Inhibitory effects of streptozotocin, tumor necrosis factor-alpha, and interleukin-1 beta on glucokinase activity in pancreatic islets and gene expression of GLUT2 and glucokinase

Treatment of streptozotocin (ST), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1 beta (IL-1 beta) resulted in destroying insulin-secreting beta-cells of pancreatic islets and impairment of islet glucose oxidation and glucose-induced insulin secretion. IL-1 beta and TNF-alpha inhibited in sulin release and glucose utilization and oxidation. It was shown that the inhibitory effects of ST, IL-1 beta, and TNF-alpha were due to impaired glu cokinase activity. Glucokinase activity was severely impaired by ST, IL-1 b eta, and TNF-alpha treatments, as confirmed by assaying enzymes and nucleot ides associated with glycolysis and glucose oxidation, On the other hand, n itric oxide was a factor of the deleterious effects of IL-1 beta, TNF-alpha , and ST on pancreatic islets, Incubation of mouse pancreatic islets with S T at various concentrations of impairing insulin secretion resulted in gene ration of nitrite, stimulation of islet guanylyl cyclase and accumulation o f cGMP, and inhibition of pancreatic islet mitochondrial aconitase activity to degree similar to those raised by IL-1 beta and TNF-alpha. When the eff ects of IL-1 beta and TNF-alpha on the gene expression of pancreatic GLUT2 and glucokinase were examined, the level of GLUT2 and glucokinase mRNA in p ancreatic islets was significantly decreased. This suggested that IL-1 beta , and TNF-alpha downregulate gene expression of GLUT2 and glucokinase in pa ncreatic beta-cells. (C) 1999 Academic Press.