Inflammation and Insulin Resistance

Recently I've read a few papers about inflammation-induced insulin resistance, and here’s a brief summary of what it’s all about.

In the first paper Inflammation and Insulin Resistance, it says that “proinflammatory cytokines such as TNF-α and chemokines can activate intracellular pathways that promote the development of insulin resistance and T2D” (Steven E. Shoelson, et al. 2006).

In the second paper Intestinal Microbiota and Type 2 Diabetes: From Mechanism Insights to Therapeutic Perspective, the author claims that “a change in gut microbiota induces low-grade inflammation that promote metabolic endotoxemia and triggers the development of inflammation via a lipopolysaccharide (LPS) and CD14/toll-like receptor (TLR) 4-dependent mechanism” (Jung-Ling Han. 2014). He also notes that "Many typical proinflammatory stimuli, including LPS, lipids, fatty acids, and chemokines activate c-Jun N-terminal kinase (JNK) and IκB kinase (IKK)-β pathways intracellularly... [increasing] the expression of numerous mediators of inflammation that can cause insulin resistance. JNK activation promotes the phosphorylation of insulin receptor substrate (IRS)-1 at serine sites, which inhibits normal signal transduction through the insulin receptor/IRS-1 axis, which also can result in insulin resistance."

Wow, that's confusing, isn't it?

Let me summarize it into a sequence.

1.      A change in gut microbiota leads to an increase in gut permeability.

2.      The increase in gut permeability leads to an increase in the amount of LPS in the bloodstream (known as metabolic endotoxemia).

3.      LPS binds to the complex mCD14 and TLR4 at the surface of innate immune cells, triggering the inflammation cascade.

4.      Cytokines such as TNF-α and chemokines secreted by macrophages and antigen-presenting cells (APC) promote inflammation of cells as well as insulin resistance through the activation of c-Jun N-terminal kinase (JNK) and IκB kinase (IKK)-β pathways, which the insulin receptor substrate-1 (IRS-1) is activated intracellularly.

Now get it?

It’s not that complicated after all, right?

Inflammation cascade

A change in gut microbiome increases gut permeability and leads to an LPS leak (metabolic endotoxemia) that results in inflammation and insulin resistance.

Reference

Jun-Ling Han, Hui-Ling Lin. 2014. Intestinal Microbiota and Type 2 Diabetes: From Mechanism Insights to Therapeutic Perspective.

Steven E. Shoelson, et al. 2006. Inflammation and Insulin Resistance.
Image 1: https://www.researchgate.net/figure/Fig-1-Schematic-illustration-of-inflammation-cascade-in-psoriasis-skin-lesion_fig1_51592687
Image 2: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4273124/