CXCR1/2 Inhibitor Ladarixin Ameliorates the Insulin Resistance of 3T3-L1 Adipocytes by Inhibiting Inflammation and Improving Insulin Signaling

Type 2 diabetes mellitus is a severe public health issue worldwide. It displays a harmful effect on different organs as the eyes, kidneys and neural cells due to insulin resistance and high blood glucose concentrations. To date, the available treatments for this disorder remain limited. Several reports have correlated obesity with type 2 diabetes. Mainly, dysfunctional adipocytes and the regulation of high secretion of inflammatory cytokines are the crucial links between obesity and insulin resistance. Several clinical and epidemiological studies have also correlated the onset of type 2 diabetes with inflammation, which is now indicated as a new target for type 2 diabetes treatment. Thus, it appears essential to discover new drugs able to inhibit the secretion of proinflammatory adipocytokines in type 2 diabetes. Adipocytes produce inflammatory cytokines in response to inflammation or high glucose levels. Once activated by a specific ligand, CXCR1 and CXCR2 mediate some cytokines’ effects by activating an intracellular signal cascade once activated by a specific ligand. Therefore, it is conceivable to hypothesize that a specific antagonist of these receptors may ameliorate type 2 diabetes and glucose metabolism. Herein, differentiated 3T3-L1-adipocytes were subjected to high glucose or inflammatory conditions or the combination of both and then treated with ladarixin, a CXCR1/2 inhibitor. The results obtained point towards the positive regulation by ladarixin on insulin sensitivity, glucose transporters GLUT1 and GLUT4, cytokine proteome profile and lipid metabolism, thus suggesting ladarixin as a potentially helpful treatment in type 2 diabetes mellitus and obesity.

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Insulin Signal Transduction Perturbations in Insulin Resistance

International Journal of Molecular Sciences ◽

10.3390/ijms22168590 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8590

Author(s):

Mariyam Khalid ◽

Juma Alkaabi ◽

Moien A. B. Khan ◽

Abdu Adem

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Signal Transduction ◽

Type 2 Diabetes Mellitus ◽

Β Cell ◽

High Blood Glucose ◽

Insulin Signal Transduction ◽

Insulin Signal

Type 2 diabetes mellitus is a widespread medical condition, characterized by high blood glucose and inadequate insulin action, which leads to insulin resistance. Insulin resistance in insulin-responsive tissues precedes the onset of pancreatic β-cell dysfunction. Multiple molecular and pathophysiological mechanisms are involved in insulin resistance. Insulin resistance is a consequence of a complex combination of metabolic disorders, lipotoxicity, glucotoxicity, and inflammation. There is ample evidence linking different mechanistic approaches as the cause of insulin resistance, but no central mechanism is yet described as an underlying reason behind this condition. This review combines and interlinks the defects in the insulin signal transduction pathway of the insulin resistance state with special emphasis on the AGE-RAGE-NF-κB axis. Here, we describe important factors that play a crucial role in the pathogenesis of insulin resistance to provide directionality for the events. The interplay of inflammation and oxidative stress that leads to β-cell decline through the IAPP-RAGE induced β-cell toxicity is also addressed. Overall, by generating a comprehensive overview of the plethora of mechanisms involved in insulin resistance, we focus on the establishment of unifying mechanisms to provide new insights for the future interventions of type 2 diabetes mellitus.

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The Antidiabetic Action of Camel Milk in Experimental Type 2 Diabetes Mellitus: An Overview on the Changes in Incretin Hormones, Insulin Resistance, and Inflammatory Cytokines

Hormone and Metabolic Research ◽

10.1055/s-0034-1368711 ◽

2014 ◽

Vol 46 (06) ◽

pp. 404-411 ◽

Cited By ~ 19

Author(s):

A. Korish

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Inflammatory Cytokines ◽

Camel Milk ◽

Incretin Hormones ◽

Experimental Type

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The effect of regular consumption of lupin-containing foods on glycaemic control and blood pressure in people with type 2 diabetes mellitus

Food & Function ◽

10.1039/c9fo01778j ◽

2020 ◽

Vol 11 (1) ◽

pp. 741-747 ◽

Cited By ~ 1

Author(s):

Natalie C. Ward ◽

Trevor A. Mori ◽

Lawrence J. Beilin ◽

Stuart Johnson ◽

Carolyn Williams ◽

...

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Blood Pressure ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Glycaemic Control ◽

High Glucose ◽

Regular Consumption ◽

P Type

Type 2 diabetes mellitus is a metabolic disorder characterized by high glucose and insulin resistance.

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Exosome-Like Vesicles as New Mediators and Therapeutic Targets for Treating Insulin Resistance and β-Cell Mass Failure in Type 2 Diabetes Mellitus

Journal of Diabetes Research ◽

10.1155/2019/3256060 ◽

2019 ◽

Vol 2019 ◽

pp. 1-7 ◽

Cited By ~ 6

Author(s):

Qian Ge ◽

Xin Xin Xie ◽

Xiaoqiu Xiao ◽

Xi Li

Keyword(s):

Diabetes Mellitus ◽

Insulin Resistance ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Cell Mass ◽

Therapeutic Targets ◽

Therapeutic Interventions ◽

High Blood Glucose ◽

Physiologic Responses

Exosome-like vesicles (ELVs), the smallest class of extracellular vesicles released from cells, function in cellular crosstalk and therefore profoundly affect physiologic responses and pathologic progression. A growing body of evidence supports a novel role for ELVs as important mediators and therapeutic targets due to their effects on regulation of both insulin signaling and β-cell mass. Pathologic conditions associated with type 2 diabetes (such as high blood glucose, inflammation, hypoxia, and fatty acids) can alter the quantity and components of ELVs secreted from the pancreas or peripheral insulin-targeting tissues. These released ELVs can either enter the blood circulation or be taken up by neighboring cells or macrophages, which can lead to insulin resistance or β-cell apoptosis. This review focuses on the roles of ELVs in insulin resistance and β-cell failure and also highlights the potential use of ELVs and exosome-based delivery systems in therapeutic interventions aimed at treating type 2 diabetes mellitus as well as the challenges associated with exosome-targeting therapeutics.

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