title: Differential hepatic distribution of insulin receptor substrates causes selective insulin resistance in diabetes and obesity.
abstract: 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.
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.|Department of Clinical Nutrition Therapy, The University of Tokyo, Tokyo 113-8655, Japan.|Clinical Nutrition Program, National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 162-8636, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Kubota
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.|Clinical Nutrition Program, National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 162-8636, Japan.|Division of Cardiovascular Medicine, Toho University, Ohashi Hospital, Tokyo 153-8515, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kubota
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kajiwara
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Tomokatsu
authors.initials: T
authors.lastname: Iwamura
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kumagai
authors.affiliation: First Department of Medicine, Hokkaido University School of Medicine, Sapporo, Hokkaido 060-8648, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.|Clinical Nutrition Program, National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 162-8636, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Inoue
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.|Clinical Nutrition Program, National Institute of Health and Nutrition, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka 162-8636, Japan.
authors.forename: Iseki
authors.initials: I
authors.lastname: Takamoto
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Sasako
authors.affiliation: Animal Research Center, Tokyo Medical University, Tokyo 160-8402, Japan.
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Kumagai
authors.affiliation: Department of Gastroenterology, Clinical Research Center, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan.
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Kohjima
authors.affiliation: Department of Gastroenterology, Clinical Research Center, National Hospital Organization Kyushu Medical Center, Fukuoka 810-8563, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Nakamuta
authors.affiliation: Division of Cardiovascular Medicine, Toho University, Ohashi Hospital, Tokyo 153-8515, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Moroi
authors.affiliation: Division of Cardiovascular Medicine, Toho University, Ohashi Hospital, Tokyo 153-8515, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Sugi
authors.affiliation: Department of Cell Biology, Japanese Foundation for Cancer Research-Cancer Institute, Tokyo 135-8550, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Noda
authors.affiliation: Department of Diabetes and Endocrinology, Yokohama City University, School of Medicine, Kanagawa 236-0004, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Kohjiro
authors.initials: K
authors.lastname: Ueki
authors.affiliation: Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D005943:Gluconeogenesis; D006706:Homeostasis; D006801:Humans; D006946:Hyperinsulinism / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D015703:Antigens, CD; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; C526298:Irs2 protein, mouse; C435941:INSR protein, human; D011972:Receptor, Insulin