Use of Glut‐4 Null Mice to Study Skeletal Muscle Glucose Uptake

Charron, Maureen J.; Gorovits, Naira; Laidlaw, J Skye; Ranalletta, Mollie; Katz, Ellen B.

doi:10.1111/j.1440-1681.2005.04189.x

Cited by 15 publications

(11 citation statements)

References 50 publications

(147 reference statements)

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“…Fam and coworkers (2012)showed that the deletion of the skeletal muscle GLUT4 on the pure C57BL6/J background strain did not impair the whole-body glucose disposal. These authors, among others (Ryder et al 1999, Charron et al 2005, Fam et al 2012, considered that other unidentified GLUTs were upregulated in an attempt to compensate the lack of GLUT4. Probably, the previous hypothesis justifies the fact that even with lower content of plasma membrane GLUT4 in EDL and soleus, the OTR/down group did not exhibit lower glycogen concentrations when compared with the CT group (Pereira et al 2014b).…”

Section: Discussionmentioning

confidence: 99%

Excessive training impairs the insulin signal transduction in mice skeletal muscles

Pereira¹,

Rocha²,

Pinto³

et al. 2016

Journal of Endocrinology

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The main aim of this investigation was to verify the effects of overtraining (OT) on the insulin and inflammatory signaling pathways in mice skeletal muscles. Rodents were divided into control (CT), overtrained by downhill running (OTR/down), overtrained by uphill running (OTR/up), and overtrained by running without inclination (OTR) groups. Rotarod, incremental load, exhaustive, and grip force tests were used to evaluate performance. Thirty-six hours after the grip force test, the extensor digitorum longus (EDL) and soleus were extracted for subsequent protein analyses. The three OT protocols led to similar responses of all performance evaluation tests. The phosphorylation of insulin receptor beta (pIRβ; Tyr), protein kinase B (pAkt; Ser473), and the protein levels of plasma membrane glucose transporter-4 (GLUT4) were lower in the EDL and soleus after the OTR/down protocol and in the soleus after the OTR/up and OTR protocols. While the pIRβ was lower after the OTR/up and OTR protocols, the pAkt was higher after the OTR/up in the EDL. The phosphorylation of IκB kinase alpha and beta (pIKKα/β; Ser180/181), stress-activated protein kinases/Jun amino-terminal kinases (pSAPK-JNK; Thr183/Tyr185), factor nuclear kappa B (pNFκB p65; Ser536), and insulin receptor substrate 1 (pIRS1; Ser307) were higher after the OTR/down protocol, but were not altered after the two other OT protocols. In summary, these data suggest that OT may lead to skeletal muscle insulin signaling pathway impairment, regardless of the predominance of eccentric contractions, although the insulin signal pathway impairment induced in OTR/up and OTR appeared to be muscle fiber-type specific. Journal of Endocrinology

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Section: Discussionmentioning

confidence: 99%

Excessive training impairs the insulin signal transduction in mice skeletal muscles

Pereira¹,

Rocha²,

Pinto³

et al. 2016

Journal of Endocrinology

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“…Therefore, why insulin deficiency in Gcgr -/-mice does not appear to alter fat or muscle metabolism is unclear. It is worth noting that glucose tolerance is not altered in muscle-specific insulin receptor KO mice (83) or in whole-body Glut4-null mice (84). In the normal dog and human, on the other hand, when insulin and glucagon secretion were simultaneously made deficient using somatostatin (30,85), insulin lack resulted in a significant decrease in glucose clearance and a consequent doubling of the plasma glucose level.…”

Section: Glucagonocentrism: Insulin Actions Are Mediated By Glucagonsmentioning

confidence: 99%

Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover

2012

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The hormone glucagon has long been dismissed as a minor contributor to metabolic disease. Here we propose that glucagon excess, rather than insulin deficiency, is the sine qua non of diabetes. We base this on the following evidence: (a) glucagon increases hepatic glucose and ketone production, catabolic features present in insulin deficiency; (b) hyperglucagonemia is present in every form of poorly controlled diabetes; (c) the glucagon suppressors leptin and somatostatin suppress all catabolic manifestations of diabetes during total insulin deficiency; (d) total β cell destruction in glucagon receptor-null mice does not cause diabetes; and (e) perfusion of normal pancreas with anti-insulin serum causes marked hyperglucagonemia. From this and other evidence, we conclude that glucose-responsive β cells normally regulate juxtaposed α cells and that without intraislet insulin, unregulated α cells hypersecrete glucagon, which directly causes the symptoms of diabetes. This indicates that glucagon suppression or inactivation may provide therapeutic advantages over insulin monotherapy.Conflict of interest: Alan D.

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“…While we did not directly measure glucose uptake in vitro in these specific muscle types from our KO mice, the evidence presented by these earlier studies support our idea of the existence of novel GLUT4-independent transporter system(s) (Ryder et al 1999a, Charron et al 2005. However, neither these early studies nor our own have identified these potential transporters.…”

Section: Discussionmentioning

confidence: 54%

“…The disposal of glucose into muscle and adipose tissue is dependent on the action of specific glucose transporters (GLUT) and the hormonal regulation of their expression and function (Charron et al 2005). The Glut4 (Slc2a4) is the main insulin-responsive transporter abundantly expressed in skeletal muscle, adipose tissue and heart (Kahn 1992, Mueckler 1994.…”

Section: Introductionmentioning

confidence: 99%

Normal muscle glucose uptake in mice deficient in muscle GLUT4

Fam

Rose

Sgambellone

et al. 2012

Journal of Endocrinology

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Skeletal muscle insulin resistance is a major characteristic underpinning type 2 diabetes. Impairments in the insulin responsiveness of the glucose transporter, Glut4 (Slc2a4), have been suggested to be a contributing factor to this disturbance. We have produced muscle-specific Glut4 knockout (KO) mice using Cre/LoxP technology on a C57BL6/J background and shown undetectable levels of GLUT4 in both skeletal muscle and heart. Our aim was to determine whether complete deletion of muscle GLUT4 does in fact lead to perturbations in glucose homoeostasis. Glucose tolerance, glucose turnover and 2-deoxyglucose uptake into muscle and fat under basal and insulin-stimulated conditions were assessed in 12-week-old KO and control mice using the oral glucose tolerance test (OGTT) and hyperinsulinaemic/euglycaemic clamp respectively. KO mice weighed w17% less and had significantly heavier hearts compared with control mice. Basally, plasma glucose and plasma insulin were significantly lower in the KO compared with control mice, which conferred normal glucose tolerance. Despite the lack of GLUT4 in the KO mouse muscle, glucose uptake was not impaired in skeletal muscle but was reduced in heart under insulin-stimulated conditions. Neither GLUT1 nor GLUT12 protein levels were altered in the skeletal muscle or heart tissue of our KO mice. High-fat feeding did not alter glucose tolerance in the KO mice but led to elevated plasma insulin levels during the glucose tolerance test. Our study demonstrates that deletion of muscle GLUT4 does not adversely affect glucose disposal and glucose tolerance and that compensation from other transporters may contribute to this unaltered homoeostasis of glucose.

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Use of Glut‐4 Null Mice to Study Skeletal Muscle Glucose Uptake

Cited by 15 publications

References 50 publications

Excessive training impairs the insulin signal transduction in mice skeletal muscles

Excessive training impairs the insulin signal transduction in mice skeletal muscles

Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover

Normal muscle glucose uptake in mice deficient in muscle GLUT4

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