Hepatic glucose production
Typical lean humans spend more than half of their lives in the post-absorptive state, with less than 5 g of glucose circulating in their blood to support life . Many tissues rely on glucose as their primary fuel source. Notable examples are brain, which has limited access to fatty acids, and erythrocytes which do not possess mitochondria and, therefore, rely on glycolysis to meet energy requirements. Even during rest the body uses roughly 8 g of glucose per hour, and during exercise this rate can increase more than twofold. The body would deplete circulating glucose in less than 30 min, resulting in severe hypoglycemia, loss of neurologic function and death, if not for a constant endogenous supply of glucose. Under most conditions, liver provides approximately 90–95% of circulating glucose. This hepatic glucose production is maintained at precisely the same rate as whole body glucose utilization, keeping blood glucose between 80 – 100 mg dL−1 regardless of nutritional state or activity level.
Hepatic glucose production is supplied by the breakdown of stored glycogen (glycogenolysis) and the synthesis of new glucose from noncarbohydrate precursors (gluconeogenesis). In humans, glycogenolysis and gluconeogenesis contribute about equally to hepatic glucose production following an overnight fast . After 48 hours of fasting, glycogen is depleted and glucose is produced almost exclusively by gluconeogenesis .
Inasmuch as most mechanistic studies referenced in this chapter have been carried out in rodent models, it is important to note that rats and mice deplete hepatic glycogen much faster, over approximately 24 and 12 h, respectively. Gluconeogenesis and glycogenolysis are regulated by hormone action and autonomic mechanisms that alter substrate supply, allostery, posttranslational modification and enzyme transcription. These regulatory mechanisms are disrupted during type 1 and 2 diabetes leading to an inability to suppress gluconeogenesis and/or glycogenolysis and the development of hyperglycemia.
The metabolic mechanism of hyperglycemia during diabetes is one of the most widely studied pathologic features of any disease. Hyperglycemia (>124 mg dL−1 glucose) occurs when the equilibrium between hepatic glucose production and peripheral glucose utilization is disrupted. Either impaired glucose utilization or elevated hepatic glucose production can cause hyperglycemia (Figure 13.1). Many but not all studies find endogenous glucose production to be increased during type 2 diabetes. Perhaps more pertinent for type 2 diabetes is the failure of hyperinsulinemia to suppress hepatic glucose production, which is indicative of hepatic insulin resistance, particularly with regard to glucose metabolism . Hepatic insulin resistance can be quantified using hyperinsulinemic-euglycemic clamp approaches . Exogenous insulin is administered to achieve hyperinsulinemia while glucose is simultaneously infused to maintain normoglycemia. The rate of glucose infusion required to maintain normoglycemia reflects both insulin mediated glucose disposal and suppression of hepatic glucose production. If an isotope tracer of glucose is co-infused, the rate of glucose appearance can be determined from the dilution of the tracer . Type 2 diabetic humans have an impaired ability to suppress both hepatic gluconeogenesis and glycogenolysis  in response to insulin, and this revelation has led to extensive efforts to understand the metabolic, hormonal, and transcriptional regulation of these pathways using genetically malleable models such as mice.
Hepatocytes store glucose as polymeric units called glycogen. Fully formed glycogen particles contain thousands of glucose molecules, and can have a molecular mass in excess of 1 × 106Da. Glycogen synthesis is an important mechanism of hepatic glucose disposal during feeding, and will be discussed later. Glycogen degradation, or glycogenolysis, converts stored glycogen into glucose during fasting. This process is initiated by removal of glucose residues one at a time from the outer, nonreducing termini of the glycogen particle. Glycogenolysis is catalyzed by the active form of glycogen phosphorylase (phosphorylase a). This enzyme catalyzes phosphorolytic cleavage of the α-1,4-glycosidic bonds of the glucose polymer to yield glucose-1-phosphate. Glucose-1-phosphate is then converted to glucose-6-phosphate by phosphoglucomutase. The G6P that is formed from glycogenolysis is hydrolyzed to free glucose via the G6Pase complex, and then transported into the circulation by GLUT2 and other emergent mechanisms. The glycogenolytic cascade is activated in liver in the fasting state by a falling insulin concentration and rising glucagon concentration. The former reduces glycogen synthesis and the latter induces glycogenolysis (Figure 13.2). However, the switch between the two conditions may not be instantaneous or complete, so glycogen synthesis and degradation can occur simultaneously. This phenomenon is called “glycogen cycling” and is most often observed in the postprandial state or hyperglycemic state . Glycogenolysis is essential for maintaining glucose supply to the brain and the central nervous system during early stages of fasting, ostensibly as a buffer until counterregulatory mechanisms fully activate gluconeogenesis. The human liver contains about 100g of glucose as glycogen, which it depletes over about 48 hours of continuous fasting .