The number of patients with Type 2 diabetes is markedly increasing worldwide and, currently, it 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. Its development is associated with a combination of pancreatic β-cell dysfunction and insulin resistance Citation[1,2]. Normal β cells compensate for insulin resistance by increasing insulin secretion; however, once hyperglycemia becomes apparent, β-cell function gradually deteriorates and insulin resistance aggravates Citation[3,4]. Such phenomena are often clinically observed in Type 2 diabetes and are well known as glucose toxicity. Similar to the deleterious effects of chronic hyperglycemia, free fatty acids (FFAs), which are essential fuels in the normal state, become toxic when they are present at excessive levels Citation[5,6]. This process is known as lipotoxicity. Under diabetic conditions, oxidative stress and endoplasmic reticulum (ER) stress are provoked, and several stress-signaling pathways, such as the c-Jun N-terminal kinase (JNK) and Ikκ B kinase (IKK) pathways, are activated in various tissues that are probably involved in the pathogenesis of Type 2 diabetes, including glucose toxicity and lipotoxocity.
Oxidative stress & Type 2 diabetes
Physiological levels of reactive oxygen species (ROS) are important to maintain various cell functions, but when an overload of ROS exceeds the capacity of the antioxidant system, oxidative stress is induced and is involved in various diseases, such as inflammation, carcinogenesis and atherosclerosis. In addition, it has been shown that oxidative stress is provoked in various tissues under diabetic conditions and, thereby, plays a role in the pathogenesis of diabetes. Under diabetic conditions, chronic hyperglycemia induces oxidative stress through the glycation reaction and electron transport chain in mitochondria. The hallmarks of Type 2 diabetes are pancreatic β-cell dysfunction and insulin resistance. It has been shown that induction of oxidative stress leads to suppression of insulin gene expression and deterioration of β-cell function, which is accompanied by reduction of the DNA binding activity of pancreatic transcription factor, PDX-1 Citation[7,8]. Furthermore, antioxidant treatment protects β cells from glucose toxicity in various diabetic model animals; β-cell mass and insulin content are preserved by antioxidant treatment Citation[9,10]. These data suggest that oxidative stress is involved in β-cell glucose toxicity found in diabetes.
Under diabetic conditions, various insulin target tissues, such as the liver, muscle and adipose tissues, become resistant to insulin. The pathophysiology of insulin resistance involves a complex network of insulin-signaling pathways; after insulin binds to the insulin receptor on the cell surface, the insulin receptor and its substrates are phosphorylated, which leads to activation of various insulin-signaling pathways. Oxidative stress is involved in the development of insulin resistance as well as the deterioration of β-cell function Citation[11]. It has been shown that oxidative stress disrupts insulin-induced cellular redistribution of insulin receptor substrate (IRS)-1 and phosphatidylinositol 3-kinase (PI3-K), and that treatment with antioxidants prevents hyperglycemia-induced insulin resistance. These results suggest that oxidative stress is involved in the development of insulin resistance found in diabetes.
Endoplasmic reticulum stress & Type 2 diabetes
The ER is an organelle that synthesizes various secretory and membrane proteins. These proteins are correctly folded and assembled by chaperones in the ER. During stressful conditions, such as an increase in the misfolded protein level, the chaperones become overloaded and the ER fails to fold and export newly synthesized proteins, leading to ER stress Citation[12–14]. Once ER stress is provoked in the cells, various pathways are activated. It has been demonstrated that expression levels of immunoglobulin-binding protein (Bip) and Lys-Asp-Glu-Leu (KDEL), both of which are ER stress markers, are higher in obese diabetic C57BL/KsJ-db/db mice compared with nondiabetic mice Citation[15], indicating that ER stress is increased under diabetic conditions. It was also reported that when Fao liver cells were treated with tunicamycin or thapsigargin, both of which are ER stress inducers, IRS-1 serine phosphorylation was increased and its tyrosine phosphorylation was decreased Citation[16]. It is noted here that IRS-1 serine phosphorylation is known to reduce insulin signaling. These results suggest that ER stress induces IRS-1 serine phosphorylation and, thereby, suppresses insulin signaling.
It was reported that mice that are deficient in X-box-binding protein (XBP)-1, a transcription factor that modulates the ER stress response, developed insulin resistance Citation[16]. The spliced form of XBP-1 is a key factor in ER stress through transcriptional regulation of various genes, including molecular chaperones. When XBP-1+/– mice were treated with a high-fat diet, hyperinsulinemia was observed and blood glucose levels were increased. There was also a significant increase in JNK activity in XBP-1+/– mice compared with wild-type mice. Consistently, IRS-1 serine phosphorylation was increased, and IRS-1 tyrosine and Akt serine phosphorylation were decreased in the XBP-1+/– mice. These results also suggest that ER stress induces IRS-1 serine phosphorylation and, thereby, suppresses insulin signaling. Oxygen-regulated protein (ORP)150, a molecular chaperone in the ER, is known to protect cells from ER stress. When ORP150 was expressed in the liver of diabetic db/db mice using an adenovirus system, glucose tolerance was ameliorated Citation[15]. The euglycemic hyperinsulinemic clamp test showed that ORP150 overexpression in the liver reduced insulin resistance and decreased hepatic glucose production. Taken together, reduction of ER stress by ORP150 overexpression decreased insulin resistance and ameliorated glucose tolerance in diabetic mice. Furthermore, it has been shown very recently that orally active chemical chaperones 4-phenyl butyric acid and taurine-conjugated ursodeoxycholic acid alleviate ER stress in cells and whole animals Citation[17]. Treatment of diabetic mice with such compounds resulted in normalization of hyperglycemia, restoration of systemic insulin sensitivity, resolution of fatty liver disease, and enhancement of insulin action in various tissues such as the liver, muscle and adipose tissues. These results further strengthen the hypothesis that ER stress is involved in the development of insulin resistance and could be a potential therapeutic target for diabetes.
Stress signaling pathway & Type 2 diabetes
Several signaling pathways, including the JNK pathway, are activated by oxidative stress in several cell types and activation of the JNK pathway is involved in suppression of insulin gene expression by oxidative stress. This suppression of the JNK pathway protects β cells from oxidative stress Citation[8]. These results were correlated with changes in DNA-binding activity of pancreatic transcription factor PDX-1. Furthermore, it has been shown that PDX-1 is translocated from the nucleus to the cytoplasm in response to oxidative stress and that suppression of the JNK pathway inhibits PDX-1 translocation by oxidative stress Citation[18]. These results suggest that oxidative stress and subsequent activation of the JNK pathway are involved in suppression of insulin gene expression and deterioration of β-cell function.
Activation of the JNK pathway is involved in the progression of insulin resistance as well as deterioration of β-cell function. It has been reported that insulin resistance is substantially reduced in mice homozygous for a targeted mutation in the JNK gene (JNK-knockout [KO] mice) Citation[19]. In addition, when the JNK-KO mice were placed on a high-fat/high-calorie diet, blood glucose levels in obese JNK-KO mice were significantly lower compared with those in obsese wild-type mice. An intraperitoneal insulin-tolerance test demonstrated that the hypoglycemic response to insulin in obese wild-type mice was lower compared with obese JNK-KO mice. Furthermore, when a targeted mutation in the JNK gene was introduced in genetically obese ob/ob mice, insulin resistance was decreased and glucose tolerance was ameliorated. It was also reported that suppression of the JNK pathway in the liver of diabetic db/db mice using an adenovirus system decreased insulin resistance and ameliorated glucose tolerance Citation[20]. The euglycemic hyperinsulinemic clamp test showed that suppression of the JNK pathway in the liver reduced hepatic glucose production and insulin resistance in db/db mice. IRS-1 serine phosphorylation was decreased and its tyrosine phosphorylation was increased by suppression of the JNK pathway. Furthermore, it has been reported that cell-permeable JNK inhibitory peptide is also effective for reduction of insulin resistance in diabetic db/db mice Citation[21]. This peptide is derived from the JNK-binding domain of JNK-interacting protein (JIP)-1 and has been reported to function as a dominant inhibitor of the JNK pathway Citation[22]. When mice were injected intraperitoneally with the peptide, this was transported into various tissues and glucose tolerance was ameliorated. The euglycemic hyperinsulinemic clamp test showed that suppression of the JNK pathway using this peptide decreased insulin resistance in db/db mice. Furthermore, hepatic glucose production was decreased and the peripheral glucose utilization rate was increased by this treatment. These results suggest that JNK plays an important role in the development of insulin resistance found in Type 2 diabetes.
In addition, the JNK pathway is known to be activated by several factors, such as oxidative stress, FFAs and tumor necrosis factor (TNF)-α, all of which are known to increase under diabetic conditions. Under diabetic conditions, oxidative stress is provoked in various tissues and is involved in the development of insulin resistance as well as the progression of β-cell deterioration. Levels of FFAs and TNF-α are also increased under diabetic conditions and are probably involved in the development of insulin resistance. Thus, we assume that improvement of insulin resistance by suppression of the JNK pathway was at least in part counterbalancing the deleterious effects of several factors, such as oxidative stress, FFAs and TNF-α. The IKK pathway is also known to be similarly activated by various stimuli, such as oxidative stress, ER stress, FFAs and various inflammatory cytokines under diabetic conditions. Activation of the IKK pathway leads to IRS-1 serine phosphorylation and, thereby, is involved in the development of insulin resistance. Indeed, it has been shown that suppression of the IKK pathway decreases insulin resistance and ameliorates glucose tolerance in diabetic mice Citation[23–25]. Therefore, it is likely that various stress signaling pathways, including JNK and IKK pathways, are involved in the development of insulin resistance and could be therapeutic targets for Type 2 diabetes.
Concluding remarks
Under diabetic conditions, oxidative and ER stress are provoked, and several stress-signaling pathways, such as the JNK and IKK pathways, are activated in various tissues, which are probably involved in the pathogenesis of Type 2 diabetes. Activation of the JNK pathway plays an important role in the progression of insulin resistance, as well as β-cell dysfunction and, thus, could be a potential therapeutic target for diabetes.
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