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

Treatment of streptozotocin (ST), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) resulted in destroying insulin-secreting β-cells of pancreatic islets and impairment of islet glucose oxidation and glucose- induced insulin secretion. IL-1β and TNF-α inhibited insulin release and glucose utilization and oxidation. It was shown that the inhibitory effects of ST, IL-1β, and TNF-α were due to impaired glucokinase activity. Glucokinase activity was severely impaired by ST, IL-1β, and TNF-α treatments, as confirmed by assaying enzymes and nucleotides associated with glycolysis and glucose oxidation. On the other hand, nitric oxide was a factor of the deleterious effects of IL-1β, TNF-α, and ST on pancreatic islets. Incubation of mouse pancreatic islets with ST at various concentrations of impairing insulin secretion resulted in generation of nitrite, stimulation of islet guanylyl cyclase and accumulation of cGMP, and inhibition of pancreatic islet mitochondrial aconitase activity to degree similar to those raised by IL-1β and TNF-α. When the effects of IL-1β and TNF-α on the gene expression of pancreatic GLUT2 and glucokinase were examined, the level of GLUT2 and glucokinase mRNA in pancreatic islets was significantly decreased. This suggested that IL-1β and TNF-α downregulate gene expression of GLUT2 and glucokinase in pancreatic β-cells.