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In vivo glucoregulation and tissue-specific glucose uptake in female Akt
substrate 160 kDa knockout rats.
Authors Zheng X, Arias EB, Qi NR, Saunders TL, Cartee GD
Submitted By Submitted Externally on 4/30/2020
Status Published
Journal PLoS ONE
Year 2020
Date Published
Volume : Pages 15 : e0223340
PubMed Reference 32053588
Abstract The Rab GTPase activating protein known as Akt substrate of 160 kDa (AS160 or
TBC1D4) regulates insulin-stimulated glucose uptake in skeletal muscle, the
heart, and white adipose tissue (WAT). A novel rat AS160-knockout (AS160-KO) was
created with CRISPR/Cas9 technology. Because female AS160-KO versus wild type
(WT) rats had not been previously evaluated, the primary objective of this study
was to compare female AS160-KO rats with WT controls for multiple, important
metabolism-related endpoints. Body mass and composition, physical activity, and
energy expenditure were not different between genotypes. AS160-KO versus WT rats
were glucose intolerant based on an oral glucose tolerance test (P<0.001) and
insulin resistant based on a hyperinsulinemic-euglycemic clamp (HEC; P<0.001).
Tissue glucose uptake during the HEC of female AS160-KO versus WT rats was: 1)
significantly lower in epitrochlearis (P<0.05) and extensor digitorum longus
(EDL; P<0.01) muscles of AS160-KO compared to WT rats; 2) not different in
soleus, gastrocnemius or WAT; and 3) ~3-fold greater in the heart (P<0.05).
GLUT4 protein content was reduced in AS160-KO versus WT rats in the
epitrochlearis (P<0.05), EDL (P<0.05), gastrocnemius (P<0.05), soleus (P<0.05),
WAT (P<0.05), and the heart (P<0.005). Insulin-stimulated glucose uptake by
isolated epitrochlearis and soleus muscles was lower (P<0.001) in AS160-KO
versus WT rats. Akt phosphorylation of insulin-stimulated tissues was not
different between the genotypes. A secondary objective was to probe processes
that might account for the genotype-related increase in myocardial glucose
uptake, including glucose transporter protein abundance (GLUT1, GLUT4, GLUT8,
SGLT1), hexokinase II protein abundance, and stimulation of the AMP-activated
protein kinase (AMPK) pathway. None of these parameters differed between
genotypes. Metabolic phenotyping in the current study revealed AS160 deficiency
produced a profound glucoregulatory phenotype in female AS160-KO rats that was
strikingly similar to the results previously reported in male AS160-KO rats.


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