Chronic metabolic diseases, including diabetes and obesity, have become a major global health threat of the twenty-first century. Maintaining glucose homeostasis is essential for survival in mammals. Complex and highly coordinated interactions between glucose-sensing mechanisms and multiple effector systems are essential for controlling glucose levels in the blood. The central nervous system (CNS) plays a crucial role in regulating glucose homeostasis. Growing evidence indicates that disruption of glucose sensing in selective CNS areas, such as the hypothalamus, is closely interlinked with the pathogenesis of obesity and type 2 diabetes mellitus. However, the underlying intracellular mechanisms of glucose sensing in the hypothalamus remain elusive. Here, we review the current literature on hypothalamic glucose-sensing mechanisms and discuss the impact of alterations of these mechanisms on the pathogenesis of diabetes.