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Lipid phosphatases as drug discovery targets for type 2 diabetes

Key Points

  • The incidence of type 2 diabetes in the United States and worldwide has reached epidemic proportions and continues to rise at an alarming rate. It is clear that more effective pharmaceutical options for the treatment of this devastating and costly disease are urgently needed.

  • Recent advances in our understanding of the molecular events by which insulin provokes its many biological responses should lead to new drug discovery opportunities. Insulin stimulation of phosphatidylinositol 3-kinase (PI3K) activity is essential for most of the hormone's metabolic responses and is reduced in insulin-resistant, diabetic individuals.

  • The identification of compounds which potentiate insulin-stimulated PI3K signaling might prove useful in the treatment of type 2 diabetics. One possible mechanism to achieve this goal is through the inhibition of lipid phosphatases that antagonize insulin-dependent PI3K signaling.

  • Phosphatase and tensin homologue on chromosome 10 (PTEN) is a lipid 3′-phosphatase which degrades PtdIns(3,4,5)P3, the important second messenger produced by PI3K activity, and antagonizes insulin signaling. While tissue-specific PTEN knockout studies in muscle and fat reveal 'therapeutic' potential, the positive metabolic impact of reduced PTEN expression in the liver is offset by the presence of hepatomegaly, liver steatosis and hepatic tumors.

  • Sequence homology 2 (SH2)-containing inositol 5′-phosphatase 2 (SHIP2) is a lipid 5′-phosphatase that also degrades PtdIns(3,4,5)P3 and attenuates insulin signaling. Genetic deletion of SHIP2 expression in mice appears to enhance insulin signaling and confer resistance to the detrimental effects of a high-fat diet, including providing dramatic protection from the development of obesity.

  • The role of human PTEN as a tumor suppressor in numerous tissues argues against the development of small molecule PTEN inhibitors for the treatment of diabetes. The apparent absence of tumor formation in SHIP2 knockout mice combined with a lack of any compelling evidence for human SHIP2 acting as a tumor suppressor is more encouraging for the potential utility of a SHIP2 inhibitor.

  • The absence of significant pharmaceutical experience in the identification and development of small-molecule inhibitors against lipid phosphatases, together with particular aspects of SHIP2 biology, present challenges to any drug discovery effort against this novel target. It is possible that recent technical advances combined with an enhanced understanding of SHIP2 biology might provide the solution required.

Abstract

The soaring incidence of type 2 diabetes has created pressure for new pharmaceutical strategies to treat this devastating disease. With much of the focus on overcoming insulin resistance, investigation has focused on finding ways to restore activation of the phosphatidylinositol 3′-kinase pathway, which is diminished in many patients with type 2 diabetes. Here we review the evidence that lipid phosphatases, specifically PTEN and SHIP2, attenuate this important insulin signalling pathway. Both in vivo and in vitro studies indicate their role in regulating whole-body energy metabolism, and possibly weight gain as well. The promise and challenges presented by this new class of drug discovery targets will also be discussed.

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Figure 1: Insulin stimulation of PI3K activity produces numerous biological responses.
Figure 2: Human PTEN protein domain structure.
Figure 3: SHIP1 and SHIP2 protein domain structures.

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Correspondence to Dan F. Lazar.

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D.F.L. is an employee and shareholder of Eli Lilly and Co.

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DATABASES

OMIM

Type 2 diabetes mellitus

Glossary

Polyphosphoinositide phosphatases

A superfamily of enzymes that act on inositol phospholipids (for example, PtdIns(3,4,5)P3) and/or water-soluble inositol phosphates (for example, Ins(1,3,4,5)P4) to remove specific phosphates while often displaying unique substrate preferences.

Pleckstrin homology domain

Pleckstrin homology domains are often found in intracellular signalling or cytoskeletal proteins and can confer several possible activities, including the capacity to bind inositol phospholipids such as PtdIns(3,4,5)P3.

GLUT4

An insulin-sensitive glucose transporter isoform with a restricted tissue distribution that includes skeletal muscle cells and adipocytes.

3T3-L1 adipocytes

Obtained by the experimental differentiation of 3T3-L1 pre-adipocytes, this cell-culture model is widely used for the in vitro study of insulin signalling.

db/db mice

A model of type 2 diabetes with obesity, insulin resistance and hyperglycaemia that is a consequence of an inactivating mutation in the leptin receptor.

ob/ob mice

Obese, insulin-resistant animals that are leptin-deficient because of a mutation in the ob gene.

Insulin tolerance test

A test that assesses the degree of glucose lowering provided by a bolus of insulin administered orally (or sometimes intravenously), thereby providing a measure of in vivo insulin sensitivity.

Adipokines

Any of several cytokines (including leptin, tumour-necrosis factor-α and adiponectin) released by adipocytes and frequently capable of modulating insulin sensitivity, appetite and/or energy metabolism.

Glucose intolerance

Impaired capacity of the body to clear glucose from the blood following administration of a sugar bolus, often reflecting insulin resistance.

Diabetic obese Zucker (fa/fa) rats

Leptin-receptor deficient animal model for which the males are particularly prone to the development of type 2 diabetes, including obesity, insulin resistance and β-cell failure.

L6 myotubes

A tissue culture model of rat skeletal muscle cells frequently used for the study of insulin signalling and metabolic activity, including the regulation of glucose uptake.

2-Deoxyglucose uptake

A method of assessing 'glucose' transport into cells that relies upon the use of a radiolabelled analogue of glucose not subject to significant intracellular metabolism.

Anorexigenic

The capacity to cause or promote the suppression of food intake.

Metabolic syndrome

Terminology sometimes used to describe the combination of obesity, insulin resistance, hyperglycaemia, dyslipidaemia and hypertension frequently observed in type 2 diabetics.

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Lazar, D., Saltiel, A. Lipid phosphatases as drug discovery targets for type 2 diabetes. Nat Rev Drug Discov 5, 333–342 (2006). https://doi.org/10.1038/nrd2007

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