Altered Glycan-dependent Signaling Induces Insulin Resistance and Hyperleptinemia

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2002 Jul 24

PMID 12136128

Citations 136

Authors

Donald A McClain

William A Lubas

Robert C Cooksey

Mark Hazel

Glendon J Parker

Dona C Love

John A Hanover

Affiliations

Soon will be listed here.

Abstract

Insulin resistance and beta cell toxicity are key features of type 2 diabetes. One leading hypothesis suggests that these abnormalities result from excessive flux of nutrients through the UDP-hexosamine biosynthetic pathway leading to "glucose toxicity." How the products of the hexosamine pathway mediate these effects is not known. Here, we show that transgenic overexpression of an enzyme using UDP-GlcNAc to modify proteins with O-GlcNAc produces the type 2 diabetic phenotype. Even modest overexpression of an isoform of O-GlcNAc transferase, in muscle and fat, leads to insulin resistance and hyperleptinemia. These data support the proposal that O-linked GlcNAc transferase participates in a hexosamine-dependent signaling pathway that is linked to insulin resistance and leptin production.

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