Role of oxidative stress, endoplasmic reticulum stress, and c-Jun N-terminal kinase in pancreatic β-cell dysfunction and insulin resistance

doi:10.1016/j.biocel.2005.04.003

The International Journal of Biochemistry & Cell Biology

Volume 37, Issue 8, August 2005, Pages 1595-1608

https://doi.org/10.1016/j.biocel.2005.04.003 Get rights and content

Abstract

Type 2 diabetes is the most prevalent and serious metabolic disease affecting people all over the world. Pancreatic β-cell dysfunction and insulin resistance are the hallmark of type 2 diabetes. Normal β-cells can compensate for insulin resistance by increasing insulin secretion and/or β-cell mass, but insufficient compensation leads to the onset of glucose intolerance. Once hyperglycemia becomes apparent, β-cell function gradually deteriorates and insulin resistance aggravates. Under diabetic conditions, oxidative stress and endoplasmic reticulum stress are induced in various tissues, leading to activation of the c-Jun N-terminal kinase pathway. The activation of c-Jun N-terminal kinase suppresses insulin biosynthesis and interferes with insulin action. Indeed, suppression of c-Jun N-terminal kinase in diabetic mice improves insulin resistance and ameliorates glucose tolerance. Thus, the c-Jun N-terminal kinase pathway plays a central role in pathogenesis of type 2 diabetes and could be a potential target for diabetes therapy.

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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Glucose stimulates the translocation of PDX-1 into the nucleus that further promotes the transcription of insulin gene, and insulin secretion-associated genes such as glucokinase (GCK) and Glut-2 [33]. With a diabetes condition, sustained high glucose suppresses the PDX-1 gene, and activates PDX-1 translocation to the cytosol, which results in reducing the binding of PDX-1 and insulin gene promotor, thereby inhibiting insulin synthesis and secretion [34]. Numerous studies report that PDX-1, GCK, and Glut-2 protein expressions were downregulated in diabetic rats, causing impaired expression and secretion of insulin [35,36].
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ReviewRole of oxidative stress, endoplasmic reticulum stress, and c-Jun N-terminal kinase in pancreatic β-cell dysfunction and insulin resistance

Abstract

Introduction

Section snippets

Oxidative stress and pancreatic β-cell dysfunction

Oxidative stress and insulin resistance

Conclusion

J Biol Chem

J Biol Chem

J Biol Chem

Cell

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Cell

Cell

Diabetes Res Clin Prac

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Mol Cell

Curr Biol

Nat Genet

Free Rad Biol Med

Metabolism

J Biol Chem

J Biol Chem

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Free Rad Biol Med

J Biol Chem

Biochem Biophys Res Commun

J Biol Chem

J Biol Chem

J Biol Chem

Biochem Biophys Res Commun

J Biol Chem

J Biol Chem

β-Cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the β-cell phenotype and maturity onset diabetes

Genes Dev

The c-Jun amino-terminal kinase pathway is preferentially activated by interleukin-1 and controls apoptosis in differentiating pancreatic β-cells

Diabetes

Integration of endoplasmic reticulum signaling in health and disease

Nat Med

Role of oxidative stress in diabetic complications: A new perspective on an old paradigm

Diabetes

Chronic exposure to free fatty acid reduces pancreatic β cell insulin content by increasing basal insulin secretion that is not compensated for by a corresponding increase in proinsulin biosynthesis translation

J Clin Invest

Cell-permeable peptide inhibitors of JNK: Novel blockers of β-cell death

Diabetes

Reduction in pancreatic transcription factor PDX-1 impairs glucose-stimulated insulin secretion

J Biol Chem

Biochemistry and molecular cell biology of diabetic complications

Nature

High glucose is necessary for complete maturation of Pdx1-VP16-expressing hepatic cells into functional insulin-producing cells

Diabetes

Mammalian MAP kinase signalling cascades

Nature

Interleukin 1β induces the formation of nitric oxide by β-cells purified from rodent islets of Langerhans: Evidence for the β-cell as a source and site of action of nitric oxide

J Clin Invest

Regulatory factor linked to late-onset diabetes?

Nature

Cytokines suppress human islet function irrespective of their effects on nitric oxide generation

J Clin Invest

Oxidative stress and stress-activated signaling pathways: A unifying hypothesis of type 2 diabetes

Endocr Rev

Pancreatic and duodenal homeobox gene 1 induces expression of insulin genes in liver and ameliorates streptozotocin-induced hyperglycemia

Nat Med

N-acetylcysteine and taurine prevent hyperglycemia-induced insulin resistance in vivo: Possible role of oxidative stress

Am J Physiol Endocrinol Metab

Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase

Nature

Endoplasmic reticulum stress and the development of diabetes

Mol Cell

Endoplasmic reticulum stress and the development of diabetes: A review

Diabetes

Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain

Genes Dev

A central role for JNK in obesity and insulin resistance

Nature

Experimental control of pancreatic development and maintenance

Proc Natl Acad Sci USA

Review
Role of oxidative stress, endoplasmic reticulum stress, and c-Jun N-terminal kinase in pancreatic β-cell dysfunction and insulin resistance