TY - JOUR

T1 - The Rho guanine dissociation inhibitor α inhibits skeletal muscle Rac1 activity and insulin action

AU - Møller, Lisbeth L V

AU - Ali, Mona Sadek

AU - Davey, Jonathan

AU - Raun, Steffen Henning

AU - Andersen, Nicoline Resen

AU - Long, Jonathan Z

AU - Qian, Hongwei

AU - Jeppesen, Jacob Fuglsbjerg

AU - Henriquez-Olguin, Carlos

AU - Frank, Emma

AU - Jensen, Thomas Elbenhardt

AU - Højlund, Kurt

AU - Wojtaszewski, Jørgen

AU - Nielsen, Joachim

AU - Chiu, Tim T

AU - Jedrychowski, Mark P

AU - Gregorevic, Paul

AU - Klip, Amira

AU - Richter, Erik A.

AU - Sylow, Lykke

N1 - CURIS 2023 NEXS 152

PY - 2023

Y1 - 2023

N2 - The molecular events governing skeletal muscle glucose uptake have pharmacological potential for managing insulin resistance in conditions such as obesity, diabetes, and cancer. With no current pharmacological treatments to target skeletal muscle insulin sensitivity, there is an unmet need to identify the molecular mechanisms that control insulin sensitivity in skeletal muscle. Here, the Rho guanine dissociation inhibitor α (RhoGDIα) is identified as a point of control in the regulation of insulin sensitivity. In skeletal muscle cells, RhoGDIα interacted with, and thereby inhibited, the Rho GTPase Rac1. In response to insulin, RhoGDIα was phosphorylated at S101 and Rac1 dissociated from RhoGDIα to facilitate skeletal muscle GLUT4 translocation. Accordingly, siRNA-mediated RhoGDIα depletion increased Rac1 activity and elevated GLUT4 translocation. Consistent with RhoGDIα's inhibitory effect, rAAV-mediated RhoGDIα overexpression in mouse muscle decreased insulin-stimulated glucose uptake and was detrimental to whole-body glucose tolerance. Aligning with RhoGDIα's negative role in insulin sensitivity, RhoGDIα protein content was elevated in skeletal muscle from insulin-resistant patients with type 2 diabetes. These data identify RhoGDIα as a clinically relevant controller of skeletal muscle insulin sensitivity and whole-body glucose homeostasis, mechanistically by modulating Rac1 activity.

AB - The molecular events governing skeletal muscle glucose uptake have pharmacological potential for managing insulin resistance in conditions such as obesity, diabetes, and cancer. With no current pharmacological treatments to target skeletal muscle insulin sensitivity, there is an unmet need to identify the molecular mechanisms that control insulin sensitivity in skeletal muscle. Here, the Rho guanine dissociation inhibitor α (RhoGDIα) is identified as a point of control in the regulation of insulin sensitivity. In skeletal muscle cells, RhoGDIα interacted with, and thereby inhibited, the Rho GTPase Rac1. In response to insulin, RhoGDIα was phosphorylated at S101 and Rac1 dissociated from RhoGDIα to facilitate skeletal muscle GLUT4 translocation. Accordingly, siRNA-mediated RhoGDIα depletion increased Rac1 activity and elevated GLUT4 translocation. Consistent with RhoGDIα's inhibitory effect, rAAV-mediated RhoGDIα overexpression in mouse muscle decreased insulin-stimulated glucose uptake and was detrimental to whole-body glucose tolerance. Aligning with RhoGDIα's negative role in insulin sensitivity, RhoGDIα protein content was elevated in skeletal muscle from insulin-resistant patients with type 2 diabetes. These data identify RhoGDIα as a clinically relevant controller of skeletal muscle insulin sensitivity and whole-body glucose homeostasis, mechanistically by modulating Rac1 activity.

KW - Insulin sensitivity

KW - Skeletal muscle

KW - Glucose uptake

KW - GLUT4 translocation

KW - Type 2 diabetes

KW - Mice

KW - Rho guanine nucleotide Dissociation Inhibitor alpha/metabolism

KW - Insulin resistance

KW - Diabetes Mellitus, Type 2 / Metabolism

U2 - 10.1073/pnas.2211041120

DO - 10.1073/pnas.2211041120

M3 - Journal article

C2 - 37364105

VL - 120

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 27

M1 - e2211041120

ER -