Targeting hepatic glucose metabolism in the treatment of type 2 diabetes

Abstract

Type 2 diabetes mellitus is characterized by the dysregulation of glucose homeostasis, resulting in hyperglycaemia. Although current diabetes treatments have exhibited some success in lowering blood glucose levels, their effect is not always sustained and their use may be associated with undesirable side effects, such as hypoglycaemia. Novel antidiabetic drugs, which may be used in combination with existing therapies, are therefore needed. The potential of specifically targeting the liver to normalize blood glucose levels has not been fully exploited. Here, we review the molecular mechanisms controlling hepatic gluconeogenesis and glycogen storage, and assess the prospect of therapeutically targeting associated pathways to treat type 2 diabetes.

Figure 1. Schematic of glucose homeostasis in non-diabetic and diabetic states

After feeding, pancreatic beta cells release insulin to inhibit gluconeogenesis and glycogenolysis in the liver, decreasing glucose output to the circulation. Insulin also acts at peripheral tissues to increase glucose uptake, resulting in decreased blood glucose. During fasting, pancreatic alpha cells release glucagon to increase gluconeogenesis and glycogenolysis in the liver, increasing circulating blood glucose. In the diabetic state, insulin action is decreased at the liver and/or peripheral tissues and glucagon action is enhanced, leading to increased hepatic gluconeogenesis and glycogenolysis, increased glucose release to the circulation, repressed glucose uptake into peripheral tissues, and increased blood glucose levels.

Figure 2. Key steps of gluconeogenesis and glycogenolysis

In gluconeogenesis, lactate and amino acids are first converted to pyruvate, either directly or indirectly through tricarboxylic acid (TCA) cycle intermediates. Pyruvate is then shuttled from the cytosol into the mitochondria where it is used to generate oxaloacetate by pyruvate carboxylase. Oxaloacetate is converted to aspartate, exported from the mitochondria and re-converted to oxaloacetate, and then is made into phosphoenolpyruvate (PEP) by PEP carboxylase (PEPCK). PEP is catalytically altered to fructose 1,6-bisphosphate, and glycerol can also enter gluconeogenesis through conversion to fructose 1,6-bisphosphate. Fructose 1,6-bisphosphate is then altered to fructose-6-phosphate by fructose 1,6-bisphosphatase (FBPase), then to glucose-6-phosphate by phosphohexose isomerase. Finally, the phosphate on glucose-6-phosphate is removed by the liver-specific enzyme glucose 6-phosphatase (G-6-Pase) to generate glucose, which can be exported to the circulation. During glycogenolysis, the glucose residues in glycogen are phosphorylated by glycogen phosphorylase to produce glucose-1-phosphate, then glucose-6-phosphate through phosphoglucomutase. The reverse reaction is catalyzed by glycogen synthase, which generates glycogen from UDP-glucose that is converted from glucose-1-phosphate by glucose-1-phosphate uridyltransferase. As in gluconeogenesis, the glucose-6-phosphate produced through glycogenolysis is converted to glucose by G-6-Pase, and released to the circulation. Enzymes that have been investigated for drug targeting are highlighted in red.

Figure 3. Regulation of gluconeogenic transcription factor and coactivator activity

a. Regulation of PGC-1α. During fasting, induction of PGC-1α in the liver is achieved through the action of glucagon, which increases cyclic AMP (cAMP), PKA activity, and CREB to increase PGC-1α transcription. Enhanced PGC-1α expression is inhibited by the Cdk inhibitor p16^Ink4a, which decreases gluconeogenic gene expression through suppression of PKA activity. Activated PGC-1α coactivates transcription of several transcription factor (TF) binding partners, including HNF4, FoxO1, and GR, to increase transcription of target genes such as PEPCK and G-6-Pase. PGC-1α activity can be altered by PTMs, including acetylation and phosphorylation which decrease its activity, and methylation which increases its activity. Insulin decreases PGC-1α activity by increasing its phosphorylation by Akt and Clk2, and S6K also inhibits PGC-1α through phosphorylation. PGC-1α acetylation is decreased by Sirt1 and increased by GCN5, whose activity is increased by Cdk4 and Sirt1 and inhibited by CITED2. PGC-1α is methylated by PRMT1. b. Regulation of FoxO activity. The transcription factor FoxO is co-activated by PGC-1α to increase transcription of gluconeogenic genes. FoxO activity is modulated by PTMs, including phosphorylation by Akt which leads to its polyubiquitination and degradation, and removal of monoubiquitination by USP7 which decreases its transcriptional activity. FoxO can also be activated through deacetylation by HDAC3 in response to insulin signaling. c. Regulation of CREB activity. CREB is a transcription factor that increases gluconeogenic gene expression from CRE-response elements when activated by a co-activator such as p300, CBP, or CRTC2. CREB activity is increased by phosphorylation at S133, which is enhanced by glucagon-stimulated PKA activity, which is inhibited by Cry1/2. CRE-response element transcription can also be increased by glucagon through dephosphorylation of CRTC2, which increases its activity as a CREB co-activator, or inhibited by insulin-dependent Sik2-mediated phosphorylation of CRTC2, decreasing its activity as a co-activator. CREB activity is inhibited by binding of the transcription factor TCF7L2 to CRE-response elements, which blocks binding of CREB. Potential therapeutic strategies and agents targeting the activity of PGC-1α, FOXO and CREB are shown. P, phosphorylation; Ac, acetylation; Me, methylation; Ub, ubiquitination.