The UPS in diabetes and obesity

Abstract

Type 2 diabetes is caused by defects in both insulin signaling and insulin secretion. Though the role of the ubiquitin proteasome system (UPS) in the pathogenesis of type 2 diabetes remains largely unexplored, the few examples present in the literature are interesting and suggest targets for drug development. Studies indicate that insulin resistance can be induced by stimulating the degradation of important molecules in the insulin signaling pathway, in particular the insulin receptor substrate proteins IRS1, IRS2 and the kinase AKT1 (Akt). In addition, a defect in insulin secretion could occur due to UPS-mediated degradation of IRS2 in the beta-cells of the pancreas. The UPS also appears to be involved in regulating lipid synthesis in adipocytes and lipid production by the liver and could influence the development of obesity. Other possible mechanisms for inducing defects in insulin signaling and secretion remain to be explored, including the role of ubiquitylation in insulin receptor internalization and trafficking. PUBLICATION HISTORY : Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com).

Figure 1

General scheme of insulin signaling. Insulin binding to its receptor activates the receptor tyrosine kinase activity. This leads to autophosphorylation of the receptor and recruitment and phosphorylation of insulin receptor substrate (IRS) proteins. Subsequently, other signaling molecules such as PI3-kinase (PI3K) and GRB2 are recruited, which leads to the activation of the Akt signaling pathway (which mediates many metabolic effects) and the MAP kinase pathway (which mediates cell proliferation), respectively. Insulin binding also leads to receptor internalization into endosomes. From endosomes, receptors can recycle back to the plasma membrane or traffic via multivesicular bodies to the lysosome for degradation. Phosphorylated IRS and the IRS-PI3K complex are signaling molecules that can be inactivated by degradation through the ubiquitin proteasome system. Receptor internalization and trafficking between the endosome and lysosome has been shown to be dependent on ubiquitylation for other receptor tyrosine kinases, but the requirement for UBIQ (ubiquitin) in the case of the insulin receptor remains speculative. In some adipocyte cell lines, the ubiquitin protein ligase CBLB (Cbl-b) has been implicated in mediating translocation of the GTR4 (GLUT4) glucose transporter to the plasma membrane via a RHOQ (Tc10)-dependent pathway.

Figure 2

General scheme of insulin secretion. In the β-cells of the pancreas, elevated blood glucose leads to increased levels of intracellular glucose-6-phosphate. Metabolism of the glucose-6-phosphate through glycolysis and mitochondrial metabolism, leads to increased levels of ATP and to lower levels of ADP. This sequentially results in inhibition of an ATP-sensitive K⁺ channel, depolarization of the plasma membrane, activation of a voltage-dependent Ca²⁺ channel, influx of Ca²⁺ and exocytosis of insulin. Mitochondrial metabolism participates in this process, not only by generating ATP, but also by modulating levels of other metabolites (e.g. GTP, cAMP, NADPH, glutamate, malonyl CoA), which might also contribute to glucose-stimulated insulin secretion. The ATP-sensitive K⁺ channel and voltage-dependent Ca²⁺ channel are sites that could be modulated by the ubiquitin proteasome system (UPS). In addition, β-cell survival can be impaired by UPS-mediated degradation of IRS2 in these cells (see text for details).