RGD Reference Report - In vivo glucoregulation and tissue-specific glucose uptake in female Akt substrate 160 kDa knockout rats. - Rat Genome Database

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In vivo glucoregulation and tissue-specific glucose uptake in female Akt substrate 160 kDa knockout rats.

Authors: Zheng, Xiaohua  Arias, Edward B  Qi, Nathan R  Saunders, Thomas L  Cartee, Gregory D 
Citation: Zheng X, etal., PLoS One. 2020 Feb 13;15(2):e0223340. doi: 10.1371/journal.pone.0223340. eCollection 2020.
RGD ID: 38596323
Pubmed: PMID:32053588   (View Abstract at PubMed)
PMCID: PMC7018090   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pone.0223340   (Journal Full-text)

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.

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
impaired glucose tolerance  IMP 38596323; 38596323 RGD 
impaired glucose tolerance inducedIMPglucose solution38596323 RGD 
insulin resistance  IMP 38596323; 38596323 RGD 
insulin resistance inducedIMPglucose solution38596323compared to female wild-typeRGD 
Objects Annotated

Genes (Rattus norvegicus)
Tbc1d4  (TBC1 domain family, member 4)
Tbc1d4em1  (TBC1 domain family, member 4; CRISPR/Cas9 system induced mutant 1,)

WI-Tbc1d4em1Gdcz  (NA)

Additional Information