The Inactivation of RabGAP Function of AS160 Promotes Lysosomal Degradation of GLUT4 and Causes Postprandial Hyperglycemia and Hyperinsulinemia

Xie, Bingxian; Chen, Qiaoli; Chen, Liang; Yang, Songfan; Wang, Hong Yu; Chen, Shuai

doi:10.2337/db16-0416

Cited by 34 publications

(29 citation statements)

References 47 publications

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“…Insulin-stimulated GLUT4 translocation onto plasma membrane was impaired in the AS160 Thr649Ala knockin mice although expression of the transporter was elevated [25]. In contrast, expression of GLUT4 was decreased in various muscles and adipose tissue of the AS160 deficient mouse models [38][39][40] as well as in skeletal muscles from human patients who harbor a pre-mature stop codon Arg 684 Ter on AS160 [15].…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the reduced GLUT4 levels in one of the TBC1D1 knockout mouse models caused a decrease in exercisestimulated glucose uptake in nonoxidative muscle fibers and consequently impaired exercise endurance [44]. It has been recently shown that the loss of AS160 GAP activity accelerates lysosomal degradation of GLUT4 [40]. A key question remaining to be answered in all the TBC1D1 mouse models is whether the effects on GLUT4 translocation or expression are dependent on the GAP activity of TBC1D1.…”

Section: Discussionmentioning

confidence: 99%

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A Tbc1d1 Ser231Ala-knockin mutation partially impairs AICAR- but not exercise-induced muscle glucose uptake in mice

et al. 2016

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. (2017). A Tbc1d1Ser231Ala-knockin mutation partially impairs AICAR-but not exercise-induced muscle glucose uptake in mice. Diabetologia, 60(2), 336-345. DOI: 10.1007/s00125-016-4151-9General rights Copyright and moral rights for the publications made accessible in Discovery Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights.• Users may download and print one copy of any publication from Discovery Research Portal for the purpose of private study or research.• You may not further distribute the material or use it for any profit-making activity or commercial gain.• You may freely distribute the URL identifying the publication in the public portal. Take down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. GAP, GTPase-activating protein; GLUT4, glucose transporter 4; PKB, protein kinase B (also known as Akt); TBC1D1, tre-2/USP6, BUB2, cdc16 domain family member 1. 2 ABSTRACTHypothesis: TBC1D1 is a Rab GTPase activating protein (RabGAP) that has been implicated in regulating GLUT4 trafficking. TBC1D1 can be phosphorylated by the AMP-activated protein kinase (AMPK) on Ser 231 , which consequently interacts with 14-3-3 proteins. Given the key role for AMPK in regulating insulin-independent muscle glucose uptake, we hypothesized that TBC1D1 Ser 231 phosphorylation and/or 14-3-3 binding may mediate AMPK-governed glucose homeostasis.Methods: Whole-body glucose homeostasis and muscle glucose uptake were assayed in mice bearing a TBC1D1 Ser231Ala knockin mutation or harboring skeletal muscle specific AMPKα1/α2 double knockout mutations in response to an AMPK-activating agent, 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside (AICAR). Exercise-induced muscle glucose uptake and exercise capacity were also determined in the TBC1D1 Ser231Ala knockin mice.Results: Skeletal muscle specific deletion of AMPKα1/α2 in mice prevented AICAR-induced hypoglycemia and muscle glucose uptake. The TBC1D1 Ser231Ala knockin mutation also attenuated the glucose-lowering effect of AICAR in mice. Glucose uptake and cell surface GLUT4 content were significantly lower in muscle isolated from the TBC1D1 Ser231Ala knockin mice upon stimulation with a submaximal dose of AICAR. However, this TBC1D1 Ser231Ala knockin mutation neither impaired exercise-induced muscle glucose uptake nor affected exercise capacity in mice.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A Tbc1d1 Ser231Ala-knockin mutation partially impairs AICAR- but not exercise-induced muscle glucose uptake in mice

et al. 2016

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“…Published research in humans has not addressed the possibility that AS160 deficiency might not have identical consequences on males versus females [6]. Several studies using AS160-KO mice reported data only [4,7] or mostly [8] in males. Other studies reported data for both male and female AS160-KO mice for some, but not all outcomes [3,9].…”

Section: Introductionmentioning

confidence: 99%

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

Zheng

Arias

et al. 2020

PLoS ONE

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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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“…In the current study, we did not observe any alterations in muscle properties in muscle-specific Egr-1 knockout mice, which suggests that a deficiency in Egr-1 alone may not affect muscle morphology and performance. Skeletal muscle, a highly metabolically active tissue, has substantial insulin sensitivity, which results in glucose transport and glycogen breakdown during exercise (35)(36)(37); however, mechanistic studies have demonstrated that acute exercise does not increase phosphorylation of the PI3K/AKT pathway (38,39), but instead activates the phosphorylation of aPKC/AS160 (40,41). Thus, it is likely that the insulin-stimulated activation of PI3K/AKT by Egr-1 deletion does not affect glucose uptake or glycogen breakdown during exercise, thus explaining why the deletion of Egr-1 does not affect running ability or blood lactate levels.…”

Section: Discussionmentioning

confidence: 99%

Early growth response‐1 negative feedback regulates skeletal muscle postprandial insulin sensitivityviaactivatingPtp 1btranscription

Tao

Chong

et al. 2018

FASEB j.

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Postprandial insulin desensitization plays a critical role in maintaining whole-body glucose homeostasis by avoiding the excessive absorption of blood glucose; however, the detailed mechanisms that underlie how the major player, skeletal muscle, desensitizes insulin action remain to be elucidated. Herein, we report that early growth response gene-1 ( Egr-1) is activated by insulin in skeletal muscle and provides feedback inhibition that regulates insulin sensitivity after a meal. The inhibition of the transcriptional activity of Egr-1 enhanced the phosphorylation of the insulin receptor (InsR) and Akt, thus increasing glucose uptake in L6 myotubes after insulin stimulation, whereas overexpression of Egr-1 decreased insulin sensitivity. Furthermore, deletion of Egr-1 in the skeletal muscle improved systemic insulin sensitivity and glucose tolerance, which resulted in lower blood glucose levels after refeeding. Mechanistic analysis demonstrated that EGR-1 inhibited InsR phosphorylation and glucose uptake in skeletal muscle by binding to the proximal promoter region of protein tyrosine phosphatase-1B (PTP1B) and directly activating transcription. PTP1B knockdown largely restored insulin sensitivity and enhanced glucose uptake, even under conditions of EGR-1 overexpression. Our results indicate that EGR-1/PTP1B signaling negatively regulates postprandial insulin sensitivity and suggest a potential therapeutic target for the prevention and treatment of excessive glucose absorption.-Wu, J., Tao, W.-W., Chong, D.-Y., Lai, S.-S., Wang, C., Liu, Q., Zhang, T.-Y., Xue, B., Li, C.-J. Early growth response-1 negative feedback regulates skeletal muscle postprandial insulin sensitivity via activating Ptp1b transcription.

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The Inactivation of RabGAP Function of AS160 Promotes Lysosomal Degradation of GLUT4 and Causes Postprandial Hyperglycemia and Hyperinsulinemia

Cited by 34 publications

References 47 publications

A Tbc1d1 Ser231Ala-knockin mutation partially impairs AICAR- but not exercise-induced muscle glucose uptake in mice

A Tbc1d1 Ser231Ala-knockin mutation partially impairs AICAR- but not exercise-induced muscle glucose uptake in mice

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

Early growth response‐1 negative feedback regulates skeletal muscle postprandial insulin sensitivityviaactivatingPtp 1btranscription

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