The International Journal of Biochemistry & Cell Biology
ReviewRole of oxidative stress, endoplasmic reticulum stress, and c-Jun N-terminal kinase in pancreatic β-cell dysfunction and insulin resistance
Introduction
The number of patients with type 2 diabetes is markedly increasing worldwide, and nowadays type 2 diabetes is recognized as the most prevalent and serious metabolic disease. In addition, type 2 diabetes is predicted to be an increasing economic and healthcare burden in the near future. Therefore, it is very important to examine a molecular mechanism for pathogenesis of type 2 diabetes and to explore a therapeutic target for diabetes. The development of type 2 diabetes is associated with a combination of pancreatic β-cell dysfunction and insulin resistance. Normal β-cells can compensate for insulin resistance by increasing insulin secretion or β-cell mass, but insufficient compensation leads to the onset of glucose intolerance. Chronic hyperglycemia is a cause of impairment of insulin biosynthesis and secretion; once hyperglycemia becomes apparent, β-cell function gradually deteriorates and insulin resistance aggravates (Jonas et al., 1999, Moran et al., 1997, Poitout and Robertson, 2002; Weir, Laybutt, Kaneto, Bonner-Weir, & Sharma, 2001). This process is called “glucotoxicity” (Fig. 1). Similar to the paradoxically deleterious effects of chronic hyperglycemia, free fatty acids, which are essential fuels in the normal state, become toxic when they are chronically present in excessive levels (Unger, 1995). This process is called “lipotoxicity” (Fig. 1). Under such conditions, oxidative stress and endoplasmic reticulum (ER) stress are provoked and the c-Jun N-terminal kinase (JNK) pathway is activated in various tissues. Here we show a role of oxidative stress, ER stress, and the JNK pathway in pancreatic β-cell dysfunction and insulin resistance; the JNK activation suppresses insulin biosynthesis and interferes with insulin action and, in reverse, suppression of the JNK pathway in diabetic mice improves insulin resistance and ameliorates glucose tolerance.
Section snippets
Oxidative stress and pancreatic β-cell dysfunction
Chronic hyperglycemia is a cause of impairment of insulin biosynthesis and secretion; once hyperglycemia becomes apparent, β-cell function gradually deteriorates (Jonas et al., 1999, Moran et al., 1997, Poitout and Robertson, 2002, Weir et al., 2001). This process is called “glucotoxicity” (Fig. 1). The mechanism for glucotoxicity is, at least in part, mediated by overloads of reactive oxygen species. Similar to the paradoxically deleterious effects of chronic hyperglycemia, free fatty acids,
Oxidative stress and insulin resistance
The hallmark of the disease is insulin resistance as well as pancreatic β-cell dysfunction. Under diabetic conditions, various insulin target tissues such as liver, muscle, and fat become resistant to insulin. The pathophysiology of insulin resistance involves a complex network of insulin signaling pathways. After insulin binds to insulin receptor on cell surface, insulin receptor and its substrates are phosphorylated, which leads to activation of various insulin signaling pathways. It has been
Conclusion
The JNK activation is involved in the progression of insulin resistance as well as deterioration of pancreatic β-cell function. Indeed, suppression of the JNK pathway in obese diabetic mice markedly improves insulin resistance and β-cell function and ameliorates glucose tolerance. Taken together, the JNK pathway plays a crucial role in the progression of insulin resistance as well as β-cell dysfunction and thus could be a potential therapeutic target for diabetes (Fig. 4).
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