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Publication
Whole body glucoregulation and tissue-specific glucose uptake in a novel Akt
substrate of 160 kDa knockout rat model.
Authors Arias EB, Zheng X, Agrawal S, Cartee GD
Submitted By Submitted Externally on 4/30/2020
Status Published
Journal PLoS ONE
Year 2019
Date Published
Volume : Pages 14 : e0216236
PubMed Reference 31034517
Abstract Akt substrate of 160 kDa (also called AS160 or TBC1D4) is a Rab GTPase
activating protein and key regulator of insulin-stimulated glucose uptake which
is expressed by multiple tissues, including skeletal muscle, white adipose
tissue (WAT) and the heart. This study introduces a novel rat AS160-knockout
(AS160-KO) model that was created using CRISPR/Cas9 technology. We compared male
AS160-KO versus wildtype (WT) rats for numerous metabolism-related endpoints.
Body mass, body composition, energy expenditure and physical activity did not
differ between genotypes. Oral glucose intolerance was detected in AS160-KO
versus WT rats (P<0.005). A hyperinsulinemic-euglycemic clamp (HEC) revealed
insulin resistance for glucose infusion rate (P<0.05) with unaltered hepatic
glucose production in AS160-KO versus WT rats. Genotype-effects on glucose
uptake during the HEC: 1) was significantly lower in epitrochlearis (P<0.01) and
extensor digitorum longus (P<0.05) of AS160-KO versus WT rats, and tended to be
lower for AS160-KO versus WT rats in the soleus (P<0.06) and gastrocnemius
(P<0.08); 2) tended to be greater for AS160-KO versus WT rats in white adipose
tissue (P = 0.09); and 3) was significantly greater in the heart (P<0.005) of
AS160-KO versus WT rats. GLUT4 protein abundance was significantly lower for
AS160-KO versus WT rats in each tissue analyzed (P<0.01-0.001) except the
gastrocnemius. Ex vivo insulin-stimulated glucose uptake was significantly lower
(P<0.001) for AS160-KO versus WT rats in isolated epitrochlearis or soleus.
Insulin-stimulated Akt phosphorylation (in vivo or ex vivo) did not differ
between genotypes for any tissue tested. Ex vivo AICAR-stimulated glucose uptake
by isolated epitrochlearis was significantly lower for AS160-KO versus WT rats
(P<0.01) without genotype-induced alteration in AMP-activated protein
phosphorylation. This unique AS160-KO rat model, which elucidated striking
genotype-related modifications in glucoregulation, will enable future research
aimed at understanding AS160's roles in numerous physiological processes in
response to various interventions (e.g., diet and/or exercise).




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