In type 2 diabetes, there is a defect in the regulation of functional β-cell mass to overcome high-fat (HF) diet-induced insulin resistance. Many signals and pathways have been implicated in β-cell function, proliferation and apoptosis. The co-ordinated regulation of functional β-cell mass by insulin signalling and glucose metabolism under HF diet-induced insulin-resistant conditions is discussed in this article. Insulin receptor substrate (IRS)-2 is one of the two major substrates for the insulin signalling. Interestingly, IRS-2 is involved in the regulation of β-cell proliferation, as has been demonstrated using knockout mice models. On the other hand, in an animal model for human type 2 diabetes with impaired insulin secretion because of insufficiency of glucose metabolism, decreased β-cell proliferation was observed in mice with β-cell-specific glucokinase haploinsufficiency (Gck⁺/⁻) fed a HF diet without upregulation of IRS-2 in β-cells, which was reversed by overexpression of IRS-2 in β-cells. As to the mechanism underlying the upregulation of IRS-2 in β-cells, glucose metabolism plays an important role independently of insulin, and phosphorylation of cAMP response element-binding protein triggered by calcium-dependent signalling is the critical pathway. Downstream from insulin signalling via IRS-2 in β-cells, a reduction in FoxO1 nuclear exclusion contributes to the insufficient proliferative response of β-cells to insulin resistance. These findings suggest that IRS-2 is critical for β-cell hyperplasia in response to HF diet-induced insulin resistance.