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Diabetes Alters the Expression and Translocation of the Insulin-Sensitive Glucose Transporters 4 and 8 in the Atria.

Maria Z, Campolo AR, Lacombe VA - PLoS ONE (2015)

Bottom Line: In the healthy atria, insulin stimulation increased both GLUT-4 and -8 translocation to the cell surface (by 100% and 240%, respectively, P<0.05).Upon insulin stimulation, we reported an increase in Akt (Th308 and s473 sites) and AS160 phosphorylation, which was positively (P<0.05) correlated with GLUT4 protein content in the healthy atria.Akt and AS160 phosphorylation was not impaired in the diabetic atria, suggesting the presence of an intact insulin signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiological Sciences, Oklahoma State University, Stillwater, United States of America.

ABSTRACT
Although diabetes has been identified as a major risk factor for atrial fibrillation, little is known about glucose metabolism in the healthy and diabetic atria. Glucose transport into the cell, the rate-limiting step of glucose utilization, is regulated by the Glucose Transporters (GLUTs). Although GLUT4 is the major isoform in the heart, GLUT8 has recently emerged as a novel cardiac isoform. We hypothesized that GLUT-4 and -8 translocation to the atrial cell surface will be regulated by insulin and impaired during insulin-dependent diabetes. GLUT protein content was measured by Western blotting in healthy cardiac myocytes and type 1 (streptozotocin-induced, T1Dx) diabetic rodents. Active cell surface GLUT content was measured using a biotinylated photolabeled assay in the perfused heart. In the healthy atria, insulin stimulation increased both GLUT-4 and -8 translocation to the cell surface (by 100% and 240%, respectively, P<0.05). Upon insulin stimulation, we reported an increase in Akt (Th308 and s473 sites) and AS160 phosphorylation, which was positively (P<0.05) correlated with GLUT4 protein content in the healthy atria. During diabetes, active cell surface GLUT-4 and -8 content was downregulated in the atria (by 70% and 90%, respectively, P<0.05). Akt and AS160 phosphorylation was not impaired in the diabetic atria, suggesting the presence of an intact insulin signaling pathway. This was confirmed by the rescued translocation of GLUT-4 and -8 to the atrial cell surface upon insulin stimulation in the atria of type 1 diabetic subjects. In conclusion, our data suggest that: 1) both GLUT-4 and -8 are insulin-sensitive in the healthy atria through an Akt/AS160 dependent pathway; 2) GLUT-4 and -8 trafficking is impaired in the diabetic atria and rescued by insulin treatment. Alterations in atrial glucose transport may induce perturbations in energy production, which may provide a metabolic substrate for atrial fibrillation during diabetes.

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Validation of the insulin-deficient (type 1) diabetic animal model.A) Mean ± SE venous blood glucose concentration obtained at baseline and up to 8 weeks in type 1 diabetic (T1Dx) and age-matched control (Con) mice (n = 9-11/group). B) Mean ± SE body weight obtained at baseline and up to 8 weeks after induction of type 1 diabetes (n = 9-11/group). C) Mean ± SE serum insulin concentration obtained at 8 weeks after induction of type 1 diabetes (n = 6-8/group). T1Dx: type 1 diabetic; Con: control; *P<0.05 vs. control; # P<0.05 vs. baseline.
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pone.0146033.g003: Validation of the insulin-deficient (type 1) diabetic animal model.A) Mean ± SE venous blood glucose concentration obtained at baseline and up to 8 weeks in type 1 diabetic (T1Dx) and age-matched control (Con) mice (n = 9-11/group). B) Mean ± SE body weight obtained at baseline and up to 8 weeks after induction of type 1 diabetes (n = 9-11/group). C) Mean ± SE serum insulin concentration obtained at 8 weeks after induction of type 1 diabetes (n = 6-8/group). T1Dx: type 1 diabetic; Con: control; *P<0.05 vs. control; # P<0.05 vs. baseline.

Mentions: In order to investigate alterations in glucose transport during diabetic conditions, we used an insulin-deficient diabetic animal model (T1Dx). As expected, within 1 week after injection, STZ-treated animals developed hyperglycemia (i.e., [glucose]>200 mg/dl), which persisted throughout the experimental period; while the control group remained euglycemic (Fig 3A). There was no difference in body weight between groups, although both control and diabetic mice weighted more (P<0.05) at the end of the experimental period (Fig 3B). In addition, serum insulin level was significantly lower in diabetic compared to control mice, confirming that STZ administration destroyed the beta cells of the pancreas (Fig 3C).


Diabetes Alters the Expression and Translocation of the Insulin-Sensitive Glucose Transporters 4 and 8 in the Atria.

Maria Z, Campolo AR, Lacombe VA - PLoS ONE (2015)

Validation of the insulin-deficient (type 1) diabetic animal model.A) Mean ± SE venous blood glucose concentration obtained at baseline and up to 8 weeks in type 1 diabetic (T1Dx) and age-matched control (Con) mice (n = 9-11/group). B) Mean ± SE body weight obtained at baseline and up to 8 weeks after induction of type 1 diabetes (n = 9-11/group). C) Mean ± SE serum insulin concentration obtained at 8 weeks after induction of type 1 diabetes (n = 6-8/group). T1Dx: type 1 diabetic; Con: control; *P<0.05 vs. control; # P<0.05 vs. baseline.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4697822&req=5

pone.0146033.g003: Validation of the insulin-deficient (type 1) diabetic animal model.A) Mean ± SE venous blood glucose concentration obtained at baseline and up to 8 weeks in type 1 diabetic (T1Dx) and age-matched control (Con) mice (n = 9-11/group). B) Mean ± SE body weight obtained at baseline and up to 8 weeks after induction of type 1 diabetes (n = 9-11/group). C) Mean ± SE serum insulin concentration obtained at 8 weeks after induction of type 1 diabetes (n = 6-8/group). T1Dx: type 1 diabetic; Con: control; *P<0.05 vs. control; # P<0.05 vs. baseline.
Mentions: In order to investigate alterations in glucose transport during diabetic conditions, we used an insulin-deficient diabetic animal model (T1Dx). As expected, within 1 week after injection, STZ-treated animals developed hyperglycemia (i.e., [glucose]>200 mg/dl), which persisted throughout the experimental period; while the control group remained euglycemic (Fig 3A). There was no difference in body weight between groups, although both control and diabetic mice weighted more (P<0.05) at the end of the experimental period (Fig 3B). In addition, serum insulin level was significantly lower in diabetic compared to control mice, confirming that STZ administration destroyed the beta cells of the pancreas (Fig 3C).

Bottom Line: In the healthy atria, insulin stimulation increased both GLUT-4 and -8 translocation to the cell surface (by 100% and 240%, respectively, P<0.05).Upon insulin stimulation, we reported an increase in Akt (Th308 and s473 sites) and AS160 phosphorylation, which was positively (P<0.05) correlated with GLUT4 protein content in the healthy atria.Akt and AS160 phosphorylation was not impaired in the diabetic atria, suggesting the presence of an intact insulin signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Physiological Sciences, Oklahoma State University, Stillwater, United States of America.

ABSTRACT
Although diabetes has been identified as a major risk factor for atrial fibrillation, little is known about glucose metabolism in the healthy and diabetic atria. Glucose transport into the cell, the rate-limiting step of glucose utilization, is regulated by the Glucose Transporters (GLUTs). Although GLUT4 is the major isoform in the heart, GLUT8 has recently emerged as a novel cardiac isoform. We hypothesized that GLUT-4 and -8 translocation to the atrial cell surface will be regulated by insulin and impaired during insulin-dependent diabetes. GLUT protein content was measured by Western blotting in healthy cardiac myocytes and type 1 (streptozotocin-induced, T1Dx) diabetic rodents. Active cell surface GLUT content was measured using a biotinylated photolabeled assay in the perfused heart. In the healthy atria, insulin stimulation increased both GLUT-4 and -8 translocation to the cell surface (by 100% and 240%, respectively, P<0.05). Upon insulin stimulation, we reported an increase in Akt (Th308 and s473 sites) and AS160 phosphorylation, which was positively (P<0.05) correlated with GLUT4 protein content in the healthy atria. During diabetes, active cell surface GLUT-4 and -8 content was downregulated in the atria (by 70% and 90%, respectively, P<0.05). Akt and AS160 phosphorylation was not impaired in the diabetic atria, suggesting the presence of an intact insulin signaling pathway. This was confirmed by the rescued translocation of GLUT-4 and -8 to the atrial cell surface upon insulin stimulation in the atria of type 1 diabetic subjects. In conclusion, our data suggest that: 1) both GLUT-4 and -8 are insulin-sensitive in the healthy atria through an Akt/AS160 dependent pathway; 2) GLUT-4 and -8 trafficking is impaired in the diabetic atria and rescued by insulin treatment. Alterations in atrial glucose transport may induce perturbations in energy production, which may provide a metabolic substrate for atrial fibrillation during diabetes.

Show MeSH
Related in: MedlinePlus