The decline in β-cell mass due to the failure of β-cell compensation is one cause of the development of type 2 diabetes. Therefore, elucidation of the mechanism by which an adaptive increase in β-cell mass occurs in vivo will lead to the development of a cure for diabetes. Insulin and insulin receptor (IR)-mediated signaling pathways play an important role in the mechanism that increases β-cell mass by compensatory β-cell proliferation in response to chronic insulin resistance. However, whether IR is required for compensatory β-cell proliferation remains controversial in some situations. It might be possible that IR acts as a scaffold for the signaling complex independent of its ligand. It has also been reported that the forkhead box protein M1/polo-like kinase 1/centromere protein A pathway plays a central role in adaptive β-cell proliferation during diet-induced obesity, hyperglycemia, pregnancy, aging and acute insulin resistance. We recently reported that the cross-talk of islets with fat tissue, in addition to the liver, through humoral factors is involved in adaptive β-cell proliferation. This accommodative response of β-cell proliferation through adipocytes was observed particularly under an acute insulin resistance state in an IR/insulin signal-independent and forkhead box protein M1/polo-like kinase 1/centromere protein A pathway-dependent manner. A remaining barrier for the treatment of human diabetes using β-cells is the differences between human and rodent islets. In this review, the focus is on signaling pathways that regulate adaptive β-cell proliferation for the treatment of diabetes considering the abovementioned issues.© 2023 The Author. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.