Article

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: 4.65). 04/2008; 75(6):1402-10. DOI: 10.1016/j.bcp.2007.12.003
Source: PubMed

ABSTRACT 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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    • "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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    • "POPULATION-BASED DISCOVERY OF BIOMARKERS expression by glucose, was decreased as the degree of liver necrosis increased in animals treated with acetaminophen. Several recent studies demonstrated that acetaminophen can affect blood glucose levels (Kendig et al., 2008) and improve glucose tolerance in mice fed a high-fat diet (Shertzer et al., 2008). The former study showed that daily administration of acetaminophen prevented approximately 70% of weight gain compared to mice fed the highfat diet alone, even at a daily dose that was lower than half of the maximum recommended weight-adjusted human dose (Kendig et al., 2008). "
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