Abstract
Dysfunctional insulin signaling is a key component of type 2 diabetes. Little is understood of the effects of systemic diabetes on retinal insulin signaling. A number of agents are used to treat patients with type 2 diabetes to normalize glucose levels and improve insulin signaling; however, little has been done to investigate the effects of these agents on retinal insulin signal transduction. We hypothesized that pioglitazone, a peroxisome proliferator-activated receptor γ (PPARγ) agonist, would normalize retinal insulin signal transduction through reduced tumor necrosis factor α (TNFα) and suppressor of cytokine signaling 3 (SOCS3) activities in whole retina and retinal endothelial cells (REC) and Müller cells. To test this hypothesis, we used the BBZDR/Wor type 2 diabetic rat model, as well as REC and Müller cells cultured in normoglycemia and hyperglycemic conditions, to investigate the effects of pioglitazone on TNFα, SOCS3, and downstream insulin signal transduction proteins. We also evaluated pioglitazone's effects on retinal function using electroretinogram and markers of apoptosis. Data demonstrate that 2 months of pioglitazone significantly increased electroretinogram amplitudes in type 2 diabetic obese rats, which was associated with improved insulin receptor activation. These changes occurred in both REC and Müller cells treated with pioglitazone, suggesting that these two cell types are key to insulin resistance in the retina. Taken together, these data provide evidence of impaired insulin signaling in type 2 diabetes rats, which was improved by increasing PPARγ activity. Further investigations of PPARγ actions in the retina may provide improved treatment options.
Highlights
Tumor necrosis factor ␣ (TNF␣) impairs insulin signaling in the retina
PPAR␥ levels were decreased in retinas from untreated type 2 diabetic BBZDR/Wor obese rats but were significantly increased in retinas from both lean and type 2 obese rats treated with pioglitazone (Fig. 1), demonstrating that systemic pioglitazone reaches the retina to elicit its effects through activation of the PPAR␥ pathway
In order to determine which cell types might be most responsive to pioglitazone actions, we investigated the effects of pioglitazone on insulin signal transduction in both retinal endothelial cells (REC) and Müller cells cultured in normal and high glucose to mimic diabetic-like conditions
Summary
Tumor necrosis factor ␣ (TNF␣) impairs insulin signaling in the retina. Results: Pioglitazone reduced TNF␣- and SOCS3-activated insulin resistance pathways in retinal cells as well as in lysates from whole rat retina. A peroxisome proliferator-activated receptor ␥ (PPAR␥) agonist, would normalize retinal insulin signal transduction through reduced tumor necrosis factor ␣ (TNF␣) and suppressor of cytokine signaling 3 (SOCS3) activities in whole retina and retinal endothelial cells (REC) and Müller cells. Data demonstrate that 2 months of pioglitazone significantly increased electroretinogram amplitudes in type 2 diabetic obese rats, which was associated with improved insulin receptor activation These changes occurred in both REC and Müller cells treated with pioglitazone, suggesting that these two cell types are key to insulin resistance in the retina. Taken together, these data provide evidence of impaired insulin signaling in type 2 diabetes rats, which was improved by increasing PPAR␥ activity. Further investigations of PPAR␥ actions in the retina may provide improved treatment options
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
