AS160 deficiency causes whole-body insulin resistance via composite effects in multiple tissues.
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.
MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Pukou District, Nanjing 210061, China.
Hong Yu
HY
Wang
Serge
S
Ducommun
Chao
C
Quan
Bingxian
B
Xie
Min
M
Li
David H
DH
Wasserman
Kei
K
Sakamoto
Carol
C
Mackintosh
Shuai
S
Chen
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D005260:Female; D020690:GTPase-Activating Proteins / Q000172:deficiency / Q000235:genetics*; D005947:Glucose / Q000378:metabolism / Q000493:pharmacokinetics; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood / Q000494:pharmacology; D066298:In Vitro Techniques; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D007333:Insulin Resistance / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects
D001786:Blood Glucose; D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; D007004:Hypoglycemic Agents; D007328:Insulin; C495693:Slc2a4 protein, mouse; C505647:Tbc1d4 protein, mouse; D038362:Glycogen Synthase Kinase 3; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose