Short-term high glucose culture potentiates pancreatic beta cell function

The exposure of pancreatic islets to high glucose is believed to be one of the causal factors of the progressive lowering of insulin secretion in the development of type 2 diabetes. The progression of beta cell failure to type 2 diabetes is preceded by an early positive increase in the insulin secretory response to glucose, which is only later followed by a loss in the secretion capacity of pancreatic islets. Here we have investigated the electrophysiological mechanisms underlying the early glucose-mediated gain of function. Rodent pancreatic islets or dispersed islet cells were cultured in medium containing either 5.6 (control) or 16.7 (high-glucose) mM glucose for 24 h after isolation. Glucose-stimulated insulin secretion was enhanced in a concentration-dependent manner in high glucose-cultured islets. This was associated with a positive effect on beta cell exocytotic capacity, a lower basal K(ATP) conductance and a higher glucose sensitivity to fire action potentials. Despite no changes in voltage-gated Ca(2+) currents were observed in voltage-clamp experiments, the [Ca(2+)](I) responses to glucose were drastically increased in high glucose-cultured cells. Of note, voltage-dependent K(+) currents were decreased and their activation was shifted to more depolarized potentials by high-glucose culture. This decrease in voltage-dependent K(+) channel (Kv) current may be responsible for the elevated [Ca(2+)](I) response to metabolism-dependent and independent stimuli, associated with more depolarized membrane potentials with lower amplitude oscillations in high glucose-cultured beta cells. Overall these results show that beta cells improve their response to acute challenges after short-term culture with high glucose by a mechanism that involves modulation not only of metabolism but also of ion fluxes and exocytosis, in which Kv activity appears as an important regulator.