Abstract
ObjectiveIncreasing evidence suggested that endoplasmic reticulum (ER) stress contributes to insulin resistance, which plays an important role in the development of type 2 diabetes mellitus (T2DM). Accumulation of endogenous nitric oxide synthase (NOS) inhibitor, asymmetric dimethylarginine (ADMA), is associated with insulin resistance, T2DM, and diabetic cardiovascular complications, although the mechanisms have not been elucidated. This study was to determine whether elevated endogenous ADMA is involved in hepatic ER stress of type 2 diabetic rats, verify their causal relationship, and elucidate the potential mechanism underlying ADMA induced ER stress in rat hepatocytes.MethodsImmunoglobulin binding protein (Bip) transcription, eukaryotic initiation factor 2α kinase (eIF2α) phosphorylation, X box-binding protein-1 (XBP-1) mRNA splicing and C/EBP homologues protein (CHOP) expression were measured to reflect ER stress. Contents of ADMA and nitrite/nitrate as well as activities or expression of NOS and dimethylarginine dimethylaminohydrolase (DDAH) were detected to show the changes in DDAH/ADMA/NOS/NO pathway. The lipid peroxidation product malondialdehyde content and antioxidant enzyme superoxide dismutase activity were analyzed to evaluate oxidative stress.ResultsER stress was provoked in the liver of type 2 diabetic rats, as expressed by increases of Bip transcription, eIF2α phosphorylation, XBP-1 splicing and CHOP expression, all of which were in parallel with the elevation of serum ADMA, suppression of NO generation, NOS and DDAH activities in the liver. Exposure of hepatocytes to ADMA or hydrogen peroxide also induced ER stress, which was associated with the inhibition of NO production and increase of oxidative stress. Treatment of hepatocytes with antioxidant pyrrolidine dithiocarbamate not only decreased ADMA-induced oxidative stress and inhibition of NO production but also reduced ADMA-triggered ER stress.ConclusionsThese results indicate that increased endogenous ADMA contributes to hepatic ER stress in type 2 diabetic rats, and the mechanism underlying ADMA-induced ER stress may relate to oxidative stress via NOS uncoupling.
Highlights
Diabetes mellitus is one of the most prevalent and serious metabolic diseases in the world
Identification of Type 2 Diabetic Rat Model After 4 weeks high-fat diet feeding plus a low dose streptozotocin (35 mg/kg, i.p) intraperitoneal injection and followed by high-fat feeding for further 8 weeks, type 2 diabetic rat model was identified by oral glucose tolerance test (OGTT), area under the curve (AUC), fasting blood glucose (FBG), fasting plasma insulin (FIns) and serum lipid profiles as well as Insulin sensitivity index (ISI)
As shown as table 3, either FIns concentration or serum levels of total cholesterol (TC), TG and low density lipoprotein-cholesterol (LDL-C) except for high density lipoprotein (HDL)-C were remarkably elevated in diabetic rats compared to control rats (P,0.05 or 0.01)
Summary
Diabetes mellitus is one of the most prevalent and serious metabolic diseases in the world. Liver as the major target organs of insulin plays important roles in the development of insulin resistance and type 2 diabetes mellitus, and the underlying mechanisms are still not fully understood. When the ER could not dispose the increased amount of unfolded protein, the activation of type I transmembrane protein kinase/ endoribonuclease (IRE1) and X box-binding protein-1 (XBP-1) mRNA splicing would occur, resulting in the expression of ER degradation enhancer mannosidase alpha-like protein and facilitation of the ER-related degradation [5]. It has been well known that the excessive expression of C/EBP homologus protein (CHOP) plays an important role in ER stress-induced apoptosis [6]. The transcription of Bip, phosphorylation of eIF2a, splicing of XBP-1 mRNA and expression of CHOP could be used as the markers of ER stress
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