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Increased systemic glucose tolerance with increased muscle glucose uptake in transgenic mice overexpressing RXRγ in skeletal muscle.

Sugita S, Kamei Y, Akaike F, Suganami T, Kanai S, Hattori M, Manabe Y, Fujii N, Takai-Igarashi T, Tadaishi M, Oka J, Aburatani H, Yamada T, Katagiri H, Kakehi S, Tamura Y, Kubo H, Nishida K, Miura S, Ezaki O, Ogawa Y - PLoS ONE (2011)

Bottom Line: Combination of RXRγ and PPARδ resulted in an increase in Glut1-Luc activity in skeletal muscle in vivo.These results show the importance of skeletal muscle gene regulation in systemic glucose metabolism.Increasing RXRγ expression may be a novel therapeutic strategy against type 2 diabetes.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.

ABSTRACT

Background: Retinoid X receptor (RXR) γ is a nuclear receptor-type transcription factor expressed mostly in skeletal muscle, and regulated by nutritional conditions. Previously, we established transgenic mice overexpressing RXRγ in skeletal muscle (RXRγ mice), which showed lower blood glucose than the control mice. Here we investigated their glucose metabolism.

Methodology/principal findings: RXRγ mice were subjected to glucose and insulin tolerance tests, and glucose transporter expression levels, hyperinsulinemic-euglycemic clamp and glucose uptake were analyzed. Microarray and bioinformatics analyses were done. The glucose tolerance test revealed higher glucose disposal in RXRγ mice than in control mice, but insulin tolerance test revealed no difference in the insulin-induced hypoglycemic response. In the hyperinsulinemic-euglycemic clamp study, the basal glucose disposal rate was higher in RXRγ mice than in control mice, indicating an insulin-independent increase in glucose uptake. There was no difference in the rate of glucose infusion needed to maintain euglycemia (glucose infusion rate) between the RXRγ and control mice, which is consistent with the result of the insulin tolerance test. Skeletal muscle from RXRγ mice showed increased Glut1 expression, with increased glucose uptake, in an insulin-independent manner. Moreover, we performed in vivo luciferase reporter analysis using Glut1 promoter (Glut1-Luc). Combination of RXRγ and PPARδ resulted in an increase in Glut1-Luc activity in skeletal muscle in vivo. Microarray data showed that RXRγ overexpression increased a diverse set of genes, including glucose metabolism genes, whose promoter contained putative PPAR-binding motifs.

Conclusions/significance: Systemic glucose metabolism was increased in transgenic mice overexpressing RXRγ. The enhanced glucose tolerance in RXRγ mice may be mediated at least in part by increased Glut1 in skeletal muscle. These results show the importance of skeletal muscle gene regulation in systemic glucose metabolism. Increasing RXRγ expression may be a novel therapeutic strategy against type 2 diabetes.

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Hyperinsulinemic-euglycemic clamp test in RXRγ mice, fed a chow                            diet.(A) Basal glucose disposal rate, (B)                            glucose infusion rate needed to maintain euglycemia,                            (C) insulin-stimulated glucose disposal rate and                                (D) clamp hepatic glucose production (hepatic                            glucose production during the clamp period) (E)                            suppression of hepatic glucose production during the clamp period in                            RXRγ mice. Male mice, 13∼16 weeks of age, were used. The number                            of animals used was 6 for control mice (open bars) and 7 for RXRγ                            mice (filled bars). * P<0.05 and **                                P<0.01 compared with respective control. N. S.,                            not significant.
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pone-0020467-g003: Hyperinsulinemic-euglycemic clamp test in RXRγ mice, fed a chow diet.(A) Basal glucose disposal rate, (B) glucose infusion rate needed to maintain euglycemia, (C) insulin-stimulated glucose disposal rate and (D) clamp hepatic glucose production (hepatic glucose production during the clamp period) (E) suppression of hepatic glucose production during the clamp period in RXRγ mice. Male mice, 13∼16 weeks of age, were used. The number of animals used was 6 for control mice (open bars) and 7 for RXRγ mice (filled bars). * P<0.05 and ** P<0.01 compared with respective control. N. S., not significant.

Mentions: To gain further insight into the glucose metabolism in RXRγ mice, we performed a hyperinsulinemic-euglycemic clamp study. Plasma insulin concentrations during the basal period were similar between genotypes (Table 3). The basal glucose disposal rate was significantly increased in RXRγ mice than in the controls (P<0.05, Fig. 3A), supporting that an insulin-independent increase in glucose uptake occurred, as observed in Fig. 2C. Meanwhile, we observed that the rate of glucose infusion needed to maintain euglycemia (glucose infusion rate) was similar between genotypes (Fig. 3B), which is consistent with the result of the insulin tolerance test (Fig. 1B). On the other hand, insulin-stimulated glucose disposal rate was higher in RXRγ mice than in the controls (P<0.01, Fig. 3C), which probably reflects the increased basal glucose disposal rate (Fig. 3A). Also, the clamp hepatic glucose production (hepatic glucose production during the clamp period) was higher in RXRγ mice than in the controls (P<0.05, Fig. 3D). Meanwhile, hepatic glucose production was similarly suppressed by insulin in both genotypes (Fig. 3E). Together, these data support the idea that Glut1, an insulin-independent glucose transporter, is involved in the increased glucose disposal in the skeletal muscle of RXRγ mice.


Increased systemic glucose tolerance with increased muscle glucose uptake in transgenic mice overexpressing RXRγ in skeletal muscle.

Sugita S, Kamei Y, Akaike F, Suganami T, Kanai S, Hattori M, Manabe Y, Fujii N, Takai-Igarashi T, Tadaishi M, Oka J, Aburatani H, Yamada T, Katagiri H, Kakehi S, Tamura Y, Kubo H, Nishida K, Miura S, Ezaki O, Ogawa Y - PLoS ONE (2011)

Hyperinsulinemic-euglycemic clamp test in RXRγ mice, fed a chow                            diet.(A) Basal glucose disposal rate, (B)                            glucose infusion rate needed to maintain euglycemia,                            (C) insulin-stimulated glucose disposal rate and                                (D) clamp hepatic glucose production (hepatic                            glucose production during the clamp period) (E)                            suppression of hepatic glucose production during the clamp period in                            RXRγ mice. Male mice, 13∼16 weeks of age, were used. The number                            of animals used was 6 for control mice (open bars) and 7 for RXRγ                            mice (filled bars). * P<0.05 and **                                P<0.01 compared with respective control. N. S.,                            not significant.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3105070&req=5

pone-0020467-g003: Hyperinsulinemic-euglycemic clamp test in RXRγ mice, fed a chow diet.(A) Basal glucose disposal rate, (B) glucose infusion rate needed to maintain euglycemia, (C) insulin-stimulated glucose disposal rate and (D) clamp hepatic glucose production (hepatic glucose production during the clamp period) (E) suppression of hepatic glucose production during the clamp period in RXRγ mice. Male mice, 13∼16 weeks of age, were used. The number of animals used was 6 for control mice (open bars) and 7 for RXRγ mice (filled bars). * P<0.05 and ** P<0.01 compared with respective control. N. S., not significant.
Mentions: To gain further insight into the glucose metabolism in RXRγ mice, we performed a hyperinsulinemic-euglycemic clamp study. Plasma insulin concentrations during the basal period were similar between genotypes (Table 3). The basal glucose disposal rate was significantly increased in RXRγ mice than in the controls (P<0.05, Fig. 3A), supporting that an insulin-independent increase in glucose uptake occurred, as observed in Fig. 2C. Meanwhile, we observed that the rate of glucose infusion needed to maintain euglycemia (glucose infusion rate) was similar between genotypes (Fig. 3B), which is consistent with the result of the insulin tolerance test (Fig. 1B). On the other hand, insulin-stimulated glucose disposal rate was higher in RXRγ mice than in the controls (P<0.01, Fig. 3C), which probably reflects the increased basal glucose disposal rate (Fig. 3A). Also, the clamp hepatic glucose production (hepatic glucose production during the clamp period) was higher in RXRγ mice than in the controls (P<0.05, Fig. 3D). Meanwhile, hepatic glucose production was similarly suppressed by insulin in both genotypes (Fig. 3E). Together, these data support the idea that Glut1, an insulin-independent glucose transporter, is involved in the increased glucose disposal in the skeletal muscle of RXRγ mice.

Bottom Line: Combination of RXRγ and PPARδ resulted in an increase in Glut1-Luc activity in skeletal muscle in vivo.These results show the importance of skeletal muscle gene regulation in systemic glucose metabolism.Increasing RXRγ expression may be a novel therapeutic strategy against type 2 diabetes.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan.

ABSTRACT

Background: Retinoid X receptor (RXR) γ is a nuclear receptor-type transcription factor expressed mostly in skeletal muscle, and regulated by nutritional conditions. Previously, we established transgenic mice overexpressing RXRγ in skeletal muscle (RXRγ mice), which showed lower blood glucose than the control mice. Here we investigated their glucose metabolism.

Methodology/principal findings: RXRγ mice were subjected to glucose and insulin tolerance tests, and glucose transporter expression levels, hyperinsulinemic-euglycemic clamp and glucose uptake were analyzed. Microarray and bioinformatics analyses were done. The glucose tolerance test revealed higher glucose disposal in RXRγ mice than in control mice, but insulin tolerance test revealed no difference in the insulin-induced hypoglycemic response. In the hyperinsulinemic-euglycemic clamp study, the basal glucose disposal rate was higher in RXRγ mice than in control mice, indicating an insulin-independent increase in glucose uptake. There was no difference in the rate of glucose infusion needed to maintain euglycemia (glucose infusion rate) between the RXRγ and control mice, which is consistent with the result of the insulin tolerance test. Skeletal muscle from RXRγ mice showed increased Glut1 expression, with increased glucose uptake, in an insulin-independent manner. Moreover, we performed in vivo luciferase reporter analysis using Glut1 promoter (Glut1-Luc). Combination of RXRγ and PPARδ resulted in an increase in Glut1-Luc activity in skeletal muscle in vivo. Microarray data showed that RXRγ overexpression increased a diverse set of genes, including glucose metabolism genes, whose promoter contained putative PPAR-binding motifs.

Conclusions/significance: Systemic glucose metabolism was increased in transgenic mice overexpressing RXRγ. The enhanced glucose tolerance in RXRγ mice may be mediated at least in part by increased Glut1 in skeletal muscle. These results show the importance of skeletal muscle gene regulation in systemic glucose metabolism. Increasing RXRγ expression may be a novel therapeutic strategy against type 2 diabetes.

Show MeSH
Related in: MedlinePlus