Compensatory beta cell growth occurs in accordance to overweight and increasing insulin demands. The proliferative actions of insulin and insulin-like growth factors are mediated via the IRS-2-PI(3)K-Akt pathway of pleiotropic insulin signaling. However, sustained activation leads to negative feedback via the mTOR-induced proteasomal degradation of IRS-2. The proliferative actions of incretins and adipokines are mediated via other pathways that ultimately converge with the IRS-2-PI(3)K-Akt axis. The incretins GIP and GLP-1 increase IRS-2 levels in beta cells by acting via the cAMP-PKA pathway, whereas leptin inhibits PTEN activity via CK2-dependent pathways. By increasing PIP(3) availability the adipokine amplifies the magnitude as well as duration of factors acting via the IRS-2-PI(3)K-Akt pathway. Considering that AMPK prevents mTOR-induced degradation of IRS-2, we propose that adiponectin and leptin cooperatively achieve compensatory beta cell growth in accordance to adiposity. In conditions of overt obesity, when adiponectin levels are too low to provide sufficient IRS-2 levels, loss of compensatory beta cell growth may occur.