Binge Drinking Induces Whole-Body Insulin Resistance by Impairing Hypothalamic Insulin Action

Lindtner, C., Scherer, T., Zielinski, E., Filatova, N., Fasshauer, M., Tonks, N. K., Puchowicz, M., Buettner, C. (January 2013) Binge Drinking Induces Whole-Body Insulin Resistance by Impairing Hypothalamic Insulin Action. Science Translational Medicine, 5 (170). ISSN 1946-6234

URL: http://www.ncbi.nlm.nih.gov/pubmed/23363978
DOI: 10.1126/scitranslmed.3005123

Abstract

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.

Item Type: Paper
Uncontrolled Keywords: tyrosine-phosphatase 1b endoplasmic-reticulum stress hepatic glucose-production adipose-tissue lipolysis alcohol-consumption metabolic syndrome leptin resistance ethanol inflammation obesity
Subjects: diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
diseases & disorders > nutritional and metabolic diseases
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
diseases & disorders > nutritional and metabolic diseases > diabetes
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes
organs, tissues, organelles, cell types and functions > tissues types and functions > suprachiasmatic nucleus > hypothalamus
organs, tissues, organelles, cell types and functions > tissues types and functions > hypothalamus

bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > protein phosphatase
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
organs, tissues, organelles, cell types and functions > tissues types and functions
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > protein tyrosine phosphatase
CSHL Authors:
Communities: CSHL labs > Tonks lab
Depositing User: Matt Covey
Date: 30 January 2013
Date Deposited: 01 Apr 2013 15:55
Last Modified: 03 Jun 2013 19:39
Related URLs:
URI: http://repository.cshl.edu/id/eprint/28040

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