As we previously demonstrated, there is an adaptive increase in insulin secretion in insulin resistance in the model of high-fat fed female mice. Since it is assumed that islets also adapt to insulin resistance with β-cell expansion, we have now examined beta volume in this experimental model. Female C57BL/6JBomTac mice were therefore fed a high-fat diet (60% fat from lard) for three, six or twelve months and beta cell volume was estimated as β-cell area per islet, individual β-cell size, and β-cell number per islet. Control animals were fed a normal chow (11% fat). We found that β-cell area per islet and total number of beta cells per islet were increased already after three months of high-fat feeding and that this increase was sustained throughout the twelve month study period. In contrast, individual beta cell size showed a dynamic pattern with a reduction after three months followed by increase after six and twelve months. The number of apoptosis (caspase-3) positive β-cells was reduced after three months, whereas there was no difference in proliferation (Ki-67) positive cells, although these were generally rarely observed. Thus, we conclude that insulin resistance accompanying high-fat feeding in mice is followed by progressive β-cell expansion as evident by early increased islet β-cell volume and total number of β-cells, whereas individual β-cell size showed a dynamic response. The model is also associated with an early reduced apoptosis, which may contribute to the increased beta cell volume.