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

Paglialunga, Sabina; Simnett, Genevieve; Robson, Holly; Hoang, Monica; Pillai, R; Arkell, Alicia M.; Simpson, Jeremy A.; Bonen, Arend; Huising, Mark O.; Joseph, Jamie W.; Holloway, Graham P.

doi:10.1139/apnm-2016-0585

Cited by 12 publications

(9 citation statements)

References 32 publications

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“…In the current study, we have shown that TBC1D1 ablation results in impaired glucose tolerance, which is consistent with previous reports implicating this protein in maintaining beta cell mass (26,27). However, the current work also demonstrates that TBC1D1 is not required for intracellular GLUT4 trafficking in response to insulin as there were no differences in ITT or in total or phosphorylated (Ser-473) Akt2 or plasma membrane GLUT4 content.…”

Section: Tbc1d1 Ko Animals Display Intact Insulin Signalingsupporting

confidence: 92%

“…Given the unaltered GLUT4 content in this KO model and the proposed role of TBC1D1 in glucose homeostasis, we first examined the effect of ablating this protein on glucose handling at the whole-body level. In support of previous work demonstrating that TBC1D1 influences beta cell mass/stability (26,27), TBC1D1 KO animals displayed impaired glucose clearance during an intraperitoneal glucose tolerance test (GTT) ( Fig. 2A) as demonstrated by an increase in the area under the curve (p Ͻ 0.05; Fig.…”

Section: Skeletal Muscle Response To Insulinsupporting

confidence: 88%

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Ablating the protein TBC1D1 impairs contraction-induced sarcolemmal glucose transporter 4 redistribution but not insulin-mediated responses in rats

Whitfield

Paglialunga

Smith³

et al. 2017

Journal of Biological Chemistry

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TBC1 domain family member 1 (TBC1D1), a Rab GTPase-activating protein and paralogue of Akt substrate of 160 kDa (AS160), has been implicated in both insulin- and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase-mediated glucose transporter type 4 (GLUT4) translocation. However, the role of TBC1D1 in contracting muscle remains ambiguous. We therefore explored the metabolic consequence of ablating TBC1D1 in both resting and contracting skeletal muscles, utilizing a rat TBC1D1 KO model. Although insulin administration rapidly increased ( < 0.05) plasma membrane GLUT4 content in both red and white gastrocnemius muscles, the TBC1D1 ablation did not alter this response nor did it affect whole-body insulin tolerance, suggesting that TBC1D1 is not required for insulin-induced GLUT4 trafficking events. Consistent with findings in other models of altered TBC1D1 protein levels, whole-animal and skeletal muscle fat oxidation was increased in the TBC1D1 KO rats. Although there was no change in mitochondrial content in the KO rats, maximal ADP-stimulated respiration was higher in permeabilized muscle fibers, which may contribute to the increased reliance on fatty acids in resting KO animals. Despite this increase in mitochondrial oxidative capacity, run time to exhaustion at various intensities was impaired in the KO rats. Moreover, contraction-induced increases in sarcolemmal GLUT4 content and glucose uptake were lower in the white gastrocnemius of the KO animals. Altogether, our results highlight a critical role for TBC1D1 in exercise tolerance and contraction-mediated translocation of GLUT4 to the plasma membrane in skeletal muscle.

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Section: Tbc1d1 Ko Animals Display Intact Insulin Signalingsupporting

confidence: 92%

Section: Skeletal Muscle Response To Insulinsupporting

confidence: 88%

Ablating the protein TBC1D1 impairs contraction-induced sarcolemmal glucose transporter 4 redistribution but not insulin-mediated responses in rats

Whitfield

Paglialunga

Smith³

et al. 2017

Journal of Biological Chemistry

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“…This gene plays a significant role in cellular functions in mammals, and defects of which are closely associated with various disease processes (Shi et al, 2018). Besides, Paglialunga et al (2017) established a vital role for CDC16 in maintaining in vivo β-cell mass. This gene may have a similar function in chickens and could be a promising gene for Ab response for ND in chickens.…”

Section: Possible Causal Variant For Antibody Response To Newcastle Disease In Indigenous Chicken In Rwandamentioning

confidence: 99%

Genome-Wide Association Study of Growth Performance and Immune Response to Newcastle Disease Virus of Indigenous Chicken in Rwanda

et al. 2021

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A chicken genome has several regions with quantitative trait loci (QTLs). However, replication and confirmation of QTL effects are required particularly in African chicken populations. This study identified single nucleotide polymorphisms (SNPs) and putative genes responsible for body weight (BW) and antibody response (AbR) to Newcastle disease (ND) in Rwanda indigenous chicken (IC) using genome-wide association studies (GWAS). Multiple testing was corrected using chromosomal false detection rates of 5 and 10% for significant and suggestive thresholds, respectively. BioMart data mining and variant effect predictor tools were used to annotate SNPs and candidate genes, respectively. A total of four significant SNPs (rs74098018, rs13792572, rs314702374, and rs14123335) significantly (p ≤ 7.6E−5) associated with BW were identified on chromosomes (CHRs) 8, 11, and 19. In the vicinity of these SNPs, four genes such as pre-B-cell leukaemia homeobox 1 (PBX1), GPATCH1, MPHOSPH6, and MRM1 were identified. Four other significant SNPs (rs314787954, rs13623466, rs13910430, and rs737507850) all located on chromosome 1 were strongly (p ≤ 7.6E−5) associated with chicken antibody response to ND. The closest genes to these four SNPs were cell division cycle 16 (CDC16), zinc finger, BED-type containing 1 (ZBED1), myxovirus (influenza virus) resistance 1 (MX1), and growth factor receptor bound protein 2 (GRB2) related adaptor protein 2 (GRAP2). Besides, other SNPs and genes suggestively (p ≤ 1.5E−5) associated with BW and antibody response to ND were reported. This work offers a useful entry point for the discovery of causative genes accountable for essential QTLs regulating BW and antibody response to ND traits. Results provide auspicious genes and SNP-based markers that can be used in the improvement of growth performance and ND resistance in IC populations based on gene-based and/or marker-assisted breeding selection.

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“…In addition, recent work from our laboratory has also shown that TBC1D1 knockout (KO) rats display a 34% reduction in β‐cell mass concomitant with dramatic reductions in insulin secretion and glucose tolerance, all of which are indicative of a diabetic phenotype (Paglialunga et al . ). Interestingly, TBC1D1 has recently been identified within the left ventricle (Quan et al .…”

Section: Introductionmentioning

confidence: 97%

“…In addition, recent work from our laboratory has also shown that TBC1D1 knockout (KO) rats display a 34% reduction in β-cell mass concomitant with dramatic reductions in insulin secretion and glucose tolerance, all of which are indicative of a diabetic phenotype ). Interestingly, TBC1D1 has recently been identified within the left ventricle (Quan et al 2015;Stockli et al 2015;Paglialunga et al 2017) and, although the functional consequence of TBC1D1 within the heart remains unknown, the expression of this protein increases following an acute infarction, suggesting it represents a biologically relevant protein within this tissue (Quan et al 2015). Moreover, because genetic and pharmacological attenuations in insulin signalling and fatty acid oxidation impair cardiac function, induce dilated cardiomyopathy and increase mortality rates (Belke et al 2002;Augustus et al 2006;Tuunanen et al 2006;DeBosch et al 2006a;DeBosch et al 2006b;Laustsen et al 2007;Chang et al 2010), determining the functional role of TBC1D1 within the heart may have clinical relevance for understanding the development of diabetic cardiomyopathy.…”

Section: Introductionmentioning

confidence: 99%

Ablating the Rab‐GTPase activating protein TBC1D1 predisposes rats to high‐fat diet‐induced cardiomyopathy

Barbeau

Houad

Huber

et al. 2020

The Journal of Physiology

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Key pointsr Although the role of TBC1D1 within the heart remains unknown, expression of TBC1D1 increases in the left ventricle following an acute infarction, suggesting a biological importance within this tissue.r We investigated the mechanistic role of TBC1D1 within the heart, aiming to establish the consequences of attenuating TBC1D1 signalling in the development of diabetic cardiomyopathy, as well as to determine potential sex differences. r TBC1D1 ablation increased plasma membrane fatty acid binding protein content and myocardial palmitate oxidation. r Following high-fat feeding, TBC1D1 ablation dramatically increased fibrosis and induced end-diastolic dysfunction in both male and female rats in the absence of changes in mitochondrial bioenergetics.r Altogether, independent of sex, ablating TBC1D1 predisposes the left ventricle to pathological remodelling following high-fat feeding, and suggests TBC1D1 protects against diabetic cardiomyopathy.Abstract TBC1D1, a Rab-GTPase activating protein, is involved in the regulation of glucose handling and substrate metabolism within skeletal muscle, and is essential for maintaining pancreatic β-cell mass and insulin secretion. However, the function of TBC1D1 within the heart is largely unknown. Therefore, we examined the role of TBC1D1 in the left ventricle and the functional consequence of ablating TBC1D1 on the susceptibility to high-fat diet-induced abnormalities. Since mutations within TBC1D1 (R125W) display stronger associations with clinical parameters in women, we further examined possible sex differences in the predisposition to diabetic cardiomyopathy. In control-fed animals, TBC1D1 ablation did not alter Pierre-Andre Barbeau completed his undergraduate (2015) and Master's (2017) degrees at the University of Guelph, having been supervised by Dr Graham Holloway in the department of Human Health and Nutritional Sciences. His research focuses on the effects of adaptive (omega 3 fatty acids and exercise) and maladaptive (high-fat feeding) paradigms on various aspects of skeletal and cardiac muscle metabolism, with a particular emphasis on mitochondrial bioenergetics. Jacy Houad attended the University of Guelph to complete an undergraduate degree (2013) in Human Kinetics, and a Master's degree (2014) insulin-stimulated glucose uptake, or echocardiogram parameters, but increased accumulation of a plasma membrane fatty acid transporter and the capacity for palmitate oxidation. When challenged with an 8 week high-fat diet, TBC1D1 knockout rats displayed a four-fold increase in fibrosis compared to wild-type animals, and this was associated with diastolic dysfunction, suggesting a predisposition to diet-induced cardiomyopathy. Interestingly, high-fat feeding only induced cardiac hypertrophy in male TBC1D1 knockout animals, implicating a possible sex difference. Mitochondrial respiratory capacity and substrate sensitivity to pyruvate and ADP were not altered by diet or TBC1D1 ablation, nor were markers of oxidative stress, or indices of overt heart failure. Altogethe...

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

Cited by 12 publications

References 32 publications

Ablating the protein TBC1D1 impairs contraction-induced sarcolemmal glucose transporter 4 redistribution but not insulin-mediated responses in rats

Ablating the protein TBC1D1 impairs contraction-induced sarcolemmal glucose transporter 4 redistribution but not insulin-mediated responses in rats

Genome-Wide Association Study of Growth Performance and Immune Response to Newcastle Disease Virus of Indigenous Chicken in Rwanda

Ablating the Rab‐GTPase activating protein TBC1D1 predisposes rats to high‐fat diet‐induced cardiomyopathy

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