Maintaining blood glucose levels through periods of fasting or excess of nutrients is a crucial function to the survival of the organism. In this review, we describe the glucose metabolism during the fed-to-fasted transition and in two metabolic diseases characterized by either an overproduction of glucose and hyperglycemia, that is, type 2 diabetes, or by a deficiency of glucose production and hypoglycemia, that is, glycogen storage disease type I. In these two pathologies, glucose-6 phosphate plays a master role in cell signaling. Indeed, the increased flux downstream of glucose-6 phosphate leads to a complete metabolism reprograming and an accumulation of lipids in the liver and kidneys. Thus, with time, type 2 diabetic patients and GSDI patients can develop hepatic tumors and chronic kidney disease.