SR-135, a peroxynitrite decomposing catalyst, enhances β-cell function and survival in B6D2F1 mice fed a high fat diet

Abstract

Peroxynitrite has been implicated in β-cell dysfunction and insulin resistance in obesity. Chemical catalysts that destroy peroxynitrite, therefore, may have therapeutic value for treating type 2 diabetes. To this end, we have recently demonstrated that Mn(III) bis(hydroxyphenyl)-dipyrromethene complexes, SR-135 and its analogues, can effectively catalyze the decomposition of peroxynitrite in vitro and in vivo through a 2-electron mechanism (Rausaria et al. 2011). To study the effects of SR-135 on glucose homeostasis in obesity, B6D2F1 mice were fed with a high fat-diet (HFD) for 12 weeks and treated with vehicle, SR-135 (5 mg/kg), or a control drug SRB for 2 weeks. SR-135 significantly reduced fasting blood glucose and insulin levels, and enhanced glucose tolerance as compared to HFD control, vehicle or SRB. SR-135 also enhanced glucose-stimulated insulin secretion based on ex vivo studies. Moreover, SR-135 increased insulin content, restored islet architecture, decreased islet size, and reduced tyrosine nitration and apoptosis. These results suggest that a peroxynitrite decomposing catalyst enhances β-cell function and survival under nutrient overload.

The Essential Element Manganese, Oxidative Stress, and Metabolic Diseases: Links and Interactions

“…Several pathogenic pathways activated in diabetes such as ROS, which are generated by high glucose levels, are responsible for metabolic abnormalities and chronic complications [ 35 ]. Moreover, oxidative stress can result in impaired islet beta cell function, cause insulin resistance, and finally lead to T2DM and obesity [ 7 , 8 ]. Normalizing levels of mitochondrial ROS prevents three pathways of hyperglycaemic damage including glucose-induced activation of protein kinase C, formation of advanced glycation end-products, sorbitol accumulation, and NF κ B activation [ 36 ].…”

“…Over the last several decades, obesity, defined as excessive fat accumulation, has become an increasingly prevalent metabolic disease [ 67 , 68 ] that is associated with increased risk of developing T2DM, cardiovascular disease, and NAFLD. Oxidative stress and production of ROS have been linked to the development of insulin resistance, T2DM, and obesity [ 7 , 8 , 69 ], suggesting a potential role for ROS in the pathogenesis of these disorders. In mouse 3T3-L1 mature adipocytes, there is an increased generation of superoxide and higher expression of antioxidant enzymes, potentially to help balance cellular ROS [ 70 , 71 ].…”

Tracking changes of the parameters of glucose-insulin homeostasis during the course of obesity in B6D2F1 mice

“…Figure 5B shows the summary of % β-cell area obtained from lean (n ¼ 12) and HFD-fed mice (n ¼ 21). Increased islet size and number in HFD- fed mice have been extensively studied previously [32,33,34]. Moreover, HFD altered not only the architecture of islets but also percent α-cells [34].…”

“…Moreover, HFD altered not only the architecture of islets but also percent α-cells [34]. Normal healthy rodent islets contain β-cells in the center and α-cells in the periphery of the islet [32,33,34]. HFD caused α-cells to migrate towards the center of the islet.…”

New Concepts in Prevention and Treatment of Diabetes 1 and 2

“…Johns et al have used two different peroxynitrite decomposition catalysts SR-110 (2016-11) and SR-135 (2015-12) to protect beta cells improving glucose homeostasis, restoring beta cell morphology and insulin tolerance in mice fed a high fat diet [12]. Salvemini in her recent review has linked opiate antinocioceptive tolerance to effects caused by peroxynitrite and demonstrated the inhibitory effects of peroxynitrite decomposition catalysts.…”