Differential hepatic distribution of insulin receptor substrates causes selective insulin resistance in diabetes and obesity

• Published in: Nature communications Vol. 7; no. 1; p. 12977
• Main Authors: Kubota, Naoto, Kubota, Tetsuya, Kajiwara, Eiji, Iwamura, Tomokatsu, Kumagai, Hiroki, Watanabe, Taku, Inoue, Mariko, Takamoto, Iseki, Sasako, Takayoshi, Kumagai, Katsuyoshi, Kohjima, Motoyuki, Nakamuta, Makoto, Moroi, Masao, Sugi, Kaoru, Noda, Tetsuo, Terauchi, Yasuo, Ueki, Kohjiro, Kadowaki, Takashi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06-10-2016; Nature Publishing Group; Nature Portfolio
• Subjects: 631/443/319/1642/137/773; 631/80/86/2367; 692/4020/4021/288; 96; 96/95; Animals; Antigens, CD - metabolism; Cell Nucleus - metabolism; Diabetes; Diabetes Mellitus - metabolism; Diabetes Mellitus, Experimental - metabolism; Fasting; Food; Gluconeogenesis; Glucose; Homeostasis; Humanities and Social Sciences; Humans; Hyperinsulinism - metabolism; Insulin - metabolism; Insulin Receptor Substrate Proteins - genetics; Insulin Receptor Substrate Proteins - metabolism; Insulin Resistance; Liver; Liver - metabolism; Male; Medical research; Medicine; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; multidisciplinary; Non-alcoholic Fatty Liver Disease - metabolism; Nutrition research; Obesity; Obesity - metabolism; Receptor, Insulin - metabolism; Science; Science (multidisciplinary); Signal Transduction; Japan
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms12977

Hepatic insulin signalling involves insulin receptor substrates (Irs) 1/2, and is normally associated with the inhibition of gluconeogenesis and activation of lipogenesis. In diabetes and obesity, insulin no longer suppresses hepatic gluconeogenesis, while continuing to activate lipogenesis, a state referred to as ‘selective insulin resistance’. Here, we show that ‘selective insulin resistance’ is caused by the differential expression of Irs1 and Irs2 in different zones of the liver. We demonstrate that hepatic Irs2-knockout mice develop ‘selective insulin resistance’, whereas mice lacking in Irs1, or both Irs1 and Irs2, develop ‘total insulin resistance’. In obese diabetic mice, Irs1/2-mediated insulin signalling is impaired in the periportal zone, which is the primary site of gluconeogenesis, but enhanced in the perivenous zone, which is the primary site of lipogenesis. While hyperinsulinaemia reduces Irs2 expression in both the periportal and perivenous zones, Irs1 expression, which is predominantly in the perivenous zone, remains mostly unaffected. These data suggest that ‘selective insulin resistance’ is induced by the differential distribution, and alterations of hepatic Irs1 and Irs2 expression.
Type 2 diabetes and obesity are associated with increased hepatic gluconeogenesis and lipogenesis, known as selective insulin resistance. Here Kubota
et al
. explain selective insulin resistance in the liver with the zonal distribution and selective insulin-mediated regulation of Irs1 and Irs2.