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Diabetes Signaling Pathway


Diabetes is a metabolic disease which affects not only the glucose metabolism but also lipid and protein metabolism. It encompasses two major types, including types 1 and 2 diabetes. Type I diabetes (T1D) is characterized by destruction of the β-cells of the pancreas and insulin is not produced, whereas type II diabetes (T2D) is characterized by a progressive impairment of insulin secretion and relative decreased sensitivity of target tissues to the action of this hormone. Despite the different etiologies of T1D and T2D, the defining feature of both forms of diabetes is the ensuing hyperglycemia or pathologically induced high blood glucose levels.

An Overview of Diabetes

Diabetes is a major worldwide health problem predisposing to markedly increased cardiovascular mortality. It is associated with multiple physio-pathological changes in the cardiovascular system. Among these, endothelial dysfunction and hemostatic disorders may at least in part account for the higher risk of coronary artery disease (CAD) while micro-angiopathy, myocardial fibrosis, and abnormal myocardial metabolism have been implicated in the pathogenesis of a specific diabetic cardiomyopathy. When it occurs in diabetic patients, heart failure (HF) is, in most cases, a consequence of CAD.

The mechanisms of diabetes

Figure 1. The mechanisms of diabetes. (Bauters, C; et al. 2003)

In addition, the pathogenesis of diabetes is not only implicated in the oxidative stress but also the hyperglycemia-induced protein glycation that generates superoxide free radicals. The generation of reactive oxygen species may lead to lipid peroxidation and formation of reactive products, which may be involved in severe damage of cell molecules and structures. The clinical diagnosis of diabetes includes determination of the levels of glycosylated hemoglobin A1c (HbA1c), which gives an overview of blood glucose levels over a 3 month period. As type II diabetes mellitus continues to increase world wide, there is an enhanced need for effective disease management.

The glycosylated hemoglobin A1c

Figure 2. The glycosylated hemoglobin A1c.

The Process of Diabetes Signaling Pathways

Increasing studies have confirmed that the pathogenesis of diabetes is related to various signaling pathways, such as insulin signaling pathway, AMPK pathway, and PPAR regulation and chromatin modification pathways. These signaling pathways have thus become the major source of the promising novel drug targets to treat metabolic diseases and diabetes.

Insulin

In diabetes, the insulin resistance is partly mediated by lowering insulin receptor (IR) expression level. This is followed by impaired tyrosine phosphorylation of IR and subsequent tyrosine phosphorylation of IRS-1 and the attenuated association the regulatory subunit (P85) of phosphoinositide-3 kinase (PI3K) with IRS-1. This results in subsequent deactivation of its catalytic subunit (P110). Therefore, when the reduction of PI3K signaling pathway occurs, the protein kinase AKT will be activated and the reduction of glucose transport will occur. PI3K subsequently activates glycogen synthase kinase (GSK) 3β pathway to regulate glycogen and lipid synthesis and stimulate glucose uptake. PI3K also regulates cell proliferation through Ras/Mek/ERK pathway.

AMPK

AMP-activated protein kinase (AMPK) acts as a central energy sensor. Activated AMPK deactivates gluconeogenic enzymes PEPCK and G6Pase thereby decreasing hepatic glucose production. It increases glucose uptake by inducing glucose transporters (GLUT). AMPK also stimulates lipid metabolism by decreasing malonyl-CoA levels through inhibiting acetyl-CoA carboxylase (ACC) and activation of malonyl-CoA decarboxylase (MCD). The natural product berberine (BBR) was discovered to reduce body weight, improve glucose tolerance, and ameliorate insulin action by activation of AMPK in peripheral tissues.

PPAR

Peroxisome proliferators-activated receptors (PPARs) are ligand-activated transcription factors, which have been used as promising therapeutic targets for drug discovery against metabolic syndrome. There are three isoforms for PPARs. PPARα is expressed in liver, heart, muscle and kidney and regulates fatty acid metabolism and transport. PPARγ is expressed in adipose, muscle and macrophage, and regulates adipogenesis and lipid storage. PPARδ is ubiquitously expressed and is involved in fat oxidation, energy expenditure and lipid storage.

The Therapy for Diabetes

The pathogenesis of diabetes is complicated, and development of the safe and effective drugs against diabetes is full of challenge. Currently, researchers have been engaged in anti-diabetic lead compound discovery by targeting the key targets or pathways involved in the disease. In comparison with synthetic compounds, natural molecules exert multiple advantages for their large-scale structure and target diversity both in single target and signaling pathway-based drug discovery strategies.

References:

1. Bauters, C; et al. Influence of diabetes mellitus on heart failure risk and outcome. Cardiovascular Diabetology. 2003.
2. Liu, Q; et al. Small molecules from natural sources, targeting signaling pathways in diabetes. Biochim Biophys Acta. 2010, 1799(10-12): 854-65.

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