REPETITIVE INVIVO TREATMENT WITH HUMAN RECOMBINANT INTERLEUKIN-1-BETAMODIFIES BETA-CELL FUNCTION IN NORMAL RATS

It is unknown whether interleukin-1 exerts a bimodal effect on Beta-ce ll function in vivo, and whether interleukin-1 has a diabetogenic acti on in normal animals. We therefore studied: (a) acute effects 2 h afte r an intraperitoneal bolus injection of 4-mu-g of recombinant human in terleukin-1 beta per kg body weight on blood glucose, plasma levels of insulin, glucagon and corticosterone in Wistar Kyoto rats, either unt reated or pre-treated with 4-mu-g/kg of interleukin-1 daily for 3 or 5 days; (b) the cumulative effects of repetitive intraperitoneal inject ions of 4-mu-g/kg interleukin-1 on blood glucose, glucose tolerance, p lasma levels of insulin, glucagon and corticosterone, pancreatic insul in content and pancreatic ultrastructure; and (c) blood glucose and pl asma concentrations of insulin, glucagon and corticosterone 10 h after the last of five intraperitoneal injections of interleukin-1, at whic h time point the inhibitory effect of short-term interleukin-1 exposur e on insulin secretion reaches its nadir in vitro. A single injection of 4-mu-g/kg of interleukin-1 caused a slight, but significant lowerin g of blood glucose 2 h after interleukin-1 injection with no significa nt changes in plasma insulin and in spite of increases in plasma gluca gon and corticosterone. A lowering of blood glucose 2 h after interleu kin-1 administration was reproduced with 40, but not 0.4-mu-g/kg of in terleukin-1, and was also seen in interleukin-1 pre-treated rats. Two hours after the fifth injection of interleukin-1, intraperitoneal gluc ose tolerance was impaired with elevated plasma insulin and corticoste rone levels and increased pancreatic insulin content, indicating a sta te of insulin resistance. Blood glucose levels significantly increased time-dependently 4-10 h after the third and fifth injection of interl eukin-1, and diabetic values (blood glucose > 11.0 mmol/l) were observ ed 6 and 10 after the fifth injection of interleukin-1. Ten hours afte r the fifth injection of interleukin-1, diabetic blood glucose levels were observed together with a 50% reduction in plasma insulin concentr ation. Ultrastructural examination showed no signs of Beta-cell lysis. In conclusion, interleukin-1 has bimodal effects on glucose homeostas is in vivo, a slight lowering of the blood glucose followed by imparie d glucose tolerance and later by diabetic blood glucose levels. Two ho urs after the last of five daily injections of interleukin-1 impaired glucose tolerance is primarily caused by a state of insulin resistance , whereas diabetic blood glucose levels are associated with inhibition of insulin secretion. Thus, interleukin-1 causes a diabetic state in normal animals, but it remains to be demonstrated that administration of interleukin-1 to normal animals leads to permanent diabetes due to Beta-cell destruction.