Abstract
Early intensive insulin therapy improves insulin sensitivity in type 2 diabetic patients; while the underlying mechanism remains largely unknown. Pigment epithelium-derived factor (PEDF), an anti-angiogenic factor, is believed to be involved in the pathogenesis of insulin resistance. Here, we hypothesize that PEDF might be down regulated by insulin and then lead to the improved insulin resistance in type 2 diabetic patients during insulin therapy. We addressed this issue by investigating insulin regulation of PEDF expression in diabetic conditions. The results showed that serum PEDF was reduced by 15% in newly diagnosed type 2 diabetic patients after insulin therapy. In adipose tissue of diabetic Sprague-Dawley rats, PEDF expression was associated with TNF-α elevation and it could be decreased both in serum and in adipose tissue by insulin treatment. In adipocytes, PEDF was induced by TNF-α through activation of NF-κB. The response was inhibited by knockdown and enhanced by over expression of NF-κB p65. However, PEDF expression was indirectly, not directly, induced by NF-κB which promoted 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) expression in adipocytes. 11β-HSD1 is likely to stimulate PEDF expression through production of active form of glucocorticoids as dexamethasone induced PEDF expression in adipose tissue. Insulin inhibited PEDF by down-regulating 11β-HSD1 expression. The results suggest that PEDF activity is induced by inflammation and decreased by insulin through targeting 11β-HSD1/glucocorticoid pathway in adipose tissue of diabetic patients.
Highlights
Pigment epithelium-derived factor (PEDF) is a 50 kDa glycoprotein that was originally identified in 1991 as a growth factor secreted by retinal pigment cells [1,2]
HOMA-B in type 2 diabetic (T2D) patients increased from 25.8±17.3 to 170.0±118.9 after insulin therapy, which indicates the β cell function of T2D patients recovered after insulin treatment
The results suggest that insulin therapy decreases PEDF in the blood of type 2 diabetes patients
Summary
Pigment epithelium-derived factor (PEDF) is a 50 kDa glycoprotein that was originally identified in 1991 as a growth factor secreted by retinal pigment cells [1,2]. Adipose tissue is a major source of PEDF [9]. Several reports have indicated that the expression of PEDF is negatively associated with insulin sensitivity [11,12,13]. The infusion of PEDF leads to insulin resistance (IR) by inducing adipose tissue lipolysis [10]. PEDF inhibits the differentiation of pre-adipocyte 3T3-L1 cells by activating the (mitogen-activated protein kinases) MAPK/ (extracellular-signal-regulated kinases) ERK signaling pathway [15] and induces lipolysis in differentiated adipocytes in an adipose triglyceride lipase (ATGL) dependent manner [9]. The suppression of adipocyte activities by PEDF may contribute to the ectopic lipid deposition and insulin resistance in obesity. PEDF is positively associated with tumor necrosis factor-α (TNF-α) in serum of type 2 diabetic patients in Japanese [12]
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