Transgenic mice overexpressing the rate-limiting enzyme for hexosamine synthesis in skeletal muscle or adipose tissue exhibit total body insulin resistance.

Abstract:

:High concentrations of glucose induce insulin resistance and impair insulin secretion in a manner that mirrors type 2 diabetes, a phenomenon known as glucose toxicity. High concentrations of hexosamines mimic these effects, leading to the hypothesis that cells use hexosamine flux as a glucose- and satiety-sensing pathway. Overexpression of the rate-limiting enzyme for hexosamine synthesis (glutamine:fructose-6-phosphate amidotransferase, GFA) in muscle and fat results in insulin resistance and hyperleptinemia. GFA overexpression targeted to liver results in hyperlipidemia and to the beta cell in increased insulin secretion. Thus, excess hexosamine flux leads to a coordinated response whereby fuel is shunted toward long-term storage, mirroring the "thrifty phenotype". The results suggest a mechanism by which chronic overnutrition leads to the phenotype of type 2 diabetes.

journal_name

Ann N Y Acad Sci

authors

Cooksey RC,McClain DA

doi

10.1111/j.1749-6632.2002.tb04268.x

subject

Has Abstract

pub_date

2002-06-01 00:00:00

pages

102-11

eissn

0077-8923

issn

1749-6632

journal_volume

967

pub_type

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