The regulation of endogenous glucose production is central to the control of blood glucose concentrations. In non-insulin-dependent diabetes mellitus (NIDDM), increased endogenous glucose production contributes to fasting hyperglycaemia. Gluconeogenesis appears to be exaggerated in NIDDM, and it may be hypothesized that an enhanced release of gluconeogenic precursors is responsible for increased total glucose output. However, it would appear that substrate-induced stimulation of gluconeogenesis fails to increase total glucose production in healthy humans and NIDDM patients. This autoregulation of endogenous glucose production may be attained by inhibition of glycogenolysis and/or gluconeogenesis from endogenous substrate. It has also been observed that stimulation of intrahepatic disposal of neoformed glucose (mainly as glycogen synthesis) contributes to autoregulation. These observations support the concept that intrahepatic disposal of glucose-6-phosphate plays a major role in the control of endogenous glucose production.