| dc.creator |
González-Navarro, Herminia |
|
| dc.creator |
Vila-Caballer, Marian |
|
| dc.creator |
Pastor, María Francisca |
|
| dc.creator |
Vinué, Ángela |
|
| dc.creator |
White, Morris F. |
|
| dc.creator |
Burks, Deborah J. |
|
| dc.creator |
Andrés, Vicente |
|
| dc.date |
2008-05-16T10:46:59Z |
|
| dc.date |
2008-05-16T10:46:59Z |
|
| dc.date |
2007-01 |
|
| dc.date.accessioned |
2017-01-31T01:20:53Z |
|
| dc.date.available |
2017-01-31T01:20:53Z |
|
| dc.identifier |
Frontiers in Bioscience 12, 2291-2298 |
|
| dc.identifier |
http://hdl.handle.net/10261/4302 |
|
| dc.identifier |
10.2741/2231 |
|
| dc.identifier.uri |
http://dspace.mediu.edu.my:8181/xmlui/handle/10261/4302 |
|
| dc.description |
This is an, un-copyedited, author manuscript that has been accepted for publication in the Frontiers in Bioscience |
|
| dc.description |
Atherosclerosis is increased in type 2 diabetic patients but the precise mechanisms underlying this predisposition remain vague. Mice deficient for insulin receptor substrate 2 (IRS2) develop type 2-like diabetes and thus, provide a model to explore the molecular connection between
deranged carbohydrate metabolism and atherosclerosis. To explore the relationship between defective insulin signalling and atherosclerosis, we have examined the development of atherosclerosis in the following groups of fat-fed mice: wild-type, diabetic Irs2-null (Irs2-/-),
atherosclerosis-prone apolipoprotein E-null (apoE-/-), and doubly-deficient apoE-/-Irs2-/-. Surprisingly, glucose levels of apoE-/-Irs2-/- mice were comparable to those seen in wild-type and apoE-/- and significantly lower than in Irs2-/- mice. Irs2-/- and apoE-/-Irs2-/- were hyperinsulinemic compared to wild-type and apoE-/- mice. Atherosclerotic lesions were barely
detectable in wild-type and Irs2-/- mice, which displayed moderate hypercholesterolemia (~280 mg/dL). Notably, atherosclerosis was significantly enhanced in apoE-/-Irs2-/- compared with apoE-/- mice, although both models displayed similar levels of severe hypercholesterolemia (>600 mg/dL). Circulating insulin levels predicted atherosclerotic lesion burden in apoE-/-Irs2-/- mice. Our results suggest that hyperinsulinemia as a result of Irs2 genetic ablation contributes to increased atherosclerosis when combined with severe hypercholesterolemia (apoE-/-Irs2-/-
mice) in the absence of hyperglycaemia, thus implicating IRS2 as an important modulator of murine hypercholesterolemia-dependent atherosclerosis. Future studies are necessary to determine whether IRS2 dysfunction may promote atherosclerosis in normoglycemic, prediabetic patients with clinical manifestations of hyperinsulinemia and insulin resistance. |
|
| dc.description |
This work was supported by grants from the Spanish Ministry of Education and Science and the European Regional Development Fund (SAF2004-03057), from Instituto de Salud Carlos III (Red de Centros RECAVA, C03/01; Red de Grupos G03-212), and from the
European Union (Marie Curie fellowship MEIF-CT-2005-024393). M.V.-C is the recipient of
a fellowship from the Regional Government of Valencia. |
|
| dc.description |
Peer reviewed |
|
| dc.format |
361905 bytes |
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| dc.format |
application/pdf |
|
| dc.language |
eng |
|
| dc.publisher |
Frontiers in Bioscience Publications |
|
| dc.rights |
openAccess |
|
| dc.subject |
Atherosclerosis |
|
| dc.subject |
Diabetes |
|
| dc.subject |
Hypercholesterolemia |
|
| dc.subject |
Insulin receptor substrate 2 |
|
| dc.subject |
Insulin |
|
| dc.subject |
Insulin resistance |
|
| dc.subject |
Genetically-modified mice |
|
| dc.title |
Plasma insulin levels predict the development of atherosclerosis when IRS2 deficiency is combined with severe hypercholesterolemia in apolipoprotein E-null mice |
|
| dc.type |
Artículo |
|