AS160 deficiency causes whole-body insulin resistance via composite effects in multiple tissues
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AS160 deficiency causes whole-body insulin resistance via composite effects in multiple tissues. / Wang, Hong Yu; Ducommun, Serge; Quan, Chao; Xie, Bingxian; Li, Min; Wasserman, David H.; Sakamoto, Kei; Mackintosh, Carol; Chen, Shuai.
I: Biochemical Journal, Bind 449, Nr. 2, 15.01.2013, s. 479-489.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - AS160 deficiency causes whole-body insulin resistance via composite effects in multiple tissues
AU - Wang, Hong Yu
AU - Ducommun, Serge
AU - Quan, Chao
AU - Xie, Bingxian
AU - Li, Min
AU - Wasserman, David H.
AU - Sakamoto, Kei
AU - Mackintosh, Carol
AU - Chen, Shuai
PY - 2013/1/15
Y1 - 2013/1/15
N2 - AS160 (Akt substrate of 160 kDa) is a Rab GTPase-activating protein implicated in insulin control of GLUT4 (glucose transporter 4) trafficking. In humans, a truncation mutation (R363X) in one allele of AS160 decreased the expression of the protein and caused severe postprandial hyperinsulinaemia during puberty. To complement the limited studies possible in humans, we generated an AS160-knockout mouse. In wild-type mice, AS160 expression is relatively high in adipose tissue and soleus muscle, low in EDL (extensor digitorum longus) muscle and detectable in liver only after enrichment. Despite having lower blood glucose levels under both fasted and random-fed conditions, the AS160-knockout mice exhibited insulin resistance in both muscle and liver in a euglycaemic clamp study. Consistent with this paradoxical phenotype, basal glucose uptake was higher in AS160-knockout primary adipocytes and normal in isolated soleus muscle, but their insulin-stimulated glucose uptake and overall GLUT4 levels were markedly decreased. In contrast, insulin-stimulated glucose uptake and GLUT4 levels were normal in EDL muscle. The liver also contributes to the AS160-knockout phenotype via hepatic insulin resistance, elevated hepatic expression of phosphoenolpyruvate carboxykinase isoforms and pyruvate intolerance, which are indicative of increased gluconeogenesis. Overall, as well as its catalytic function, AS160 influences expression of other proteins, and its loss deregulates basal and insulin-regulated glucose homoeostasis, not only in tissues that normally express AS160, but also by influencing liver function.
AB - AS160 (Akt substrate of 160 kDa) is a Rab GTPase-activating protein implicated in insulin control of GLUT4 (glucose transporter 4) trafficking. In humans, a truncation mutation (R363X) in one allele of AS160 decreased the expression of the protein and caused severe postprandial hyperinsulinaemia during puberty. To complement the limited studies possible in humans, we generated an AS160-knockout mouse. In wild-type mice, AS160 expression is relatively high in adipose tissue and soleus muscle, low in EDL (extensor digitorum longus) muscle and detectable in liver only after enrichment. Despite having lower blood glucose levels under both fasted and random-fed conditions, the AS160-knockout mice exhibited insulin resistance in both muscle and liver in a euglycaemic clamp study. Consistent with this paradoxical phenotype, basal glucose uptake was higher in AS160-knockout primary adipocytes and normal in isolated soleus muscle, but their insulin-stimulated glucose uptake and overall GLUT4 levels were markedly decreased. In contrast, insulin-stimulated glucose uptake and GLUT4 levels were normal in EDL muscle. The liver also contributes to the AS160-knockout phenotype via hepatic insulin resistance, elevated hepatic expression of phosphoenolpyruvate carboxykinase isoforms and pyruvate intolerance, which are indicative of increased gluconeogenesis. Overall, as well as its catalytic function, AS160 influences expression of other proteins, and its loss deregulates basal and insulin-regulated glucose homoeostasis, not only in tissues that normally express AS160, but also by influencing liver function.
KW - Akt substrate of 160 kDa (AS160)
KW - Glucose transport
KW - Insulin resistance
KW - Liver
KW - Muscle
UR - http://www.scopus.com/inward/record.url?scp=84871447109&partnerID=8YFLogxK
U2 - 10.1042/BJ20120702
DO - 10.1042/BJ20120702
M3 - Journal article
C2 - 23078342
AN - SCOPUS:84871447109
VL - 449
SP - 479
EP - 489
JO - Biochemical Journal
JF - Biochemical Journal
SN - 0264-6021
IS - 2
ER -
ID: 239566182