Home / Resources / Clinical Gems / International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #72: Regulation of Glucose Metabolism in Liver Part 8 of 11

International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #72: Regulation of Glucose Metabolism in Liver Part 8 of 11

Apr 25, 2017

Linking molecular and metabolic regulation of hepatic glucose metabolism

Cross-talk between metabolism and molecular biology is an emerging mechanism of metabolic regulation and is particularly relevant to the control glucose metabolism in liver. Some transcription factors and nuclear receptors are activated in response to metabolites. During fasting lipid metabolites are released that activate PPARα and induce the gene expression of oxidative metabolism. The activation of mitochondrial metabolism, as described earlier, has a positive effect on gluconeogenesis and ketogenesis [57]. In contrast, hypoxia inducible factor-1α (HIF-1α) is a transcription factor that upregulates glycolysis and suppresses mitochondrial respiration when TCA cycle intermediates (e.g. fumarate, succinate, and α-ketoglutarate) are elevated. Although most commonly related to mitochondrial dysfunction in heart disease and cancer, constitutive stabilization of hepatic HIF by loss of the von Hippel-Lindau protein results in dramatically impaired hepatic TCA cycle, respiration, blunted gluconeogenesis, hepatic steaotosis, and hypoglycemic death [58]. The physiologic role of HIF in liver has not been rigorously studied. Other proteins, such as AMPK [59] and sirtuins [60], mediate the phosphorylation and acetylation of multitudes of enzymes, cell signaling proteins and transcription factors in response to cellular energy status.



AMP activated protein kinase (AMPK) is activated in response to elevated AMP (i.e., low energy). AMPK generally activates metabolic pathways that produce cellular energy and suppresses pathways that consume energy [24,59,61]. In liver, AMPK suppresses anabolic pathways like gluconeogenesis, lipogenesis, and cholesterol synthesis [61] and activates β-oxidation via PGC-1α [62]. Among AMPK’s most acute responses to energy demand is the rapid phosphorylation and inactivation of acetyl-CoA carboxylase (ACC) [63] resulting in lower malonyl-CoA, activated CPT1 and increased oxidative metabolism [64]. AMPK activation is exquisitely sensitive to the energetic stress of gluconeogenesis [65]. The normal induction of hepatic AMPK during fasting does not occur when gluconeogenesis is blunted [66]. Thus, among its many other functions, AMPK helps the liver match energy production to the energy demand of gluconeogenesis.


Sirtuins are a class of NAD+ dependent deacetylase that regulate transcription and posttranslational activity by deacetylating key sites of numerous proteins [60]. There are 7 sirtuins in humans, with sirt1 and sirt3 playing important roles in the deacetylation of cytosolic/nuclear and mitochondrial proteins, respectively. Because of their dependence on NAD+, sirtuins are potentially redox sensitive and thus metabolically regulated. For example, the cytosolic/nuclear sirt1 upregulates gluconeogenesis by deacetylating several important regulatory factors including PGC1-α and FOXO1. However, sirt1 also suppresses CREB-mediated gluconeogenic gene expression which may reduce gluconeogenesis during starvation as ketone produc- tion predominates and gluconeogenic precursors become limited. Mitochondrial sirt3 may influence gluconeogenesis by modifying the activity of β-oxidation and the TCA cycle [67].

Hepatic glucose disposal


Carbohydrate ingestion switches liver from a net glucose pro- ducer to a net glucose consumer [68]. This switch is rapid, and potentiated by specialized isoforms of glycolytic enzymes that promote glucose uptake and phosphorylation only when glucose concentration is high. In addition, feeding alters hormones that mediate the phosphorylation and expression patterns of glycolytic and gluconeogenic enzymes to favor catabolism of glucose. Net hepatic uptake of glucose (1) reduces circulating glucose concentration, (2) replenishes hepatic glycogen, and (3) converts carbohydrate to lipid for long-term energy storage (Figure 13.8). In this section we consider the factors that regulate hepatic glucose uptake and utilization.

Glucose uptake

A family of facilitated glucose transporters with unique tissue distribution and kinetic properties emerged from the work of several laboratories in the late 1980s and early 1990s. The major glucose transporter isoform of liver and pancreatic islets, GLUT2, was the second member of the family identified. All facilitated glucose transporters are equilibrium-based transporters that are capable of bidirectional glucose transport across cellular membranes, with the directionality determined by the relative intracellular and extracellular glucose concentrations. GLUT2 has a low affinity (Km > 10 mM) but a high capacity for glucose transport relative to other members of its gene family. Thus GLUT2 transports large amounts of glucose into the hepatocyte, but only when the glucose concentration is high (10 mM). In normal physiology, liver takes up significant amounts of glucose only during meal absorption.


Glucose phosphorylation in liver is primarily catalyzed by glucokinase (hexokinase IV). Like GLUT2, glucokinase (GK) has a lower affinity for glucose and a higher catalytic capacity than the other members of its gene family (i.e., hexokinases I, II, and II) [69]. Glucokinase is expressed liver, the islets of Langerhans, and certain specialized neuroendocrine cells in the pituitary and gastrointestinal tract, whereas hexokinase I is found in brain, red blood cells and many other tissues, and hexokinase II is predominantly expressed in muscle and adipose tissue. Glucokinase has an S0.5 for glucose of about 8mM, sigmoidal substrate dependency (indicated by a Hill coefficient of 1.7), and unlike hexokinases I and II, is not allosterically inhibited by the product of its reaction, glucose-6-P [69]. Thus, hepatocytes transport and phosphorylate glucose with kinetic features that allow net glucose uptake only during digestion.

In addition to the unique kinetics of hepatic glucokinase, its activity is also controlled by hormonal regulation of transcription and compartmental segregation. During fasting, glucokinase is sequestered in the nucleus by a glucokinase regulatory protein (GKRP). Ingestion of carbohydrate stimulates dissociation of glucokinase from GKRP and translocation of the enzyme from the nucleus to the cytosol where it can be active. Compartmentalization of glucokinase in the nucleus not only prevents glucose phosphorylation during gluconeogenesis, but also protects the enzyme from protein degradation. The acute induction of glucokinase by translocation to the cytosol is supplemented by a 20 – 30-fold increase in insulin-mediated glucokinase gene expression [70,71]. These large changes in glucokinase mRNA are accompanied by more modest changes in glucokinase enzyme activity [71]. The time frame for changes in glucokinase enzyme activity due to insulin action is 30–60 min.

A key illustration of glucokinase in control of human fuel homeostasis comes from the discovery that a form of non-insulin-dependent diabetes mellitus (NIDDM) known as maturity-onset diabetes of the young (MODY) type 2 is caused by mutations in the glucokinase gene [72]. All MODY-2 patients are heterozygous, with one normal and one mutated glucokinase allele. Most, but not all, mutant enzymes associated with MODY-2 exhibit large decreases in enzymatic activity due to changes in kcat and S0.5 for glucose and Km for ATP. MODY-2 patients have impaired hepatic glucose disposal, leading to an increase in net hepatic glucose production and reduced glycogen storage compared to normal subjects [73]. In addition, patients with MODY-2 have a defect in glucose-stimulated insulin secretion, due to the important role that glucokinase plays in regulating the rate of glycolysis and thereby the production of key stimulus/secretion coupling factors in islet β cells.

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