Impaired beta-cell functions induced by chronic exposure of cultured humanpancreatic islets to high glucose

In type 2 diabetes, chronic hyperglycemia has been suggested to be detrimen tal to beta-cell function, causing reduced glucose-stimulated insulin secre tion and disproportionately elevated proinsulin. In the present study, we i nvestigated the effect on several beta-cell functions of prolonged in vitro exposure of human pancreatic islet cultures to high glucose concentrations . Islets exposed to high glucose levels (33 mmol/l) for 4 and 9 days showed dramatic decreases in glucose-induced insulin release and in islet insulin content, with increased proportion of proinsulin-like peptides relative to insulin. The depletion in insulin stores correlated with the reduction in insulin mRNA levels and human insulin promoter transcriptional activity. We also demonstrated that high glucose dramatically lowered the binding activ ity of pancreatic duodenal homeobox 1 (the glucose-sensitive transcription factor), whereas the transcription factor rat insulin promoter element 3b1 activator was less influenced and insulin enhancer factor 1 remained unaffe cted. Most of these p-cell impairments mere partially reversible when islet s first incubated for 6 days in high glucose were transferred to normal glu cose (5.5 mmol/l) concentrations for 3 days. We conclude that cultured huma n islets are sensitive to the deleterious effect of high glucose concentrat ions at multiple functional levels, and that such mechanisms may play an im portant role in the decreased insulin production and secretion of type 2 di abetic patients.