Comparative Modulations of Insulin Secretion, Pancreatic Insulin Content, and Proinsulin mRNA in Rats: Effects of 50% Pancreatectomy and Dexamethasone Administration

Abstract

These studies compared measurements of in vivo insulin secretion, insulin stores, and insulin synthesis. Rats were studied at 24 wk of age, either 1 or 20 wk after a sham operation (Sham) or 50% pancreatectomy (Px), reducing β-cell number. By 20 wk after surgery, an adaptation to pancreatectomy was apparent from results of serial glucose tolerance tests, done in a preliminary protocol. Some of the rats also received dexamethasone (ShamDex and PxDex, respectively), imposing insulin resistance. Insulin secretion was assessed with the acute insulin response to arginine under basal (AIR_bas) and maximum glucose-potentiated (AIR_max) states. Pancreatic insulin was measured, and insulin synthesis was estimated by measurement of proinsulin mRNA. At 1 wk after surgery, there was no difference among Sham and Px rats in AIR_bas, but in the Px rats, expected reductions of AIR_max, pancreatic insulin, and proinsulin mRNA were found. ShamDex rats had a markedly augmented AIR_bas and increased AIR_max and proinsulin mRNA. However, pancreatic insulin was reduced both in ShamDex and PxDex rats. At 20 wk after surgery, the predicted adaptation to Px was substantiated by AIR_max and proinsulin mRNA in Px rats not different from those in Sham rats, but pancreatic insulin in the Px rats remained low. AIR_bas and proinsulin mRNA were augmented in ShamDex and PxDex rats, but pancreatic insulin was again reduced, and in PxDex rats, low AIR_max and fed hyperglycemia were seen. Linear correlations of AIR_bas and AIR_max with proinsulin mRNA were observed over a roughly fourfold range of secretion and synthesis. Greater augmentation of secretion than of synthesis, occurring when conditions stressful to β-cells were imposed, may have produced the reduction of insulin stores seen among ShamDex and PxDex rats and, as a result of the depleted stores, the unexpectedly low AIR_max in PxDex rats seen at 20 wk after surgery. These findings may be pertinent to investigations of insulin secretion and insulin stores accompanying spontaneous diabetes in animals and humans.