Disruption of Adipose Rab10-Dependent Insulin Signaling Causes Hepatic Insulin Resistance

Abstract

Insulin controls glucose uptake into adipose and muscle cells by regulating the amount of GLUT4 in the plasma membrane. The effect of insulin is to promote the translocation of intracellular GLUT4 to the plasma membrane. The small Rab GTPase, Rab10, is required for insulin-stimulated GLUT4 translocation in cultured 3T3-L1 adipocytes. Here we demonstrate that both insulin-stimulated glucose uptake and GLUT4 translocation to the plasma membrane are reduced by about half in adipocytes from adipose-specific Rab10 knockout (KO) mice. These data demonstrate that the full effect of insulin on adipose glucose uptake is the integrated effect of Rab10-dependent and Rab10-independent pathways, establishing a divergence in insulin signal transduction to the regulation of GLUT4 trafficking. In adipose-specific Rab10 KO female mice, the partial inhibition of stimulated glucose uptake in adipocytes induces insulin resistance independent of diet challenge. During euglycemic-hyperinsulinemic clamp, there is no suppression of hepatic glucose production despite normal insulin suppression of plasma free fatty acids. The impact of incomplete disruption of stimulated adipocyte GLUT4 translocation on whole-body glucose homeostasis is driven by a near complete failure of insulin to suppress hepatic glucose production rather than a significant inhibition in muscle glucose uptake. These data underscore the physiological significance of the precise control of insulin-regulated trafficking in adipocytes.

Absence of Carbohydrate Response Element Binding Protein in Adipocytes Causes Systemic Insulin Resistance and Impairs Glucose Transport

“…Abnormalities in the cellular machinery that regulates Glut4 trafficking may also play a role. This is supported by studies showing that disruption of Glut4 trafficking in adipocytes by deleting Rab10 (Ras-related protein 10) also reduces glucose transport without impairing insulin signaling or Glut4 content (Vazirani et al, 2016). Indeed, loss of ChREBP in adipocytes delays insulin-stimulated Glut4 exocytosis.…”

Hypothalamic Insulin Resistance in Obesity: Effects on Glucose Homeostasis

“…For instance, adipose-specific GLUT4 -/- mice exhibited insulin resistance in skeletal muscle and liver without affecting adiposity [208]. Furthermore, mice with adipose-specific Rab10 deletion, a GTPase required for insulin-stimulated GLUT4 translocation, displayed hepatic insulin resistance despite normal insulin suppression of plasma FFAs [209]. …”

Adenovirus Protein E4-ORF1 Activation of PI3 Kinase Reveals Differential Regulation of Downstream Effector Pathways in Adipocytes

“…However, previous studies have demonstrated both Rab10-dependent and independent insulin signaling to Glut4 (Sadacca et al, 2013, Vazirani et al, 2016). Thus, we next sought to determine whether E4-ORF1 effect on Glut4 trafficking is dependent on AS160-Rab10 signaling module.…”

“…Rab10 ablation reduces Glut4 translocation by about 50% establishing that the full effect of insulin on Glut4 is the sum of Rab10-dependent and Rab10-independent mechanisms (Sano et al, 2007, Vazirani et al, 2016). Rab10 affects Glut4 translocation at a step prior to Glut4 vesicle docking to the PM (Bai et al, 2007, Sano et al, 2007).…”