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Diabetes has been identified as a significant and independent risk factor for the development or increased severity of respiratory infections. However, the role of glucose transport in the healthy and diseased lung has received little attention. Specifically, the protein expression of the predominant glucose transporter (GLUT) isoforms in the adult lung remains largely to be characterized in both healthy and diabetic states. Type 1 diabetes was induced via streptozotocin and rescued via subcutaneous semi-osmotic insulin pump for 8 weeks. The gene and/or protein expression of the most predominant GLUT isoforms from Classes I and III, including the major insulin-sensitive isoform (i.e., GLUT4) and novel isoforms (i.e., GLUT-8 and GLUT-12), was quantified in the lung of healthy and diabetic mice via qRT-PCR and/or Western blotting. Pulmonary cell surface GLUT protein was measured using a biotinylated photolabeling assay, as a means to evaluate GLUT trafficking. Diabetic mice demonstrated significant alterations of total pulmonary GLUT protein expression, which were isoform- and location-dependent. Long-term insulin treatment rescued the majority of GLUT protein expression alterations in the lung during diabetes, as well as GLUT-4 and -8 trafficking to the pulmonary cell surface. These alterations in glucose homeostasis during diabetes may contribute to an increased severity of pulmonary infection during diabetes and may point to novel metabolic therapeutic strategies for diabetic patients with concurrent respiratory infections. [ABSTRACT FROM AUTHOR]

Neuregulin (NRG), a paracrine factor in myocytes, promotes cardiac development via the ErbB receptors. NRG-1β also improves cardiac function and cell survival after myocardial infarction (MI), although the mechanisms underlying these cardioprotective effects are not well elucidated. Increased glucose uptake has been shown to be cardio-protective during MI. We hypothesized that treatment with a recombinant version of NRG-1β, glial growth factor 2 (GGF2), will enhance glucose transport in the healthy myocardium and during MI. Cardiac myocytes were isolated from MI and healthy adult rats, and subsequently incubated with or without insulin or GGF2. Glucose uptake was measured using a fluorescent D-glucose analog. The translocation of glucose transporter (GLUT) 4 to the cell surface, the rate-limiting step in glucose uptake, was measured using a photolabeled biotinylation assay in isolated myocytes. Similar to insulin, acute in vitro GGF2 treatment increased glucose uptake in healthy cardiac myocytes (by 40 and 49%, respectively, P = 0.002). GGF2 treatment also increased GLUT4 translocation in healthy myocytes by 184% (P < 0.01), while ErbB 2/4 receptor blockade (by afatinib) abolished these effects. In addition, GGF2 treatment enhanced Akt phosphorylation (at both threonine and serine sites, by 75 and 139%, respectively, P = 0.029 and P = 0.01), which was blunted by ErbB 2/4 receptor blockade. GGF2 treatment increased the phosphorylation of AS160 (an Akt effector) by 72% (P < 0.05), as well as the phosphorylation of PDK-1 and PKC (by 118 and 92%, respectively, P < 0.05). During MI, cardiac GLUT4 translocation was downregulated by 44% (P = 0.004) and was partially rescued by both in vitro insulin and GGF2 treatment. Our data demonstrate that acute GGF2 treatment increased glucose transport in cardiac myocytes by activating the ErbB 2/4 receptors and subsequent key downstream effectors (i.e., PDK-1, Akt, AS160, and PKC). These findings highlight novel mechanisms of action of GGF2, which warrant further investigation in patients with heart failure. [ABSTRACT FROM AUTHOR]

Diabetes has been identified as major risk factor for atrial fibrillation (AF). Although glucose and insulin disturbances during diabetes may affect atrial function, little is known about the potential pathogenic role of glucose metabolism during AF. Glucose transport into the cell via glucose transporters (GLUTs) is the rate-limiting step of glucose utilization. Although GLUT4 is the major isoform, GLUT8 has emerged as a novel insulin-sensitive cardiac isoform. We hypothesized that atrial glucose homeostasis will be impaired during insulin resistance-induced AF. AF was induced by transesophageal atrial pacing in healthy mice and following a long-term high-fat-diet-induced insulin resistance. Active cell surface GLUT content was measured using the biotinylated photolabeling assay in the intact perfused heart. Atrial fibrosis, advanced glycation end products (AGEs) and glycogen were measured in the atria using histological analyses. Animals fed a high-fat-diet were obese and mildly hyperglycemic, and developed insulin resistance compared to controls. Insulin-resistant (IR) animals demonstrated an increased vulnerability to induced AF, as well as spontaneous AF. Insulin-stimulated translocation of GLUT4 and GLUT8 was down-regulated in the atria of IR animals, as well as their total protein expression. We also reported the absence of fibrosis, glycogen and AGE accumulation in the atria of IR animals. In the absence of structural remodeling and atrial fibrosis, these data suggest that insulin signaling dysregulation, resulting in impaired glucose transport in the atria, could provide a metabolic arrhythmogenic substrate and be a novel early pathogenic factor of AF. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]