Losartan counteracts the effects of cardiomyocyte swelling on glucose uptake and insulin receptor substrate-1 levels

Background: Previous studies have suggested that the pathogenesis of abdominal aortic aneurysm (AAA) is associated with the local proteinases activation and the degradation of matrix proteins by matrix metalloproteinases (MMPs) produced from activated macrophages. One of the major features of diabetes mellitus (DM)-induced vascular pathology is severe arterial calcification. Although recent large epidemiological studies have shown that DM is an independent negative risk factor for AAA, the effects of hyperglycemia on macrophages are still controversial. We have hypothesized that hyperglycemia suppresses macrophage activation through altered glucose transportation. Methods and Results: RAW264.7 cells, a murine macrophage cell line were cultured under high glucose conditions (HG group, 15.5 mM glucose) or normal glucose conditions (NG group, 5.5 mM glucose) for 7days. Cells from both groups were then transferred to normal glucose condition and stimulated with recombinant murine sRANKL. Macrophage activation, confirmed by TRAP staining positive cells, and MMP-9 expression were induced in NG group but were significantly suppressed in HG group. Glucose uptake was increased during osteoclastogenesis in NG group but not in HG group. To elucidate the underlying mechanism for this observation, we studied glucose transporters (GLUTs). Although GLUT-1 and GLUT-3 expression were not affected in either groups, the membrane translocation of GLUT-1 was significantly increased in NG group during macrophage activation but not in HG group. Insulin receptor and insulin receptor substrate-1 (IRS-1) mRNA, known to stimulate membrane translocation of GLUT, were both decreased in HG group compared to NG group. Conclusions: Our results showed hyperglycemia suppresses macrophage activation. Our results also indicated that under normal conditions, recombinant murine sRANKL increases glucose uptake during macrophage activation. In contrast, this increase is impaired in high glucose pre-treated cells. We conclude that this impairment is due, in part, to suppressed GLUT-1 membrane translocation through down regulation of insulin receptor and IRS-1

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Functional Studies of Akt Isoform Specificity in Skeletal Muscle in Vivo; Maintained Insulin Sensitivity Despite Reduced Insulin Receptor Substrate-1 Expression

Molecular Endocrinology ◽

10.1210/me.2006-0154 ◽

2007 ◽

Vol 21 (1) ◽

pp. 215-228 ◽

Cited By ~ 70

Author(s):

Mark E. Cleasby ◽

Tracie A. Reinten ◽

Gregory J. Cooney ◽

David E. James ◽

Edward W. Kraegen

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Glucose Metabolism ◽

Insulin Receptor ◽

Glucose Uptake ◽

Glycogen Synthase ◽

Insulin Receptor Substrate ◽

Insulin Receptor Substrate 1 ◽

Short Hairpin

Abstract The phosphoinositide 3-kinase/Akt pathway is thought to be essential for normal insulin action and glucose metabolism in skeletal muscle and has been shown to be dysregulated in insulin resistance. However, the specific roles of and signaling pathways triggered by Akt isoforms have not been fully assessed in muscle in vivo. We overexpressed constitutively active (ca-) Akt-1 or Akt-2 constructs in muscle using in vivo electrotransfer and, after 1 wk, assessed the roles of each isoform on glucose metabolism and fiber growth. We achieved greater than 2.5-fold increases in total Ser473 phosphorylation in muscles expressing ca-Akt-1 and ca-Akt-2, respectively. Both isoforms caused hypertrophy of muscle fibers, consistent with increases in p70S6kinase phosphorylation, and a 60% increase in glycogen accumulation, although only Akt-1 increased glycogen synthase kinase-3β phosphorylation. Akt-2, but not Akt-1, increased basal glucose uptake (by 33%, P = 0.004) and incorporation into glycogen and lipids, suggesting a specific effect on glucose transport. Consistent with this, short hairpin RNA-mediated silencing of Akt-2 caused reductions in glycogen storage and glucose uptake. Consistent with Akt-mediated insulin receptor substrate 1 (IRS-1) degradation, we observed approximately 30% reductions in IRS-1 protein in muscle overexpressing ca-Akt-1 or ca-Akt-2. Despite this, we observed no decrease in insulin-stimulated glucose uptake. Furthermore, a 68% reduction in IRS-1 levels induced using short hairpin RNAs targeting IRS-1 also did not affect glucose disposal after a glucose load. These data indicate distinct roles for Akt-1 and Akt-2 in muscle glucose metabolism and that moderate reductions in IRS-1 expression do not result in the development of insulin resistance in skeletal muscle in vivo.

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