Conversely, negative modulation of REV-ERBα may also improve β-cell function under glucotoxicity via upregulation of BMAL1. This is in line with a recent observation that clock amplitude-enhancing compound Nobiletin (as opposed to SR9009) enhances in vitro glucose-stimulated insulin secretion in T2DM human islets, whereas enhancement of β-cell circadian clock in vivo via conditional overexpression of Bmal1 improves insulin secretion and glucose tolerance in mice exposed to diet-induced obesity [49, 50]. Here, CLOCK is linked to obesity due to melanocortin 4 receptor deficiency.