Discovery of TBC1D1 as an Insulin-, AICAR-, and Contraction-stimulated Signaling Nexus in Mouse Skeletal Muscle

Taylor, Eric B.; Ding, An; Kramer, Henning F.; Yu, Haiyan; Fujii, Nobuharu; Roeckl, Katja S.C.; Bowles, Nicole; Hirshman, Michael F.; Xie, Jingui; Feener, Edward P.; Goodyear, Laurie J.

doi:10.1074/jbc.m708839200

Cited by 217 publications

(318 citation statements)

References 43 publications

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“…Knockdown of AS160 in adipocytes increases PM GLUT4 levels, consistent with the role of AS160 as a negative regulator (5,11,12). TBC1D1 is a close homolog of AS160 that is highly expressed in skeletal muscle and so has been postulated to play a role in exercise-mediated GLUT4 trafficking (13)(14)(15)(16)(17). AS160 and TBC1D1 have identical domain structures.…”

Section: /2mentioning

confidence: 72%

The RabGAP TBC1D1 Plays a Central Role in Exercise-Regulated Glucose Metabolism in Skeletal Muscle

et al. 2015

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Insulin and exercise stimulate glucose uptake into skeletal muscle via different pathways. Both stimuli converge on the translocation of the glucose transporter GLUT4 from intracellular vesicles to the cell surface. Two Rab guanosine triphosphatases-activating proteins (GAPs) have been implicated in this process: AS160 for insulin stimulation and its homolog, TBC1D1, are suggested to regulate exercise-mediated glucose uptake into muscle. TBC1D1 has also been implicated in obesity in humans and mice. We investigated the role of TBC1D1 in glucose metabolism by generating TBC1D1 2/2 mice and analyzing body weight, insulin action, and exercise. TBC1D12/2 mice showed normal glucose and insulin tolerance, with no difference in body weight compared with wild-type littermates. GLUT4 protein levels were reduced by ∼40% in white TBC1D1 2/2 muscle, and TBC1D1 2/2 mice showed impaired exercise endurance together with impaired exercise-mediated 2-deoxyglucose uptake into white but not red muscles. These findings indicate that the RabGAP TBC1D1 plays a key role in regulating GLUT4 protein levels and in exercise-mediated glucose uptake in nonoxidative muscle fibers.

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Section: /2mentioning

confidence: 72%

The RabGAP TBC1D1 Plays a Central Role in Exercise-Regulated Glucose Metabolism in Skeletal Muscle

et al. 2015

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“…For instance, TBC1D4 and TBC1D1 protein abundance in the current study are only modestly lower (216% and 245%) in human type I versus II fibers. In mice, a high (.10-fold) TBC1D4 and a low (,20%) TBC1D1 content are evident in the type I fiber-abundant soleus compared with the type II fiber-abundant extensor digitorum longus muscle (40). In rats, no significant correlations between MHC isoform abundance in various muscles and either TBC1D1 or TBC1D4 protein content were found (21).…”

Section: Discussionmentioning

confidence: 83%

Human Muscle Fiber Type–Specific Insulin Signaling: Impact of Obesity and Type 2 Diabetes

et al. 2014

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Skeletal muscle is a heterogeneous tissue composed of different fiber types. Studies suggest that insulinmediated glucose metabolism is different between muscle fiber types. We hypothesized that differences are due to fiber type-specific expression/regulation of insulin signaling elements and/or metabolic enzymes. Pools of type I and II fibers were prepared from biopsies of the vastus lateralis muscles from lean, obese, and type 2 diabetic subjects before and after a hyperinsulinemiceuglycemic clamp. Type I fibers compared with type II fibers have higher protein levels of the insulin receptor, GLUT4, hexokinase II, glycogen synthase (GS), and pyruvate dehydrogenase-E1a (PDH-E1a) and a lower protein content of Akt2, TBC1 domain family member 4 (TBC1D4), and TBC1D1. In type I fibers compared with type II fibers, the phosphorylation response to insulin was similar (TBC1D4, TBC1D1, and GS) or decreased (Akt and PDH-E1a). Phosphorylation responses to insulin adjusted for protein level were not different between fiber types. Independently of fiber type, insulin signaling was similar (TBC1D1, GS, and PDH-E1a) or decreased (Akt and TBC1D4) in muscle from patients with type 2 diabetes compared with lean and obese subjects. We conclude that human type I muscle fibers compared with type II fibers have a higher glucose-handling capacity but a similar sensitivity for phosphoregulation by insulin.Skeletal muscle is important for whole-body insulinstimulated glucose disposal (1), and skeletal muscle insulin resistance is a common phenotype of obesity and type 2 diabetes (T2D) (2). Skeletal muscle is a heterogeneous tissue composed of different fiber types, which can be divided according to myosin heavy chain (MHC) isoform expression. Studies in rodents show that insulin-stimulated glucose uptake in the oxidative type I fiber-dominant muscles is higher than in muscles with a high degree of glycolytic type II fibers (3-6). Whether this phenomenon is due to differences in locomotor activity of individual muscles or a direct consequence of the fiber-type composition is largely unknown. In incubated rat muscle, insulin-induced glucose uptake was higher (;100%) in type IIa (oxidative/glycolytic) compared with IIx and IIb (glycolytic) fibers (7,8), suggesting that insulin-mediated glucose uptake is related to the oxidative capacity of the muscle fiber. In humans, a positive correlation between proportions of type I fibers in muscle and whole-body insulin sensitivity has been demonstrated (9-11). Furthermore, insulin-stimulated glucose transport in human muscle strips was associated with the relative type I fiber content (12). Thus, it is likely that human type I fibers are more important than type II fibers for maintaining glucose homeostasis in response to insulin. Indeed, a decreased proportion of type I fibers has been found in various insulin resistant states such as the metabolic syndrome (9), obesity (13,14), T2D in some (10,13,14) but not all (12,15) studies and following bedrest (16), as well as in tetraplegic patients (17), ...

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“…However, insulin, together with either AICAR or contraction, increased AS160 phosphorylation in an additive manner, indicating that AS160 is a point of convergence linking insulin, contraction, and AICAR signaling. On the other hand, Taylor et al observed a dissociation between AS160 protein expression and apparent AS160 PAS phosphorylation among types of muscles and identified the AS160 paralog protein TBC1D1 (Taylor et al 2008). They also observed an increased TBC1D1 phosphorylation in vivo stimulated by insulin, contraction, and the AMP-activated protein kinase (AMPK) activator AICAR.…”

Section: Convergent Mechanisms Of Glucose Uptake: Role Of As160 and Tmentioning

confidence: 89%

General aspects of muscle glucose uptake

Alvim

Cheuhen

Machado

et al. 2015

An. Acad. Bras. Ciênc.

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Glucose uptake in peripheral tissues is dependent on the translocation of GLUT4 glucose transporters to the plasma membrane. Studies have shown the existence of two major signaling pathways that lead to the translocation of GLUT4. The first, and widely investigated, is the insulin activated signaling pathway through insulin receptor substrate-1 and phosphatidylinositol 3-kinase. The second is the insulin-independent signaling pathway, which is activated by contractions. Individuals with type 2 diabetes mellitus have reduced insulin-stimulated glucose uptake in skeletal muscle due to the phenomenon of insulin resistance. However, those individuals have normal glucose uptake during exercise. In this context, physical exercise is one of the most important interventions that stimulates glucose uptake by insulin-independent pathways, and the main molecules involved are adenosine monophosphate-activated protein kinase, nitric oxide, bradykinin, AKT, reactive oxygen species and calcium. In this review, our main aims were to highlight the different glucose uptake pathways and to report the effects of physical exercise, diet and drugs on their functioning. Lastly, with the better understanding of these pathways, it would be possible to assess, exactly and molecularly, the importance of physical exercise and diet on glucose homeostasis. Furthermore, it would be possible to assess the action of drugs that might optimize glucose uptake and consequently be an important step in controlling the blood glucose levels in diabetic patients, in addition to being important to clarify some pathways that justify the development of drugs capable of mimicking the contraction pathway.

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Discovery of TBC1D1 as an Insulin-, AICAR-, and Contraction-stimulated Signaling Nexus in Mouse Skeletal Muscle

Cited by 217 publications

References 43 publications

The RabGAP TBC1D1 Plays a Central Role in Exercise-Regulated Glucose Metabolism in Skeletal Muscle

The RabGAP TBC1D1 Plays a Central Role in Exercise-Regulated Glucose Metabolism in Skeletal Muscle

Human Muscle Fiber Type–Specific Insulin Signaling: Impact of Obesity and Type 2 Diabetes

General aspects of muscle glucose uptake

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