Osteocalcin (OC) is encoded by the bone γ-carboxyglutamate (Gla) protein (BGLAP) gene, and it is released by osteoblasts during osteogenesis. Its expression can be modulated by growth factors, hormones, cytokines and physical stimuli via signal transduction pathways, binding to the BGLAP gene promoter or interactions with nuclear transcription factors. It was recently demonstrated that uncarboxylated OC improves glucose tolerance and insulin sensitivity in mice by increasing the expression and secretion of insulin in β-cells and of adiponectin in adipocytes. Humans with type 2 diabetes have significantly lower serum levels of OC than healthy individuals and indeed, serum OC levels have been inversely correlated with fasting plasma glucose, fasting insulin and the homeostasis model assessment of insulin resistance (HOMA-IR) index. Moreover, several drugs have been shown to influence OC expression and its serum concentration. This review summarizes the molecular mechanisms involved in the modulation of OC expression, and discusses the potential relevance of OC in the pathogenesis and treatment of diabetes.