Glucose-induced [Ca2+](i) abnormalities in human pancreatic islets - Important role of overstimulation

Chronic hyperglycemia desensitizes beta -cells to glucose. To further defin e the mechanisms behind desensitization and the role of overstimulation, we tested human pancreatic islets for the effects of long-term elevated gluco se levels on cytoplasmic free Ca2+ concentration ([Ca2+](i)) and its relati onship to overstimulation. Islets were cultured for 48 h with 5.5 or 27 mmo l/l glucose. Culture with 27 mmol/l glucose obliterated postculture insulin responses to 27 mmol/l glucose. This desensitization was specific for gluc ose versus arginine, Desensitization was accompanied by three major [Ca2+]( i) abnormalities: 1) elevated basal [Ca2+](i),) loss of a glucose-induced r ise in [Ca2+](i) and 3) perturbations of oscillatory activity with a decrea se in glucose-induced slow oscillations (0.2-0.5 min(-1)). Coculture with 0 .3 mmol/l diazoxide was performed to probe the role of overstimulation. Nei ther glucose nor diazoxide affected islet glucose utilization or oxidation, Coculture with diazoxide and 27 mmol/l glucose significantly (P < 0.05) re stored postculture insulin responses to glucose and lowered basal [Ca2+](i) and normalized glucose-induced oscillatory activity. However, diazoxide co mpletely failed to revive an increase in [Ca2+](i) during postculture gluco se stimulation. In conclusion, desensitization of glucose-induced insulin s ecretion in human pancreatic islets is induced in parallel with major gluco se-specific [Ca2+](i) abnormalities. Overstimulation is an important but no t exclusive factor behind [Ca2+](i) abnormalities.