Abstract
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 KATP conductance and a higher glucose sensitivity to fire action potentials. Despite no changes in voltage-gated Ca2+ currents were observed in voltage-clamp experiments, the [Ca2+]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 [Ca2+]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.
Highlights
A hallmark of type 2 diabetes is a reduced insulin secretory capacity
In islets cultured at 16.7 mM glucose, basal insulin secretion was 53% higher and the glucose-stimulated insulin secretion (GSIS) already started at 5.6 mM (EC50 7.67 mM)
We have studied the effects of 24 h in vitro culture of rodent beta cells and islets with high glucose, which recapitulates the early gain-of-function, marked by hyperinsulinaemia, during the development of glucose intolerance
Summary
A hallmark of type 2 diabetes is a reduced insulin secretory capacity. When combined with insulin resistance, this results in impaired glucose tolerance and diabetes. Normal fasting plasma glycaemia is observed in glucose intolerance, the postprandial blood glucose and the corresponding insulin response are elevated in this period In this scenario, hyperinsulinemia is characterized as a beta cell response to the intermittent exposure of pancreatic beta cells to high glucose levels as a consequence of insulin resistance. In short-term exposure, while there is some opposite evidence[6,7,8], it has been shown that the exposure of beta cells to elevated glucose levels can promote an improvement in cell function[9,10,11] This raises the interesting possibility that the hyperinsulinaemia in prediabetic individuals may not just be an insulin secretory response to overcome changes in glycaemia imposed by insulin resistance. We have investigated functional changes in beta cells after 24 h exposure to control (5.6 mM) and high (16.7 mM) glucose using an in vitro model of glucose intolerance
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