Rho Family GTPases and Rho GEFs in Glucose Homeostasis

Abstract

Dysregulation of glucose homeostasis leading to metabolic syndrome and type 2 diabetes is the cause of an increasing world health crisis. New intriguing roles have emerged for Rho family GTPases and their Rho guanine nucleotide exchange factor (GEF) activators in the regulation of glucose homeostasis. This review summates the current knowledge, focusing in particular on the roles of Rho GEFs in the processes of glucose-stimulated insulin secretion by pancreatic β cells and insulin-stimulated glucose uptake into skeletal muscle and adipose tissues. We discuss the ten Rho GEFs that are known so far to regulate glucose homeostasis, nine of which are in mammals, and one is in yeast. Among the mammalian Rho GEFs, P-Rex1, Vav2, Vav3, Tiam1, Kalirin and Plekhg4 were shown to mediate the insulin-stimulated translocation of the glucose transporter GLUT4 to the plasma membrane and/or insulin-stimulated glucose uptake in skeletal muscle or adipose tissue. The Rho GEFs P-Rex1, Vav2, Tiam1 and β-PIX were found to control the glucose-stimulated release of insulin by pancreatic β cells. In vivo studies demonstrated the involvement of the Rho GEFs P-Rex2, Vav2, Vav3 and PDZ-RhoGEF in glucose tolerance and/or insulin sensitivity, with deletion of these GEFs either contributing to the development of metabolic syndrome or protecting from it. This research is in its infancy. Considering that over 80 Rho GEFs exist, it is likely that future research will identify more roles for Rho GEFs in glucose homeostasis.

Rho GTPases in Skeletal Muscle Development and Homeostasis

“…It is worth noting, however, that these results are controversial since muscle-specific knock-in mice expressing a constitutively active version of ROCK1 become insulin resistant [ 128 ]. These and other functions of Rho GTPases in the regulation of glucose homeostasis have already been extensively reviewed elsewhere [ 26 , 27 ].…”

“…Their roles in the regulation of physiological and pathological processes are equally wide. For example, it is known that Rho GTPases coordinate the differentiation of several cell types and that they play crucial roles in the regulation of immunological responses, blood pressure levels, and glucose homeostasis [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. As a result, alterations in their activity due to mutations, changes in expression and the deregulation of upstream and downstream signals can lead to a number of diseases such as cancer or cardiovascular, neurological, autoimmune, and immunodeficiency disorders [ 28 , 33 , 34 ].…”

“…In this review, we will address their intrinsic roles in those processes that have been discovered during these last years. Prior reviews on some of these aspects can be found elsewhere [ 10 , 24 , 26 , 32 , 35 , 36 ].…”

Caveolin-1 Regulates Cellular Metabolism: A Potential Therapeutic Target in Kidney Disease

“…Furthermore, in diabetic mice, the RhoA/ROCK/NF-κB signaling pathway is inhibited when pancreatic islets are transplanted into mice, and the production of podocyte inflammatory factors such as IL-6 and MCP-1, is reduced, reversing podocyte damage (Huang et al, 2021). Recently, the role of Rho family GTPases in regulating cell glucose metabolism and maintaining glucose homeostasis has also received increasing attention (Møller et al, 2019;Machin et al, 2021). Therefore, whether Rock inhibitors indirectly affect Cav-1-related signaling pathways to regulate kidney energy metabolism still needs to be addressed.…”

Dual High-Resolution α-Glucosidase and PTP1B Inhibition Profiling Combined with HPLC-PDA-HRMS-SPE-NMR Analysis for the Identification of Potentially Antidiabetic Chromene Meroterpenoids from Rhododendron capitatum

“…Type 2 diabetes (T2D) is a multifactorial metabolic disease characterized by chronic hyperglycemia, and T2D accounts for approximately 90% of all diabetes cases . In a healthy body, glucose homeostasis is maintained through insulin secretion from pancreatic β-cells in response to an increase in the blood glucose level, which activates the glucose uptake in cells of skeletal muscles and adipose tissues . However, for T2D patients, this activation is impaired, resulting in steadily increasing insulin release over time.…”