TPL2 (Therapeutic Targeting Tumor Progression Locus-2)/ATF4 (Activating Transcription Factor-4)/SDF1α (Chemokine Stromal Cell-Derived Factor-α) Axis Suppresses Diabetic Retinopathy.

RATIONALE: Diabetic retinopathy is characterized by vasopermeability, vascular leakage, inflammation, blood-retinal barrier breakdown, capillary degeneration, and neovascularization. However, the mechanisms underlying the association between diabetes mellitus and progression retinopathy remain unclear. OBJECTIVE: TPL2 (tumor progression locus 2), a serine-threonine protein kinase, exerts a pathological effect on vascular angiogenesis. This study investigated the role of Nε-(carboxymethyl)lysine, a major advanced glycation end products, and the involved TPL2-related molecular signals in diabetic retinopathy using models of in vitro and in vivo and human samples. METHODS AND RESULTS: Serum Nε-(carboxymethyl)lysine levels and TPL2 kinase activity were significantly increased in clinical patients and experimental animals with diabetic retinopathy. Intravitreal administration of pharmacological blocker or neutralizing antibody inhibited TPL2 and effectively suppressed the pathological characteristics of retinopathy in streptozotocin-induced diabetic animal models. Intravitreal VEGF (vascular endothelial growth factor) neutralization also suppressed the diabetic retinopathy in diabetic animal models. Mechanistic studies in primary human umbilical vein endothelial cells and primary retinal microvascular endothelial cells from streptozotocin-diabetic rats, db/db mice, and samples from patients with diabetic retinopathy revealed a positive parallel correlation between Nε-(carboxymethyl)lysine and the TPL2/chemokine SDF1α (stromal cell-derived factor-α) axis that is dependent on endoplasmic reticulum stress-related molecules, especially ATF4 (activating transcription factor-4). CONCLUSIONS: This study demonstrates that inhibiting the Nε-(carboxymethyl)lysine-induced TPL2/ATF4/SDF1α axis can effectively prevent diabetes mellitus-mediated retinal microvascular dysfunction. This signaling axis may include the therapeutic potential for other diseases involving pathological neovascularization or macular edema.

Association of salivary alpha 2-macroglobulin levels and clinical characteristics in type 2 diabetes.

AIMS/INTRODUCTION: Studies suggest that salivary proteins can be used as potential non-invasive markers for clinical diagnosis and screening for diabetes. Previous reports showed that plasma alpha 2-macroglobulin (A2MG) levels were higher in diabetic patients, especially with diabetic complications. We investigated the relationship between salivary A2MG values and clinical characteristics in patients with type 2 diabetes. MATERIALS AND METHODS: A total of 91 adults were recruited from our outpatient clinics. The study the patients' collected general and biochemical data, and blood glucose (fasting glucose, glycated hemoglobin [HbA1c]) data. Plasma and salivary A2MG levels were examined by enzyme-linked immunosorbent assay. RESULTS: The salivary A2MG levels were significantly positively correlated with plasma A2MG levels, fasting glucose HbA1c and periodontitis status. After 3 months of follow up, the net change of salivary A2MG values positively correlated with the net change of fasting glucose, HbA1c and triglyceride levels, but negatively correlated with high-density lipoprotein cholesterol changes. Furthermore, the correlations between salivary A2MG and fasting glucose HbA1c were better than plasma A2MG, respectively. CONCLUSIONS: Our data show that salivary A2MG levels have better correlation with fasting glucose HbA1c and periodontitis status than plasma A2MG in diabetic patients. Salivary A2MG concentration might serve as a non-invasive marker for clinical diabetic control.