Molecular Mechanisms of Antipsychotic Drug-Induced Diabetes

Abstract

Antipsychotic drugs (APDs) are widely prescribed to control various mental disorders. As mental disorders are chronic diseases, these drugs are often used over a life-time. However, APDs can cause serious glucometabolic side-effects including type 2 diabetes and hyperglycaemic emergency, leading to medication non-compliance. At present, there is no effective approach to overcome these side-effects. Understanding the mechanisms for APD-induced diabetes should be helpful in prevention and treatment of these side-effects of APDs and thus improve the clinical outcomes of APDs. In this review, the potential mechanisms for APD-induced diabetes are summarized so that novel approaches can be considered to relieve APD-induced diabetes. APD-induced diabetes could be mediated by multiple mechanisms: (1) APDs can inhibit the insulin signaling pathway in the target cells such as muscle cells, hepatocytes and adipocytes to cause insulin resistance; (2) APD-induced obesity can result in high levels of free fatty acids (FFA) and inflammation, which can also cause insulin resistance. (3) APDs can cause direct damage to β-cells, leading to dysfunction and apoptosis of β-cells. A recent theory considers that both β-cell damage and insulin resistance are necessary factors for the development of diabetes. In high-fat diet-induced diabetes, the compensatory ability of β-cells is gradually damaged, while APDs cause direct β-cell damage, accounting for the severe form of APD-induced diabetes. Based on these mechanisms, effective prevention of APD-induced diabetes may need an integrated approach to combat various effects of APDs on multiple pathways.

Keywords: antipsychotics; apoptosis; diabetes mellitus; insulin resistance; metabolic disorders; obesity; pancreatic beta cell.

Figure 1

Insulin signaling pathways and antipsychotic effects. Insulin binds to insulin receptors to activate IRS1, leading to activation of PI3K, which converts PIP2 into PIP3, PIP3 brings Akt2 on to the membrane where PDK1/2 and mTORC2 phosphorylate Akt2. Akt2 activates AS160, which blocks Rab-GAP, leading to increased Rab-GTP, causing translocation of GLUT4 to the membrane for glucose transportation. Antipsychotics can diminish insulin-induced IRS-1 phosphorylation and inhibit Akt activity causing insulin resistance. Akt2, protein kinase 2; pAMPK, phosphor-AMP-activated protein kinase; APDs, antipsychotic drugs; GLUT4; glucose transporter type 4; IRS1, insulin receptor substrate 1; PI3K, phosphoinositide 3-kinase; PIP2, phosphatidylinositol (3,4)-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PDK1/2, phosphoinositide-dependent kinase-1; mTORC2 mammalian target of rapamycin complex 2 and SH2, Src homology 2.

Figure 2

Antipsychotics cause insulin resistance via obesity. Antipsychotics block receptors 5-HT2C, histamine H1 and D2 receptors resulting in a decrease in POMC and an increase in NPY production, leading to increased appetite. Increased food intake results in obesity, which is associated with insulin resistance via increased FFA, leptin and TNF-α. pAMPK, phosphor-AMP-activated protein kinase; APDs, antipsychotic drugs; FFA, free fatty acids; D2, dopamine D2 receptor; 5-HT2C, Serotonin 5-HT2C receptor; NPY, neuropeptide Y; POMC, proopiomelanocortin; TNF-α, tumor necrosis factor alpha.

Figure 3

The effects of antipsychotics on β-cells. Antipsychotics can block ATP and M3, adrenergic α1 and 5-HT2A receptor-mediated insulin secretion. APDs act on the mitochondrial apoptotic pathway, leading to decreased Bcl-2 ratio, increased cytochrome c release, Apaf/caspase activation and apoptosis. APDs, antipsychotic drugs; ATP, adenosine triphosphate; M3R, muscarinic M3 receptor; Apaf, apoptotic protease activating factor.