular activation that is known to occur after prolonged exposure to high glucose levels. This activated state of the beta-cell popu lation is also held responsible for its higher secretory responsiveness to 5 mmol/L arginine at a submaximal (5 mmol/L) glucose concentration (8-fold higher proinsulin levels than in the control population). It results, toget her with the reduction in cellular insulin content, in 7- to 10-fold higher proinsulin over insulin ratios in the medium; at 5 mmol/L glucose, this ex tracellular ratio is similar to that in the cells. These data add direct su pport to the view that a disproportionate hyperproinsulinemia can result fr om a sustained activation of human beta-cells after prolonged exposure to e levated glucose levels.