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Title: The causal effect of obesity on prediabetes and insulin resistance reveals the important role of adipose tissue in insulin resistance
Award ID(s):
1705197
NSF-PAR ID:
10283373
Author(s) / Creator(s):
; ; ; ; ; ; ; ; ; ; ; ; ; ; ;
Editor(s):
Hauser, Elizabeth R.
Date Published:
Journal Name:
PLOS Genetics
Volume:
16
Issue:
9
ISSN:
1553-7404
Page Range / eLocation ID:
e1009018
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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  1. Abstract Insulin receptor (IR) signaling is central to normal metabolic control and is dysregulated in metabolic diseases such as type 2 diabetes. We report here that IR is incorporated into dynamic clusters at the plasma membrane, in the cytoplasm and in the nucleus of human hepatocytes and adipocytes. Insulin stimulation promotes further incorporation of IR into these dynamic clusters in insulin-sensitive cells but not in insulin-resistant cells, where both IR accumulation and dynamic behavior are reduced. Treatment of insulin-resistant cells with metformin, a first-line drug used to treat type 2 diabetes, can rescue IR accumulation and the dynamic behavior of these clusters. This rescue is associated with metformin’s role in reducing reactive oxygen species that interfere with normal dynamics. These results indicate that changes in the physico-mechanical features of IR clusters contribute to insulin resistance and have implications for improved therapeutic approaches. 
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