Korean Diabetes J.  2010 Jun;34(3):137-145. 10.4093/kdj.2010.34.3.137.

Inflammation and Insulin Resistance: An Old Story with New Ideas

• Kim JK

• KMID: 2222368
• DOI: http://doi.org/10.4093/kdj.2010.34.3.137

Abstract

Years before insulin was discovered, anti-inflammatory sodium salicylate was used to treat diabetes in 1901. Intriguingly for many years that followed, diabetes was viewed as a disorder of glucose metabolism, and then it was described as a disease of dysregulated lipid metabolism. The diabetes research focused on the causal relationship between obesity and insulin resistance, a major characteristic of type 2 diabetes. It is only within the past 20 years when the notion of inflammation as a cause of insulin resistance began to surface. In obesity, inflammation develops when macrophages infiltrate adipose tissue and stimulate adipocyte secretion of inflammatory cytokines, that in turn affect energy balance, glucose and lipid metabolism, leading to insulin resistance. This report reviews recent discoveries of stress kinase signaling involving molecular scaffolds and endoplasmic reticulum chaperones that regulate energy balance and glucose homeostasis. As we advance from a conceptual understanding to molecular discoveries, a century-old story of inflammation and insulin resistance is re-born with new ideas.

Keyword

Obesity; Inflammation; Insulin resistance; Stress kinase

MeSH Terms

Adipocytes
Adipose Tissue
Cytokines
Endoplasmic Reticulum
Glucose
Homeostasis
Inflammation
Insulin
Insulin Resistance
Lipid Metabolism
Macrophages
Obesity
Phosphotransferases
Sodium Salicylate
Cytokines
Glucose
Insulin
Phosphotransferases
Sodium Salicylate

Figure

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  Fig. 1 cJun NH2-terminal kinase 1 (JNK1) regulates energy balance and glucose and lipid homeostasis via cell-autonomous manner. Based on the findings from mice with JNK1 deficiency selectively in adipose tissue, liver, skeletal muscle, or nervous system: 1) adipose tissue JNK1 promotes interleukin-6 (IL-6) secretion which causes hepatic insulin resistance in obesity, 2) liver JNK1 reduces lipid metabolism and insulin clearance thereby preventing hepatic steatosis and insulin resistance, 3) skeletal muscle JNK1 mediates insulin resistance, adipose tissue inflammation, and suppresses muscle lipoprotein lipase thereby altering circulating triglyceride levels, and 4) nervous system JNK1 mediates the negative feedback regulation of hypothalamic-pituitary-thyroid axis and promotes negative energy balance by increasing food intake and reducing energy expenditure.

• 

  Fig. 2 Kinase suppressor of Ras 2 (KSR2) regulates obesity and insulin resistance by activating AMP-activated protein kinase (AMPK). KSR2 regulates lipid metabolism by activating AMPK, which phosphorylates and inactivates acetyl CoA carboxylase (ACC), and this leads to reduced malonyl CoA level that relieves its inhibition of carnitine:palmitoyl-CoA transferase-1 (CPT1), a rate-controlling step in mitochondrial fatty acid oxidation. As a result, KSR2 increases lipid oxidation and reduces lipid storage and obesity. KSR2-mediated AMPK activation also increases glucose metabolism and insulin action.

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