Regulation of hepatic glucose metabolism in health and disease

Abstract

The liver is crucial for the maintenance of normal glucose homeostasis - it produces glucose during fasting and stores glucose postprandially. However, these hepatic processes are dysregulated in type 1 and type 2 diabetes mellitus, and this imbalance contributes to hyperglycaemia in the fasted and postprandial states. Net hepatic glucose production is the summation of glucose fluxes from gluconeogenesis, glycogenolysis, glycogen synthesis, glycolysis and other pathways. In this Review, we discuss the in vivo regulation of these hepatic glucose fluxes. In particular, we highlight the importance of indirect (extrahepatic) control of hepatic gluconeogenesis and direct (hepatic) control of hepatic glycogen metabolism. We also propose a mechanism for the progression of subclinical hepatic insulin resistance to overt fasting hyperglycaemia in type 2 diabetes mellitus. Insights into the control of hepatic gluconeogenesis by metformin and insulin and into the role of lipid-induced hepatic insulin resistance in modifying gluconeogenic and net hepatic glycogen synthetic flux are also discussed. Finally, we consider the therapeutic potential of strategies that target hepatosteatosis, hyperglucagonaemia and adipose lipolysis.

Figure 1. Control of hepatic gluconeogenesis

Hepatic gluconeogenesis is regulated by the availability of substrates (light blue boxes), allostery from metabolites (green boxes), transcriptional mechanisms (purple boxes) and cellular redox state (dark blue boxes). Lipolysis in white adipose tissue (WAT) produces nonesterified fatty acids (NEFA) and glycerol, both of which can stimulate gluconeogenesis. The β-oxidation of NEFA yields mitochondrial acetyl-CoA, which promotes gluconeogenesis by allosterically activating pyruvate carboxylase (PC), which, in turn, catalyses the conversion of pyruvate to the gluconeogenic substrate oxaloacetate. Glycerol can be phosphorylated and converted into the gluconeogenic precursor dihydroxyacetone phosphate (DHAP). This process is inhibited by metformin, a non-competitive inhibitor of mitochondrial glycerol-3-phosphate dehydrogenase (mGPD). Inhibition of mGPD impairs the production of DHAP, which results in a decrease in gluconeogenesis from glycerol. Furthermore, the increased cytosolic redox state ([NADH⁺]:[NAD⁺]) that results from the inhibition of mGPD inhibits the redox-dependent enzyme lactate dehydrogenase (LDH), thus limiting the production of pyruvate, and thus gluconeogenesis, from lactate. The transcriptional regulation of gluconeogenesis by glucagon and insulin is relatively slow compared with the effects of these hormones on hepatic glycogen metabolism, acting primarily through transcriptional activation and repression, respectively, of the genes that encode the gluconeogenic cytosolic enzymes phosphoenolpyruvate carboxykinase (PCK1) and glucose-6-phosphatase (G6PC). The binding of insulin to the insulin receptor (INSR) leads to the activation of AKT, which phosphorylates and excludes the transcription factor Forkhead box O1 (FOXO1) from the nucleus. In the absence of insulin, FOXO1 promotes gluconeogenic gene transcription with its co-activator peroxisome proliferator-activated receptor-γ co-activator 1α (PGC1α; encoded by PGC1a). Glucagon binding to the glucagon receptor (GCGR) increases intracellular concentrations of cAMP and activates protein kinase A (PKA), which phosphorylates the inositol-1,4,5-trisphosphate receptor (IP₃R), increasing cytosolic Ca²⁺ levels and activating CREB-regulated transcription co-activator 2 (CRTC2). However, GCGR-dependent activation of PKA also acts acutely by inducing inhibitory phosphorylation of glycolytic regulatory enzymes, including 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (PFK2/FBPase-2) and liver-type pyruvate kinase (L-PK), to decrease glucose oxidation and thereby favour net glucose production. Small up and down arrows represent an increase or decrease, respectively, in protein level or activity. Dotted arrows represent glycolysis. CBP, CREB-binding protein; CREB, cAMP-responsive element-binding protein 1; GLUT2, glucose transporter 2.

Figure 2. Control of hepatic glycogen metabolism

a| Under fasted conditions, glycogenolysis is activated and glycogen synthesis is suppressed. Activation of the glucagon receptor (GCGR) induces increased intracellular concentrations of cyclic AMP (cAMP; indicated by an up arrow), which leads to the activation of protein kinase A (PKA). Activated PKA inhibits the transcription of the glucokinase (GCK) gene; inhibits the dissociation of GCK from glucokinase regulatory protein (GKRP), and thus induces the nuclear sequestration of GCK; phosphorylates, and thus inactivates, glycogen synthase; and phosphorylates and activates phosphorylase kinase, which activates glycogen phosphorylase by phosphorylating Ser15. Phosphorylated, active glycogen phosphorylase also binds to and inhibits the G_L subunit of protein phosphatase 1 (PP1), which prevents the PP1-dependent dephosphorylation and inactivation of glycogen synthase. The coordinated activation of glycogen phosphorylase and inhibition of glycogen synthase result in net glycogenolysis. b | Under fed conditions, hormonal and allosteric mechanisms coordinate the stimulation of glycogen synthesis through direct and indirect pathways. Glucose promotes the dissociation of GCK from GKRP, which leads to the cytoplasmic translocation of GCK; glucose also allosterically inhibits glycogen phosphorylase. The ‘direct pathway’ of glycogen synthesis involves the conversion of glucose to glucose-6-phosphate and its subsequent incorporation into glycogen, with all six carbons of the glucosyl unit intact. The ‘indirect pathway’ of glycogen synthesis involves the conversion of glucose to pyruvate, and pyruvate to glucose-6-phosphate, before incorporation into glycogen. Glucose-6-phosphate both allosterically activates glycogen synthase and is a substrate for glycogen synthesis. Insulin activates AKT, which, in turn, induces the transcription of GCK and the cytoplasmic translocation of GCK and activates phosphodiesterase 3B (PDE3B), which decreases intracellular levels of cAMP (indicated by a down arrow) and leads to the inhibition of the PKA-dependent processes described in part a. Active PP1 with its G_L targeting subunit dephosphorylates and inactivates glycogen phosphorylase, and dephosphorylates and activates glycogen synthase. The coordinated inhibition of glycogen phosphorylase and activation of glycogen synthase result in net hepatic glycogen synthesis. In parts a, b the insulin receptor (INSR) and glucagon receptor (GCGR) are shown in faded colours for context, and grey inhibitory arrows depict the processes in which they are not dominant. The dashed arrows indicate dephosphorylation. Small up and down arrows indicate an increase or decrease, respectively, in protein level or activity. GLUT2, glucose transporter 2; pSer15, phosphorylated Ser15.

Figure 3. Framework for understanding the insulin-dependent regulation of hepatic glucose metabolism

a| Under normal physiological conditions, the direct actions of hepatocellular insulin (dark blue boxes) primarily facilitate net hepatic glycogen synthesis through the activation of glucokinase (GCK) and glycogen synthase. Insulin receptor (INSR)-dependent inactivation of Forkhead box O1 (FOXO1) decreases the transcription of gluconeogenic genes, but this is a relatively slow mechanism that does not mediate the acute suppression of hepatic gluconeogenesis by insulin. Suppression of lipolysis in white adipose tissue (WAT), which is an indirect mechanism of hepatic insulin action (green boxes), acutely suppresses hepatic gluconeogenesis by decreasing the delivery of nonesterified fatty acids (NEFA) and glycerol to the liver, which results in reduced acetyl-CoA-dependent activation of pyruvate carboxylase (PC), and decreased gluconeogenesis from glycerol. The direct stimulation of net hepatic glycogen synthesis and the indirect suppression of hepatic gluconeogenesis collectively suppress hepatic glucose production (HGP). b | In type 2 diabetes mellitus (T2DM), the direct (dark blue boxes) and indirect (green boxes) effects of insulin are impaired through different mechanisms. Lipid-induced hepatic insulin resistance increases hepatic levels of diacylglycerol (DAG), which results in the activation of protein kinase Cε (PKCε) and thereby impairs direct hepatic insulin signalling through PKCε-dependent phosphorylation of INSR at Thr1160. This inhibits the INSR-dependent stimulation of hepatic glycogen synthesis in response to insulin. Impaired INSR signalling is indicated by grey arrows. In WAT, macrophage activation and consequent inflammatory signalling, as well as intrinsic adipocyte dysfunction, increase lipolysis and promote adipocyte insulin resistance, resulting in the continued delivery of NEFA and glycerol to the liver despite high plasma concentrations of insulin. Continued delivery of NEFA and glycerol to the liver promotes hepatic lipid accumulation and PKCε-mediated hepatic insulin resistance, and promotes gluconeogenesis by increasing hepatic acetyl-CoA and gluconeogenesis from glycerol. Impaired net hepatic glycogen synthesis and unrestrained hepatic gluconeogenesis together lead to increases in HGP. Small up and down arrows indicate an increase or decrease, respectively, in protein level or activity. DAG, diacylglycerol.

Figure 4. Therapeutic opportunities for dysregulated hepatic glucose metabolism

a| In patients with type 2 diabetes mellitus (T2DM), lipid-induced hepatic insulin resistance might result from activation of the diacylglycerol (DAG)–protein kinase Cε (PKCε) axis and the consequent inhibition of insulin receptor (INSR) signalling through inhibitory phosphorylation of INSR at Thr1160. This leads to impaired insulin stimulation of hepatic glycogen synthesis. In parallel, inappropriate increases in adipose lipolysis can drive hepatic gluconeogenesis through increases in hepatic acetyl-CoA and pyruvate carboxylase (PC) activity, and promote ectopic lipid accumulation in liver and muscle. These processes promote the increased hepatic glucose production (HGP) that occurs in T2DM. b | These contributors to increased HGP can be pharmacologically targeted. Mechanisms that target lipid-induced hepatic insulin resistance (purple ovals) include the selective induction of mitochondrial uncoupling in the liver (for example, with 2,4-dinitrophenol (DNP) analogues, such as DNP-methyl ether (DNPME) and other liver-targeted mitochondrial uncoupling agents) to increase hepatic fat oxidation, or mixed agonism of incretin, glucagon and/or thyroid hormone receptors (for example, a mixed agonist of glucagon receptor (GCGR), gastric inhibitory polypeptide receptor (GIPR) and glucagon-like peptide 1 receptor (GLP1R)) to promote fat oxidation. A second therapeutic strategy is to target excessive lipolysis (light green ovals) by promoting the sequestration of lipids in white adipose tissue (WAT). The inhibition of lipolysis or the stimulation of lipogenesis in WAT is predicted to decrease hepatic lipid accumulation and reverse lipid-induced hepatic insulin resistance by decreasing delivery of lipids to the liver. The thiazolidinediones (TZD) are agonists of the lipogenic transcription factor peroxisome proliferator-activated receptor-γ (PPARγ). The inhibition of lipolysis with GPR109A agonists, or with WAT-specific adipose triglyceride lipase (ATGL) inhibitors, would also be predicted to reverse dysregulated glucose metabolism through these mechanisms. Glucagon antagonism (red oval) represents a third potential therapeutic strategy to target the hyperglucagonaemia and excessive hepatic glucose production associated with T2DM if it can be dissociated from on-target adverse effects (for example, hepatic steatosis). Small up and down arrows indicate an increase or decrease, respectively, in protein level or activity. The grey arrow depicts inhibition of lipolysis. ACC, acetyl-CoA carboxylase; TAG, triacylglycerol.