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Binge Drinking Induces Whole-Body Insulin Resistance by Impairing Hypothalamic Insulin Action
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    Individuals with a history of binge drinking have an increased risk of developing the metabolic syndrome and type 2 diabetes. Whether binge drinking impairs glucose homeostasis and insulin action is unknown. To test this, we treated Sprague-Dawley rats daily with alcohol (3 g/kg) for three consecutive days to simulate human binge drinking and found that these rats developed and exhibited insulin resistance even after blood alcohol concentrations had become undetectable. The animals were resistant to insulin for up to 54 hours after the last dose of ethanol, chiefly a result of impaired hepatic and adipose tissue insulin action. Because insulin regulates hepatic glucose production and white adipose tissue lipolysis, in part through signaling in the central nervous system, we tested whether binge drinking impaired brain control of nutrient partitioning. Rats that had consumed alcohol exhibited impaired hypothalamic insulin action, defined as the ability of insulin infused into the mediobasal hypothalamus to suppress hepatic glucose production and white adipose tissue lipolysis. Insulin signaling in the hypothalamus, as assessed by insulin receptor and AKT phosphorylation, decreased after binge drinking. Quantitative polymerase chain reaction showed increased hypothalamic inflammation and expression of protein tyrosine phosphatase 1B (PTP1B), a negative regulator of insulin signaling. Intracerebroventricular infusion of CPT-157633, a small-molecule inhibitor of PTP1B, prevented binge drinking-induced glucose intolerance. These results show that, in rats, binge drinking induces systemic insulin resistance by impairing hypothalamic insulin action and that this effect can be prevented by inhibition of brain PTP1B.

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    DK074873/DK/NIDDK NIH HHS/United States
    U24 DK076169/DK/NIDDK NIH HHS/United States
    U24 DK76169/DK/NIDDK NIH HHS/United States
    P41 RR018522/RR/NCRR NIH HHS/United States
    R03 DK082724/DK/NIDDK NIH HHS/United States
    U62 PS001145/PS/NCHHSTP CDC HHS/United States
    DK083568/DK/NIDDK NIH HHS/United States
    P50 AG005138/AG/NIA NIH HHS/United States
    DK082724/DK/NIDDK NIH HHS/United States
    K08 DK074873/DK/NIDDK NIH HHS/United States
    R01 CA053840/CA/NCI NIH HHS/United States
    P60 DK020541/DK/NIDDK NIH HHS/United States
    R01 DK083658/DK/NIDDK NIH HHS/United States
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