Insulin resistance and hyperinsulinemia are generally associated with obesity. Obese non-diabetic individuals develop a compensatory beta-cell response to adjust insulin levels to the increased demand, maintaining euglycemia. Although several studies indicate that this compensation relies on structural changes, the existence of beta-cell functional adaptations is incompletely understood. Here, we fed female mice with high-fat-diet (HFD) for 12 weeks. These animals became obese, hyperinsulinemic, insulin resistant and mild glucose intolerant while fed and fasting glycemia was comparable in HFD and control mice. Islets from HFD animals exhibited increased beta-cell mass and hypertrophy. Additionally, they had enhanced insulin gene expression and content and augmented glucose-induced insulin secretion. Electrophysiological examination of beta-cells from both groups showed no differences in KATP channel open probability and conductance. However, action potentials elicited by glucose had larger amplitude in obese mice. Glucose-induced Ca(2+) signals in intact islets, in isolated beta-cells and individual beta-cells within islets were also increased in HFD mice. Additionally, a higher proportion of glucose-responsive cells was present in obese mice. In contrast, whole-cell Ca(2+) current densities were similar in both groups. Capacitance measurements showed that depolarization-evoked exocytosis was enhanced in HFD beta-cells compared with controls. Although this augment was not significant when capacitance increases of the whole beta-cell population were normalized to cell size, the exocytotic output varied significantly when beta-cells were distributed by size ranges. All these findings indicate that beta-cell functional adaptations are present in the islet compensatory response to obesity.