Elevated fasting glucose is commonly used to diagnose diabetes mellitus (DM), and enhanced hepatic glucose production is the major cause of fasting hyperglycemia in DM. During fasting, the major glucose source switches to gluconeogenesis (GNG) which produces glucose from small metabolites such as lactate, glycerol and amino acids. It is believed that lactate is the major substrate contributing to GNG through a process commonly known as the Cori cycle. However, lactate is largely generated from glucose and resynthesized to glucose via the Cori cycle, making lactate the largest direct contributor to glucose carbon but not necessarily a good source for new carbon entering GNG.
Wang et al. fasted mice for 6, 12, and 18 hours to study the relative contribution of different GNG substrates under different fasting conditions. By performing a comprehensive flux analysis, they demonstrate that lactate is the dominant direct contributor but a minor overall net carbon contributor to GNG under all three fasted conditions. Instead, glycerol is the dominant net carbon source for GNG during short and prolonged fasting. Elevated glycerol is an important biomarker for the development of hyperglycemia and type 2 DM, and patients with type 2 DM also show increased gluconeogenic flux from glycerol. Given the importance of glycerol as the dominant carbon source of gluconeogenesis, the glycerol metabolic pathway is a potentially important therapeutic target in patients with DM.