The liver regulates nutrient supply to the entire body. Antoine Lavoisier first scientifically disputed the concept of vitalism by proving that the combustion of material in the blood formed the basis of life and mechanical work by muscle. He suggested that these nutrients were not only absorbed by digestion but that liver played an important anabolic role in maintaining life . Less than a century later, Claude Bernard observed that blood glucose persists in the absence of food, and that it is produced by liver from a substance that he called glycogen. Others pointed out that glucose is continuously supplied to the vessels of even the fasted (glycogen depleted) liver, which may have been the earliest detection of gluconeogenesis. Based on lower glucose in the venous blood of muscle, Bernard proposed that glucose was one of the combustible nutrients suggested by Lavoisier’s experiments . The next generation of scientists, such as Carl and Gerty Cori and others proved that lactate and other metabolites produced by glucose metabolism in muscle could be used as substrates to replenish glucose in liver. The cycle wherein glucose is used by peripheral tissue for glycolysis and the resultant lactate is cleared by liver to resynthesize glucose is known as the Cori cycle.
Hepatic glucose synthesis, storage, and release are under the elegant control of hormone signaling networks unimaginable to early investigators. The discovery of insulin as a critical pancreatic hormone regulating glucose metabolism, and its lack as the cause of type 1 diabetes ranks among the most important medical breakthroughs of the twentieth century. Banting, Macleod and colleagues were awarded the Nobel prize in 1922, only a year after they discovered that pancreatic insulin extracts prevented death in type 1 diabetics . Counterregulatory hormones, including glucagon, epinephrine, and certain glucocorticoids, which counter the actions of insulin by stimulating hepatic glucose production were discovered soon after. A major advance in understanding the mechanism of hormone action came in 1948 when Sutherland and coworkers demonstrated the existence of a glucagon-sensitive “glycogenolytic cascade” of kinase reactions which activates glycogen phosphorylase and controls the release of glucose from liver . In a span of 150 years, vitalism was replaced by metabolism and the liver was identified as the source of a life-sustaining carbohydrate.
During the last century our understanding of hepatic carbohydrate metabolism grew exponentially, and broadened to include roles in lipid metabolism. The exact biochemistry of gluconeogenesis, the process that converts simple substrates into glucose, was defined. The complexities by which the gluconeogenesis is regulated are still being sorted out by researchers today. In addition, the duality of liver metabolism, embodied by its ability to both make glucose and oxidize lipid during fasting, but consume glucose and synthesize lipid upon feeding became a unique and defining feature of liver physiology. This fed-to-fasted transition is marshaled by the actions of insulin, glucagon, and other counterregulatory hormones. At the molecular level, the structure and function of enzymes involved in glucose metabolism revealed fundamental mechanisms of metabolic regulation, such as phosphorylation and allosteric modifications that proved to be generalizable to all of biology.
The development of modern molecular and genetic tools has unveiled cell signaling pathways that link the regulation of hepatic glucose metabolism hormone mediated transcription and activity of specific enzymes. The dissection of molecular pathways using mouse genetics has revealed unexpected results and new paradigms of regulation. The traditional molecular physiology of liver, once explained by the adversarial influences of insulin and glucagon, is joined by a host of new hormones, transcription factors, nuclear receptors, and energy sensors. The growing complexity of our understanding of liver metabolism continues to stimulate partnerships between molecular biology, physiology, and flux/metabolomics based approaches in the hope is that these contemporary approaches will reveal a unified understanding of liver metabolism and its regulation.
Many diseases disrupt hepatic glucose metabolism, but none impact modern society more than diabetes. Caused by insulin insufficiency (type 1 diabetes) or insulin resistance (type 2 diabetes), elevated blood glucose is the hallmark of these diseases. The lack or ineffectiveness of insulin and the prevailing actions of counterregulatory hormones like glucagon cause the simultaneous overproduction and impaired disposal of glucose by the liver (Figure 13.1). Thus, following sugar ingestion, poorly controlled type 1 diabetics are unable to suppress hepatic glucose production, have impaired glucose uptake and rapidly develop hyperglycemia. In addition the total loss of insulin and ablation of glucose catabolism potently activates hepatic fat catabolism and induces excessive ketone production and ketoacidosis that can be fatal in untreated type 1 diabetes. In type 2 diabetes, insulin levels and action are partially retained but defects of hepatic glucose production and uptake persist. Despite impaired insulin signaling to pathways which suppress glucose production, tangential signaling pathways continue to stimulate the conversion of glucose to lipid and cholesterol — a so-called “insulin paradox.” This residual insulin action and other emerging mechanisms promote dyslipidemia as a significant feature of insulin resistance. Thus, both forms of diabetes cause elevated hepatic glucose production and impaired glucose uptake, but impinge differently on the way hepatic glucose and lipid metabolism interact.
The important role of dysregulated hepatic glucose balance in the pathology of diabetes has motivated more than a century of research into the fundamental regulatory mechanisms of liver glucose metabolism. Over the past decade, modern tools of molecular biology, genetics, biochemistry, physiology, and metabolomics/flux have provided a vast amount of insight into regulatory mechanisms of hepatic glucose metabolism. This chapter is an extension of the third edition of the International Textbook of Diabetes Mellitus  and devoted to integrating this new information with classic knowledge of regulatory paradigms of glucose metabolism in liver.