A defect late in stimulus-secretion coupling impairs insulin secretion in Goto-Kakizaki diabetic rats

A widely accepted genetically determined rodent model for human type 2 diab etes is the Goto-Kakizaki (GK) rat; however, the lesion(s) in the pancreati c islets of these rats has not been identified. Herein intact islets from G K rats (aged 8-14 weeks) were studied, both immediately after isolation and after 18 h in tissue culture. Despite intact contents of insulin and prote in, GK islets had markedly deficient insulin release in response to glucose , as well as to pure mitochondrial fuels or a non-nutrient membrane-depolar izing stimulus (40 mmol/l K+). In contrast, mastoparan (which activates GTP -binding proteins [GBPs]) completely circumvented any secretory defect. Bas al and stimulated levels of adenine and guanine nucleotides, the activation of phospholipase C by Ca2+ or glucose, the secretory response to pertussis toxin, and the activation of selected low-molecular weight GBPs were not i mpaired. Defects were found, however, in the autophosphorylation and cataly tic activity of cytosolic nucleoside diphosphokinase (NDPK), which may prov ide compartmentalized GTP pools to activate G-proteins; a deficient content of phosphoinositides was also detected. These studies identify novel, here tofore unappreciated, defects late in signal transduction in the islets of our colony of GK rats, possibly occurring at the site of activation by NDPK of a mastoparan-sensitive G-protein-dependent step in exocytosis.