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Adiponectin Resistance Exacerbates Insulin Resistance in Insulin Receptor Transgenic/Knockout Mice

¹ Department of Medicine, Columbia University, New York, New York
² Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York
³ Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York

Address correspondence and reprint requests to Domenico Accili, MD, Columbia University Medical Center, 1150 St. Nicholas Ave., #238, New York, NY 10032. E-mail: da230{at}columbia.edu

Abbreviations: AMPK, AMP-activated protein kinase; FoxO1, forkhead box O1; HGP, hepatic glucose production; IL, interleukin; Insr, insulin receptor; PPAR, peroxisome proliferator–activated receptor

OBJECTIVE— Adiponectin increases insulin sensitivity and contributes to insulin's indirect effects on hepatic glucose production.

RESEARCH DESIGN AND METHODS— To examine adiponectin's contribution to insulin action, we analyzed adiponectin levels and activation of AMP-activated protein kinase (AMPK) in insulin receptor transgenic/knockout mice (L1), a genetic model of resistance to insulin's indirect effects on hepatic glucose production.

RESULTS— In euglycemic, insulin-resistant L1 mice, we detected hyperadiponectinemia with normal levels of adiponectin receptor-1 and -2. Moreover, adiponectin administration is unable to lower glucose levels or induce activation of AMPK, consistent with a state of adiponectin resistance. In a subset of hyperglycemic L1 mice, we observed decreased mRNA expression of AdipoR2 in liver and muscle, as well as decreased peroxisome proliferator–activated receptor (PPAR) target gene expression in liver, raising the possibility that deterioration of adiponectin/AdipoR2 signaling via PPAR activation contributes to the progression from compensated insulin resistance to diabetes. In contrast, we failed to detect changes in other markers of the systemic or local inflammatory response.

CONCLUSIONS— These data provide evidence for a mechanism of adiponectin resistance and corroborate the notion that adiponectin potentiates hepatic insulin sensitivity.

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