Glucose phosphorylation (Table 14.2)
Glucose phosphorylation and glucose transport are tightly coupled phenomena. Isoenzymes of HK (HK-I to HK-IV) catalyze the first committed intracellular step of glucose metabolism, the conversion of glucose to G-6-P [19,93,96,97]. HK-I, HK-II, HK-III are single-chain peptides that have a number of properties in common, including a very high affinity for glucose and product inhibition by G-6-P. HK-IV, also called glucokinase, has a lower affinity for glucose and is not inhibited by G-6-P. Glucokinase (HK-IVB) is believed to be the glucose sensor in the β cell, whereas HK-IVL plays an important role in the regulation of hepatic glucose metabolism.
In human skeletal muscle HK-II transcription is regulated by insulin . HK-I is also present in human skeletal muscle but is not regulated by insulin. In response to physiologic euglycemic hyperinsulinemia, HK-II cytosolic activity, protein content, and mRNA levels increase by 50% to 200% in healthy subjects  and this is associated with the translocation of HK-II from the cytosol to the mitochondria . In contrast, insulin has no effect on HK-I activity, protein content, or mRNA levels.
Glycogen synthesis (Figure 14.15)
After glucose enters the cell and is phosphorylated, it can either be converted to glycogen or enter the glycolytic pathway. Of the glucose that enters the glycolytic pathway, approximately 90% is oxidized. In the low physiologic range of hyperinsulinemia, glycogen synthesis and glucose oxidation are of approximately equal quantitative importance. With increasing plasma insulin concentrations, glycogen synthesis becomes predominant [63,68]. Glycogen synthase is the key insulin- regulated enzyme that controls the rate of muscle glycogen for- mation [100 – 102]. Insulin enhances glycogen synthase activity by stimulating a cascade of phosphorylation-dephosphorylation reactions that ultimately lead to the activation of PP-1 (also called glycogen synthase phosphatase). The regulatory subunit (G) of PP-1 has two serine phosphorylation sites, called site 1 and site 2. Phosporylation of site 2 by cyclic adenosine monophosphate-dependent kinase (PKA) inactivates PP-1, while phosphorylation of site 1 by insulin activates PP-1, leading to the stimulation of glycogen synthase. Phosphorylation of site 1 of PP-1 by insulin in muscle is catalyzed by insulin- stimulated protein kinase-1, which is part of a family of serine/threonine protein kinases termed ribosomal S6-kinases. The effect of insulin on glycogen synthase gene transcription and translation in vivo has been studied by employing the euglycemic insulin clamp in combination with muscle biopsies. Most studies have shown that insulin does not increase glycogen synthase mRNA or protein expression in human muscle in vivo. Rather, insulin converts the inactive (phosphorylated) form of glycogen synthase to the active (dephosphorylated) form of the enzyme [56–58].
Glucose oxidation accounts for approximately 90% of total glycolytic flux, while anaerobic glycolysis accounts for the other 10% . Two enzymes, PFK and PDH, play central roles in the regulation of glycolysis and glucose oxidation, respectively. PFK represents a key functional step in control of glycolysis [103,104]. However, insulin does not exert any direct effect on this enzyme, which is primarily regulated by the energy (ATP) and fuel (citrate, acetyl-CoA) status of the cell. However, insulin indirectly stimulates PFK by increasing fructose-2,3-bisphophate, a potent activator of PFK. Insulin has no effect on muscle PFK activity, mRNA levels, or protein content in nondiabetic individuals . Insulin also regulates flux through glycolysis by increasing the activity of the multienzyme complex, PDH [106,107]. This enzyme is activated by insulin, which stimulates PDH phosphatases, thus converting the enzyme from its inactive phosphorylated form to its active dephosphorylated form (Figure 14.17). The PDH complex enzyme is also inhibited by its products, acetyl-CoA and reduced nicotinamide adenine dinucleotide (NADH).