Interactions of the advanced glycation end product inhibitor pyridoxamine and the antioxidant α-lipoic acid on insulin resistance in the obese Zucker rat

Department of Physiology, Muscle Metabolism Laboratory, University of Arizona College of Medicine, Tucson, AZ 85721-0093, USA.
Metabolism: clinical and experimental (Impact Factor: 3.89). 11/2008; 57(10):1465-72. DOI: 10.1016/j.metabol.2008.05.018
Source: PubMed


Oxidative stress and protein glycation can contribute to the development of insulin resistance and complications associated with type 2 diabetes mellitus. The antioxidant alpha-lipoic acid (ALA) reduces oxidative stress and the formation of advanced glycation end products (AGEs) and improves insulin sensitivity in skeletal muscle and liver. The AGE inhibitor pyridoxamine (PM) prevents irreversible protein glycation, thereby reducing various diabetic complications. The potential interactive effects of ALA and PM in the treatment of whole-body and skeletal muscle insulin resistance have not been investigated. Therefore, this study was designed to determine the effects of combined ALA and PM treatments on reducing muscle oxidative stress and ameliorating insulin resistance in prediabetic obese Zucker rats. Obese Zucker rats were assigned to either a control group or to a treatment group receiving daily injections of the R-(+)-enantiomer of ALA (R-ALA, 92 mg/kg) or PM (60 mg/kg), individually or in combination, for 6 weeks. The individual and combined treatments with R-ALA and PM were effective in significantly (P < .05) reducing plantaris muscle protein carbonyls (33%-40%) and urine-conjugated dienes (22%-38%), markers of oxidative stress. The R-ALA and PM in combination resulted in the largest reductions of fasting plasma glucose (23%), insulin (16%), and free fatty acids (24%) and of muscle triglycerides (45%) compared with alterations elicited by individual treatment with R-ALA or PM. Moreover, the combination of R-ALA and PM elicited the greatest enhancement of whole-body insulin sensitivity both in the fasted state and during an oral glucose tolerance test. Finally, combined R-ALA/PM treatments maintained the 44% enhancement of in vitro insulin-mediated glucose transport activity in soleus muscle of obese Zucker rats treated with R-ALA alone. Collectively, these results document a beneficial interaction of the antioxidant R-ALA and the AGE inhibitor PM in the treatment of whole-body and skeletal muscle insulin resistance in obese Zucker rats.

Download full-text


Available from: Markus Matuschek, Jun 08, 2015
  • Source
    • "O 2 • G, H 2 O 2 and •! OH (Bajaj and Khan, 2012; Moussa, 2008 "
    [Show abstract] [Hide abstract]
    ABSTRACT: Oxidative stress is the outcome of an imbalance between the production and neutralization of reactive oxygen and nitrogen species (RONS) such that the antioxidant capacity of cell is overwhelmed. The present review briefly summarized the underlying role of overwhelming levels of RONS in the pathophysiology of diabetes mellitus (DM). The review is based on using keywords to obtain information from publications in PubMed, ScienceDirect and Google Scholar from 1970- 2015. The primary causative factor of oxidative stress in DM is hyperglycemia, which operates via several mechanisms. However, the individual contribution of other intermediary factors to hyperoxidative stress remains undefined, in terms of the dose response relationship between hyperglycemia and overall oxidative stress in DM. Intuitively, the inhibition and/or scavenging of intracellular free radical formation provide a therapeutic strategy to prevent oxidative stress and ensuing pathologic conditions. The integration of antioxidants formulations into conventional therapeutic interventions, either by ingestion of natural antioxidants or through dietary supplementation should be encouraged for a holistic approach to the management and prevention of DM and complications associated with the pathology.
    Full-text · Article · May 2015 · International Journal of Biological Chemistry
  • Source
    • "Exploration of the mechanisms of neuropathic changes preceding overt diabetes is complicated by the lack of animal models that develop prediabetes and obesity first and then spontaneously transit to overt diabetes. For this reason, the mechanisms underlying prediabetes per se as well as end-organ damage associated with this condition are studied in Zucker fatty (fa/fa) rats (Henriksen et al., 2011; Muellenbach et al., 2008; Oltman et al., 2005, 2008; Tong et al., 2010; Zhou et al., 1998) and high-fat diet (HFD) fed mice (Coppey et al., 2011; Longo et al., 2011; Shevalye et al., 2012b; Sparks et al., 2005; Zawalich et al., 1995) that maintain metabolic abnormalities characteristic for prediabetes i.e., hyperinsulinemia, impaired glucose tolerance in the absence of overt hyperglycemia, hypertriglyceridemia and/or increased non-esterified fatty acid abundance, as well as hypercholesterolemia , during their whole life span. Both models exhibit nerve conduction deficit, small sensory nerve fiber dysfunction, and biochemical abnormalities in the peripheral nerve, spinal cord, and vasa nervorum (Coppey et al., 2011; Lupachyk et al., 2012; Obrosova et al., 2007; Oltman et al., 2005, 2008; Vincent et al., 2009; Watcho et al., 2010), and are, therefore, suitable for dissection of relative contribution of these phenomena to peripheral neuropathy in prediabetes . "
    [Show abstract] [Hide abstract]
    ABSTRACT: Growing evidence suggests that prediabetes and metabolic syndrome are associated with increased risk for the development of microvascular complications including retinopathy, nephropathy, and, most commonly, peripheral painful neuropathy and/or autonomic neuropathy. The etiology of these disabling neuropathies is unclear, and several clinical and experimental studies implicated obesity, impaired fasting glycemia/impaired glucose tolerance, elevated triglyceride and non-esterified fatty acids, as well as oxidative-nitrative stress. Endoplasmic reticulum stress resulting from abnormal folding of newly synthesized proteins and leading to the impairment of metabolism, transcriptional regulation, and gene expression, is emerging as a key mechanism of metabolic diseases including obesity and diabetes. We evaluated the role for this phenomenon in prediabetic neuropathy using two animal models i.e., Zucker (fa/fa) rats and high-fat diet fed mice which displayed obesity and impaired glucose tolerance in the absence of overt hyperglycemia. Endoplasmic reticulum stress manifest in upregulation of the glucose-regulated proteins BiP/GRP78 and GRP94 of unfolded protein response was identified in the sciatic nerve of Zucker rats. A chemical chaperone, trimethylamine oxide, blunted endoplasmic reticulum stress and alleviated sensory nerve conduction velocity deficit, thermal and mechanical hypoalgesia, and tactile allodynia. A selective inhibitor of eukaryotic initiation factor-2α dephosphorylation, salubrinal, improved glucose intolerance and alleviated peripheral nerve dysfunction in high-fat diet fed mice. Our findings suggest an important role of endoplasmic reticulum stress in the neurobiology of prediabetic peripheral neuropathy, and identify a new therapeutic target.
    Full-text · Article · Nov 2012 · Experimental Neurology
  • Source
    • "The flood of ROS generated in the neuronal and glial mitochondria during ischemic insults can be acutely devastating to the brain tissue (Aliev et al., 2002). Antioxidant stress is a major, if not primary mechanism linking obesity and metabolic disorders, especially insulin resistance or diabetes in animal models (Styskal et al., 2012) and alleviation of many symptoms is being reported in many studies by a regular consumption of antioxidants (Muellenbach et al., 2008, 2009; Curtis et al., 2010). Similar associations have been made between cardiac health and oxidative stress (Dai et al., 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Oxidative damage caused by free radicals plays an important role in the causation and progression of many diseases, including aging. Free-radical damage is countered by many mechanisms, including both active antioxidant enzymatic activity in our body and passive antioxidants. Antioxidant response of our body can accommodate increased oxidative damage in diseased states to a level but beyond that level, additional antioxidants are required to combat the increased stress. Apart from the regular dietary sources of antioxidants, many traditional herbal medicines demonstrate a potential to boost antioxidant activity. Rasayana chikitsa that deals with rejuvenation and revitalization is a branch of the Indian traditional medical system of ayurveda. We review some select herbs described in rasayana chikitsa that have been assessed by modern means for stimulating intrinsic antioxidant responses in humans. A critical evaluation of rasayana chikitsa will likely provide urgently needed, actual stimulants of our physiological antioxidant responses and not just more passive antioxidants to add to an already large catalog.
    Full-text · Article · Jul 2012 · Frontiers in Neuroscience
Show more