Acetaminophen normalizes glucose homeostasis in mouse models for diabetes

Department of Environmental Health and Center for Environmental Genetics, University of Cincinnati Medical Center, Cincinnati, OH 45267, USA.
Biochemical pharmacology (Impact Factor: 5.01). 04/2008; 75(6):1402-10. DOI: 10.1016/j.bcp.2007.12.003
Source: PubMed


Loss of pancreatic beta cell insulin secretion is the most important element in the progression of type 1 and type 2 diabetes. Since oxidative stress is involved in the progressive loss of beta cell function, we evaluated the potential for the over-the-counter analgesic drug and antioxidant, acetaminophen (APAP), to intervene in the diabetogenic process. We used mouse models for type 1 diabetes (streptozotocin) and type 2 diabetes (high-fat diet) to examine the ability of APAP to intervene in the progression of diabetes. In C57BL/6J mice, streptozotocin caused a dosage dependent increase in fasting blood glucose (FBG), from 100 to >600mg/dl. Daily APAP (20mg/kg BW, gastric gavage), significantly prevented and partially reversed the increase in FBG levels produced by streptozotocin. After 10 weeks on a high-fat diet, mice developed fasting hyperinsulemia and impaired glucose tolerance compared to animals fed a control diet. APAP largely prevented these changes in insulin and glucose tolerance. Furthermore, APAP prevented most of the increase in body fat in mice fed the high-fat diet. One protective mechanism for APAP is suggested by studies using isolated liver mitochondria, where low micromolar concentrations abolished the production of reactive oxygen that might otherwise contribute to the destruction of pancreatic beta-cells. These findings suggest that administration of APAP to mice, in a dosage used safely by humans, reduces the production of mitochondrial reactive oxygen and concomitantly prevents the development of type 1 and type 2 diabetes in established animal models.

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    • "A beneficial effect of salubrinal on HFD-induced prediabetic neuropathy in the current study is likely mediated through both amelioration of the prediabetic condition per se, and the biochemical changes in the peripheral nervous system independent of the wholebody glucose homeostasis. Our findings are in line with several previous reports (Hoehn et al., 2009; Shertzer et al., 2008; Weisberg et al., 2008) indicating that a HFD-fed mouse is not an ideal model for dissection of pathogenetic mechanisms underlying prediabetes-associated end-organ damage, because pharmacological and genetic manipulations abrogating oxidative and now ER stress in this model interfere with the HFD-induced prediabetic phenotype per se. Evaluation of salubrinal on neuropathy in other models of prediabetes and in overt diabetes has never been performed. "
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    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
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    • "Both models exhibit nerve conduction deficit, small sensory nerve fiber dysfunction, and clearly manifested oxidative-nitrosative stress in the peripheral nerve and vasa nervorum [21] [22] [23] [24] [25] and are, therefore, suitable for dissection of relative contribution of these phenomena to peripheral neuropathy in prediabetes. Zucker fa/fa rat with genetically predetermined obesity, hyperinsulinemia, and other afore-mentioned metabolic abnormalities is the preferential model for this kind of studies, as many pharmacological interventions, including those alleviating oxidative stress, have been reported to interfere with the prediabetic condition per se in high-fat diet fed rodents [26] [27] [28]. "
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    ABSTRACT: Peripheral neuropathy develops in human subjects with prediabetes and metabolic syndrome before overt hyperglycemia. The contributions of impaired glucose tolerance and insulin signaling, hypertriglyceridemia and/or increased nonesterified fatty acids (NEFA), and hypercholesterolemia to this condition remain unknown. Niacin and its derivatives alleviate dyslipidemia with a minor effect on glucose homeostasis. This study evaluated the roles of impaired glucose tolerance versus dyslipidemia in prediabetic neuropathy using Zucker fatty (fa/fa) rats and the niacin derivative acipimox, as well as the interplay of hypertriglyceridemia, increased NEFA, and oxidative-nitrosative stress. Sixteen-week-old Zucker fatty rats with impaired glucose tolerance, obesity, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and increased NEFA displayed sensory nerve conduction velocity deficit, thermal and mechanical hypoalgesia, and tactile allodynia. Acipimox (100 mg kg(-1) day(-1), 4 weeks) reduced serum insulin, NEFA, and triglyceride concentrations without affecting glucose tolerance and hypercholesterolemia. It alleviated sensory nerve conduction velocity deficit and changes in behavioral measures of sensory function and corrected oxidative-nitrosative stress, but not impaired insulin signaling, in peripheral nerve. Elevated NEFA increased total and mitochondrial superoxide production and NAD(P)H oxidase activity in cultured human Schwann cells. In conclusion, hypertriglyceridemia and/or increased NEFA concentrations cause prediabetic neuropathy through oxidative-nitrosative stress. Lipid-lowering agents and antioxidants may find a use in the management of this condition.
    Full-text · Article · Feb 2012 · Free Radical Biology and Medicine
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    • "Interestingly, extensive animal and in vitro studies have suggested that acetaminophen possesses remarkable antioxidant properties when used within the therapeutic dosage. Acetaminophen is phenolic in structure with a substituent at the para position relative to the hydroxyl group (Figure 1) which allows it to react with reactive species (Dinis et al., 1994; Shertzer et al., 2008). For example, Shertzer et al. (2008) using cell-free assay systems demonstrated that acetaminophen at a concentrations of 2–10 μM is able to directly scavenge reactive oxygen. "
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    ABSTRACT: Acetaminophen, also known as APAP or paracetamol, is one of the most widely used analgesics (pain reliever) and antipyretics (fever reducer). According to the U.S. Food and Drug Administration, currently there are 235 approved prescription and over-the-counter drug products containing acetaminophen as an active ingredient. When used as directed, acetaminophen is very safe and effective; however when taken in excess or ingested with alcohol hepatotoxicity and irreversible liver damage can arise. In addition to well known use pain relief and fever reduction, recent laboratory and pre-clinical studies have demonstrated that acetaminophen may also have beneficial effects on blood glucose levels, skeletal muscle function, and potential use as cardioprotective and neuroprotective agents. Extensive laboratory and pre-clinical studies have revealed that these off-label applications may be derived from the ability of acetaminophen to function as an antioxidant. Herein, we will highlight these novel applications of acetaminophen, and attempt, where possible, to highlight how these findings may lead to new directions of inquiry and clinical relevance of other disorders.
    Preview · Article · Nov 2011 · Frontiers in Pharmacology
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