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Targeting hepatic glucose metabolism in the treatment of type 2 diabetes

Nature Reviews Drug Discovery volume 15, pages 786–804 (2016)Cite this article

Subjects

Key Points

  • Type 2 diabetes is characterized by elevated blood glucose levels and insulin resistance. Current diabetes drugs can lower blood glucose but often have side effects, and the most widely used drug — metformin — does not have a clear mechanism of action.

  • Targeting glucose and glycogen metabolism in the liver is a strategy for type 2 diabetes treatment, as it can decrease hepatic glucose output, but this approach has not been fully explored.

  • Gluconeogenic and glycogenolytic enzymes or their regulators present numerous drug targets that are currently being investigated or have the potential to be developed.

  • Transcriptional co-activators and transcription factors are emerging diabetes drug targets with the ability to control entire gene programmes involved in glucose and glycogen metabolism. It may be possible to specifically target these transcriptional regulators by modulating their protein–protein interactions or post-translational modifications.

  • Novel diabetes drugs would most probably be used in combination with existing therapies to enable sustained blood glucose suppression, and so that each drug could be used at a lower concentration to limit side effects. Drugs decreasing hepatic glucose output may be most effectively used with drugs that work by other mechanisms, such as thiazolidinediones or sodium-glucose co-transporter 2 (SGLT2) inhibitors.

  • Challenges of inhibiting hepatic glucose output include preventing hypoglycaemia, enabling tissue-specific targeting, analysing the possible effects of redirecting carbons to triglyceride or cholesterol synthesis, and avoiding lactic acidosis.

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.

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Figure 1: Schematic of glucose homeostasis in non-diabetic and diabetic states.
Figure 2: Key steps of gluconeogenesis and glycogenolysis.
Figure 3: Regulation of gluconeogenic transcription factor and co-activator activity.

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Acknowledgements

A.K.R. received funding from the National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) at the US National Institutes of Health (NIH) (F32 DK102293-01). K.S. was funded by the American Heart Association (15POST22880002). C.D.J.T. received funding from the American Diabetes Association (1-16-PDF-111). P.P. was funded by the NIH NIDDK (R01 DK069966, DK081418, DK089883) and the American Diabetes Association.

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  1. Department of Cancer Biology, and Department of Cell Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, 02115, Massachusetts, USA

    Amy K. Rines, Kfir Sharabi, Clint D. J. Tavares & Pere Puigserver

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PowerPoint slides

Glossary

Type 2 diabetes

A chronic disease of aberrant glucose homeostasis that is characterized by elevated blood glucose levels and insulin resistance.

Sulfonylureas

Type 2 diabetes drugs that stimulate insulin secretion from the pancreas through inhibition of KATP channels in β-cells.

Thiazolidinediones

Insulin-sensitizing type 2 diabetes drugs that act as peroxisome proliferator-activated receptor-γ (PPARγ) agonists (also known as glitazones).

Gluconeogenesis

A metabolic pathway utilizing carbon substrates to generate glucose.

Hyperinsulinaemia

Excess insulin levels in the blood, often caused by insulin resistance.

Hypoglycaemia

Suppressed blood glucose below normal levels.

Glycogenolysis

A metabolic pathway that breaks down glycogen into glucose.

Hyperglycaemia

Elevated blood glucose above normal levels.

Hepatic steatosis

Fatty liver disease.

Lactic acidosis

Increased acidity in the body due to a build-up of lactate; a potential complication associated with inhibition of hepatic gluconeogenesis.

Insulin secretagogues

Agents that increase insulin release from the pancreas.

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Rines, A., Sharabi, K., Tavares, C. et al. Targeting hepatic glucose metabolism in the treatment of type 2 diabetes. Nat Rev Drug Discov 15, 786–804 (2016). https://doi.org/10.1038/nrd.2016.151

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