Cover Story Current Issue

Despite intensive drug development efforts and public health initiatives, obesity is increasing in incidence and predicted to affect over 50% of all adults worldwide by 2035. Being chronically overweight increases the risk of serious disease co-morbidities that, in turn, increase mortality and healthcare costs. Behavioral approaches to combat obesity, such as diet and exercise, rarely produce lasting weight loss commonly due to compensatory hyperphagia and hypometabolism. These limitations have stimulated interest in pharmacotherapies that target gut-derived peptide hormones involved in the regulation of energy homeostasis, such as PYY, GIP, CCK, and GLP-1. These peptides are secreted by different enteroendocrine cells distributed throughout the intestine in response to food intake, subsequently enhancing satiation signaling and ultimately promotes meal termination. However, a major challenge of FDA-approved and experimental weight-loss medications that target GI-derived satiation signals is the frequent occurrence of nausea and vomiting.

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Current Issue

Inhibition of Unc119b improves insulin sensitivity through potentiation of Rac1 activation in skeletal muscle and brown adipose tissue

Ayushi Mittal, Paul Buscaglia, Dhiraj Srivastava, Nikolai O. Artemyev, Julien A. Sebag

Inhibition of Unc119b improves insulin sensitivity through potentiation of Rac1 activation in skeletal muscle and brown adipose tissue

 

Objectives

A hallmark of type II diabetes is an impairment of the glucose transporter GLUT4 translocation to the plasma membrane of specialized cells in response to insulin. Identifying mechanisms involved in this defect is critical to developing treatments that restore insulin sensitivity. We previously identified a small molecule insulin sensitizer, C59, which improves insulin-stimulated GLUT4 translocation through binding to Unc119b, however, the role and mechanism of Unc119b-mediated regulation of GLUT4 trafficking is unknown.

Methods

Here we use in vitro systems and rodent models of insulin resistance with genetic manipulations of Unc119b expression to uncover the role of this protein in the regulation of glucose homeostasis.

Results

We demonstrate that Unc119b is an endogenous inhibitor of GLUT4 translocation which contributes to the development of insulin resistance in obese individuals. We show that Unc119b interacts with Rac1 and inhibits its activation by insulin, resulting in reduced GLUT4 translocation. Both the prenylated C-terminus of Rac1 and C59 bind to the same site within Unc119b, thus suggesting that C59 enhances GLUT4 translocation by interfering with the action of Unc119b on Rac1.

Conclusions

Overall, this study identifies Unc119b as a critical regulator of glucose homeostasis, uncovers its role in GLUT4 trafficking, and identifies the mechanism of action of a new class of insulin sensitizers.

 

Articles in Press

Inhibition of Unc119b improves insulin sensitivity through potentiation of Rac1 activation in skeletal muscle and brown adipose tissue

Ayushi Mittal, Paul Buscaglia, Dhiraj Srivastava, Nikolai O. Artemyev, Julien A. Sebag

Inhibition of Unc119b improves insulin sensitivity through potentiation of Rac1 activation in skeletal muscle and brown adipose tissue

 

Objectives

A hallmark of type II diabetes is an impairment of the glucose transporter GLUT4 translocation to the plasma membrane of specialized cells in response to insulin. Identifying mechanisms involved in this defect is critical to developing treatments that restore insulin sensitivity. We previously identified a small molecule insulin sensitizer, C59, which improves insulin-stimulated GLUT4 translocation through binding to Unc119b, however, the role and mechanism of Unc119b-mediated regulation of GLUT4 trafficking is unknown.

Methods

Here we use in vitro systems and rodent models of insulin resistance with genetic manipulations of Unc119b expression to uncover the role of this protein in the regulation of glucose homeostasis.

Results

We demonstrate that Unc119b is an endogenous inhibitor of GLUT4 translocation which contributes to the development of insulin resistance in obese individuals. We show that Unc119b interacts with Rac1 and inhibits its activation by insulin, resulting in reduced GLUT4 translocation. Both the prenylated C-terminus of Rac1 and C59 bind to the same site within Unc119b, thus suggesting that C59 enhances GLUT4 translocation by interfering with the action of Unc119b on Rac1.

Conclusions

Overall, this study identifies Unc119b as a critical regulator of glucose homeostasis, uncovers its role in GLUT4 trafficking, and identifies the mechanism of action of a new class of insulin sensitizers.

 

SAVE THE DATE!

13th
Helmholtz Diabetes Conference 
Munich, 21-23. Sep 2026                                                                                                                             

2024 impact factor: 6.6

You are what you eat

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