Deletion of Both Rab-GTPase–Activating Proteins TBC14KO and TBC1D4 in Mice Eliminates Insulin- and AICAR-Stimulated Glucose Transport. Diabetes 2015;64:746–759

Chadt, Alexandra; Immisch, Anja; Wendt, Christian de; Springer, Christian; Zhou, Zhou; Stermann, Torben; Holman, Geoffrey D.; Loffing‐Cueni, Dominique; Loffing, Johannes; Joost, Hans‐Georg; Al-Hasani, Hadi

doi:10.2337/db15-er04

Cited by 14 publications

(20 citation statements)

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“…C–G). InsR–Akt pathway regulates TBC1D4 to stimulate the translocation of GLUT4 to plasma membrane . Together, these data support the notion that WNK1 may contribute to GLUT4 translocation by the stimulation of InsR signaling cascades.…”

Section: Resultssupporting

confidence: 78%

WNK1 kinase is essential for insulin‐stimulated GLUT4 trafficking in skeletal muscle

Kim

Hwang

et al. 2018

FEBS Open Bio

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With‐no‐lysine 1 (WNK1) kinase is a substrate of the insulin receptor/Akt pathway. Impaired insulin signaling in skeletal muscle disturbs glucose transporter 4 (GLUT4) translocation associated with the onset of type 2 diabetes (T2D). WNK1 is highly expressed in skeletal muscle. However, it is currently unknown how insulin signaling targeting WNK1 regulates GLUT4 trafficking in skeletal muscle, and whether this regulation is perturbed in T2D. Hereby, we show that insulin phosphorylates WNK1 at its activating site via a phosphatidylinositol 3‐kinase‐dependent mechanism. WNK1 promotes the cell surface abundance of GLUT4 via regulating TBC1D4. Of note, we observed insulin resistance and decreased WNK1 phosphorylation in T2D db/db mice as compared to the control mice. These results provide a new perspective on WNK1 function in the pathogenesis of hyperglycemia in T2D.

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Section: Resultssupporting

confidence: 78%

WNK1 kinase is essential for insulin‐stimulated GLUT4 trafficking in skeletal muscle

Kim

Hwang

et al. 2018

FEBS Open Bio

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“…] insulin plasma levels (Szekeres et al 2012), subsequent reports have not replicated this finding. Specifically, although not statistically different, the single KO of TBC1D1 appears to display the lowest insulin value during a GTT compared with WT, AS160 KO, or combined AS160-TBC1D1 double KO mice (Szekeres et al 2012;Dokas et al 2013;Chadt et al 2015;Hargett et al 2016). Moreover, it has recently been reported that combined AS160-TBC1D1 ablation decreases serum insulin concentrations during a GTT, whereas AS160 independent KO does not.…”

Section: Tbc1d1 Is Required To Maintain Pancreatic ␤-Cell Massmentioning

confidence: 81%

“…In the present study we examined a TBC1D1-deficient rat model to address the role of TBC1D1 in glucose homeostasis in vivo. While current murine models of TBC1D1 deficiency report a ϳ50% reduction in skeletal muscle GLUT4 content (Szekeres et al 2012;Dokas et al 2013;Chadt et al 2015;Hargett et al 2016), this finding confounds insulin sensitivity results in mice. In the present study, we demonstrated that the rat model of TBC1D1 deficiency has normal GLUT4 protein expression, allowing for a discriminative investigation into the role of TBC1D1 in glucose homeostasis.…”

Section: Discussionmentioning

confidence: 97%

“…Knockdown experiments in isolated wild-type (WT) rat pancreatic cells suggest that TBC1D1 is required for ␤-cell proliferation (Rutti et al 2014), ultimately influencing insulin secretion rates. However, discrepant results between cell and animal models have made it difficult to understand the role of TBC1D1 in insulin signaling within the pancreas, as whole-body TBC1D1-and AS160-deficient mice have been reported to have normal, reduced, or increased plasma insulin concentrations during a glucose tolerance test (GTT) (Szekeres et al 2012;Dokas et al 2013;Chadt et al 2015;Hargett et al 2016). Therefore, the in vivo functional influence of TBC1D1 within the pancreas remains under debate.…”

Section: Introductionmentioning

confidence: 99%

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The Rab-GTPase activating protein, TBC1D1, is critical for maintaining normal glucose homeostasis and β-cell mass

Paglialunga

Simnett

Robson

et al. 2017

Appl. Physiol. Nutr. Metab.

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Tre-2/USP6, BUB2, cdc16 domain family, member 1 (TBC1D1), a Rab-GTPase activating protein, is a paralogue of AS160, and has been implicated in the canonical insulin-signaling cascade in peripheral tissues. More recently, TBC1D1 was identified in rat and human pancreatic islets; however, the islet function of TBC1D1 remains not fully understood. We examined the role of TBC1D1 in glucose homeostasis and insulin secretion utilizing a rat knockout (KO) model. Chow-fed TBC1D1 KO rats had improved insulin action but impaired glucose-tolerance tests (GTT) and a lower insulin response during an intraperitoneal GTT compared with wild-type (WT) rats. The in vivo data suggest there may be an islet defect. Glucose-stimulated insulin secretion was higher in isolated KO rat islets compared with WT animals, suggesting TBC1D1 is a negative regulator of insulin secretion. Moreover, KO rats displayed reduced β-cell mass, which likely accounts for the impaired whole-body glucose homeostasis. This β-cell mass reduction was associated with increased active caspase 3, and unaltered Ki67 or urocortin 3, suggesting the induction of apoptosis rather than decreased proliferation or dedifferentiation may account for the decline in islet mass. A similar phenotype was observed in TBC1D1 heterozygous animals, highlighting the sensitivity of the pancreas to subtle reductions in TBC1D1 protein. An 8-week pair-fed high-fat diet did not further alter β-cell mass or apoptosis in KO rats, suggesting that dietary lipids per se, do not lead to a further impairment in glucose homeostasis. The present study establishes a fundamental role for TBC1D1 in maintaining in vivo β-cell mass.

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“…Purified GST‐Rab fusion proteins (0.6 μ m ) were loaded with 0.1 μ m [γ‐ 32 P]GTP (Hartmann Analytic, Braunschweig, Germany) in 20 m m Tris/HCl, 5 m m MgCl 2 , 1 m m DTT, 0.02% (w/v) BSA, pH 8.0 as described . After adding 0.6 μ m purified GST‐GAP domains, aliquots were removed at time 0 and 16 min, and radioactive [ 32 P]phosphate was separated from nucleotides by filtration through activated charcoal . Radioactivity in the filtrate was determined by scintillation counting.…”

Section: Methodsmentioning

confidence: 99%

Rab28 is a TBC1D1/TBC1D4 substrate involved in GLUT4 trafficking

et al. 2016

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The Rab-GTPase-activating proteins (GAPs) TBC1D1 and TBC1D4 play important roles in the insulin-stimulated translocation of the glucose transporter GLUT4 from intracellular vesicles to the plasma membrane in muscle cells and adipocytes. We identified Rab28 as a substrate for the GAP domains of both TBC1D1 and TBC1D4 in vitro. Rab28 is expressed in adipose cells and skeletal muscle, and its GTP-binding state is acutely regulated by insulin. We found that in intact isolated mouse skeletal muscle, siRNAmediated knockdown of Rab28 decreases basal glucose uptake. Conversely, in primary rat adipose cells, overexpression of Rab28-Q72L, a constitutively active mutant, increases basal cell surface levels of an epitope-tagged HA-GLUT4. Our results indicate that Rab28 is a novel GTPase involved in the intracellular retention of GLUT4 in insulin target cells.

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Deletion of Both Rab-GTPase–Activating Proteins TBC14KO and TBC1D4 in Mice Eliminates Insulin- and AICAR-Stimulated Glucose Transport. Diabetes 2015;64:746–759

Cited by 14 publications

References 0 publications

WNK1 kinase is essential for insulin‐stimulated GLUT4 trafficking in skeletal muscle

WNK1 kinase is essential for insulin‐stimulated GLUT4 trafficking in skeletal muscle

The Rab-GTPase activating protein, TBC1D1, is critical for maintaining normal glucose homeostasis and β-cell mass

Rab28 is a TBC1D1/TBC1D4 substrate involved in GLUT4 trafficking

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