1,721,023 research outputs found
Insulin action in vascular endothelium: potential mechanisms linking insulin resistance with hypertension RID B-1970-2008
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Postbinding characterization of five naturally occurring mutations in the human insulin receptor gene: impaired insulin-stimulated c-jun expression and thymidine incorporation despite normal receptor autophosphorylation
No full textSome patients with extreme insulin resistance have mutations in their insulin receptor gene. We previously identified five such mutations located in the extracellular domain of the insulin receptor (Asn-->Lys15, His-->Arg209, Phe-->Val382, Lys-->Glu460, and Asn-->Ser462) and studied the effects of these mutations upon posttranslational processing, insulin binding, and tyrosine autophosphorylation. We now characterize the ability of these mutant receptors to mediate biological actions of insulin in transfected NIH-3T3 fibroblasts. All cell lines expressing mutant receptors showed marked impairment in insulin-stimulated c-jun expression and thymidine incorporation when compared with cells expressing wild-type human insulin receptors. The most severe impairment was seen in cells expressing the Val382 mutant (a mutation which causes an intrinsic defect in receptor autophosphorylation). These cells had insulin responses similar to the untransfected cells (used as a negative control). In contrast, cells expressing the Lys15 mutant have the ability to achieve a normal level of maximal autophosphorylation but require an abnormally high concentration of insulin to do so (as the result of decreased insulin binding affinity). These cells show a higher basal rate and much lower insulin stimulation of both c-jun expression and thymidine incorporation when compared with the cells expressing the wild-type human insulin receptors. This pattern is also seen in the cells expressing the other mutants with normal autophosphorylation (Arg209, Glu460, and Ser462). Although the most severe defects in insulin action are seen with the mutation which has an intrinsic defect in receptor autophosphorylation, the ability to undergo normal autophosphorylation does not seem to preclude mutations from impairing the ability of receptors to mediate some of the actions of insulin
Insulin-stimulated activation of eNOS requires IRS-1 to couple signaling from the insulin receptor to PI 3-kinase pathways RID B-1970-2008
No full textAdiponectin stimulates production of endothelin-1 (ET-1) and nitric oxide (NO) from vascular endothelium using signaling pathways both overlapping and distinct from those used by insulin RID B-1970-2008
No full textAdiponectin stimulates production of nitric oxide in vascular endothelial cells RID B-1970-2008
No full textAdiponectin is secreted by adipose cells and mimics
many metabolic actions of insulin. However, mechanisms
by which adiponectin acts are poorly understood.
The vascular action of insulin to stimulate endothelial
production of nitric oxide (NO), leading to vasodilation
and increased blood flow is an important component of
insulin-stimulated whole body glucose utilization.
Therefore, we hypothesized that adiponectin may also
stimulate production of NO in endothelium. Bovine aortic
endothelial cells in primary culture loaded with the
NO-specific fluorescent dye 4,5-diaminofluorescein diacetate
(DAF-2 DA) were treated with lysophosphatidic
acid (LPA) (a calcium-releasing agonist) or adiponectin
(10 g/ml bacterially produced full-length adiponectin).
LPA treatment increased production of NO by 4-fold.
Interestingly, adiponectin treatment significantly increased
production of NO by 3-fold. Preincubation of
cells with wortmannin (phosphatidylinositol 3-kinase
inhibitor) blocked only adiponectin- but not LPA-mediated
production of NO. Using phospho-specific antibodies,
we observed that either adiponectin or insulin treatment
(but not LPA treatment) caused phosphorylation
of both Akt at Ser473 and endothelial nitric-oxide synthase
(eNOS) at Ser1179 that was inhibitable by wortmannin.
We next transfected bovine aortic endothelial
cells with dominant-inhibitory mutants of Akt (Akt-
AAA) or AMP-activated protein kinase (AMPK) (AMPKK45R).
Neither mutant affected production of NO in response
to LPA treatment. Importantly, only AMPKK45R,
but not Akt-AAA, caused a significant partial
inhibition of NO production in response to adiponectin.
Moreover, AMPK-K45R inhibited phosphorylation of
eNOS at Ser1179 in response to adiponectin but not in
response to insulin. We conclude that adiponectin has
novel vascular actions to directly stimulate production
of NO in endothelial cells using phosphatidylinositol
3-kinase-dependent pathways involving phosphorylation
of eNOS at Ser1179 by AMPK. Thus, the effects of
adiponectin to augment metabolic actions of insulin in vivo may be due, in part, to vasodilator actions of
adiponectin
Reciprocal relationships between insulin resistance and endothelial dysfunction - Molecular and pathophysiological mechanisms RID B-1970-2008
No full textEndothelial dysfunction contributes to cardiovascular diseases, including hypertension, atherosclerosis, and
coronary artery disease, which are also characterized by insulin resistance. Insulin resistance is a hallmark of metabolic
disorders, including type 2 diabetes mellitus and obesity, which are also characterized by endothelial dysfunction.
Metabolic actions of insulin to promote glucose disposal are augmented by vascular actions of insulin in endothelium
to stimulate production of the vasodilator nitric oxide (NO). Indeed, NO-dependent increases in blood flow to skeletal
muscle account for 25% to 40% of the increase in glucose uptake in response to insulin stimulation. Phosphatidylinositol
3-kinase– dependent insulin-signaling pathways in endothelium related to production of NO share striking similarities
with metabolic pathways in skeletal muscle that promote glucose uptake. Other distinct nonmetabolic branches of
insulin-signaling pathways regulate secretion of the vasoconstrictor endothelin-1 in endothelium. Metabolic insulin
resistance is characterized by pathway-specific impairment in phosphatidylinositol 3-kinase– dependent signaling, which
in endothelium may cause imbalance between production of NO and secretion of endothelin-1, leading to decreased
blood flow, which worsens insulin resistance. Therapeutic interventions in animal models and human studies have
demonstrated that improving endothelial function ameliorates insulin resistance, whereas improving insulin sensitivity
ameliorates endothelial dysfunction. Taken together, cellular, physiological, clinical, and epidemiological studies
strongly support a reciprocal relationship between endothelial dysfunction and insulin resistance that helps to link
cardiovascular and metabolic diseases. In the present review, we discuss pathophysiological mechanisms, including
inflammatory processes, that couple endothelial dysfunction with insulin resistance and emphasize important therapeutic
implications
Activation of eNOS by insulin is independent of Ca++ but requires phosphorylation by Akt at Ser(1179) RID B-1970-2008
No full textAdiponectin stimulates production of nitric oxide in endothelial cells trough AMPK-dependent phosphorylation of eNOS at Ser1179
No full textInsulin-stimulated activation of eNOS is independent of Ca2+ but requires phosphorylation by Akt at Ser(1179) RID B-1970-2008
No full textVasodilator actions of insulin are mediated by activation
of endothelial nitric-oxide synthase (eNOS) and subsequent
production of NO. Phosphatidylinositol 3-kinase and Akt
play important roles in insulin-signaling pathways leading
to production of NO in vascular endothelium. Here we dissected
mechanisms whereby insulin activates eNOS by using
the fluorescent dye DAF-2 to directly measure NO production
in single cells. Insulin caused a rapid increase in
intracellular NO in NIH-3T3IR cells transiently transfected
with eNOS. The stimulation of NO production by lysophosphatidic
acid (LPA) was abrogated by pretreatment of cells
with the calcium chelator 1,2-bis(2-aminophenoxy)ethane-
N,N,N,N-tetraacetic acid. Remarkably, in the same cells,
insulin-stimulated production of NO was unaffected. However,
cells expressing the eNOS-S1179A mutant (disrupted
Akt phosphorylation site) did not produce detectable NO in
response to insulin, whereas the response to LPA was similar
to that observed in cells expressing wild-type eNOS.
Moreover, production of NO in response to insulin was
blocked by coexpression of an inhibitory mutant of Akt,
whereas the response to LPA was unaffected. Phosphorylation
of eNOS at Ser1179 was observed only in response to
treatment with insulin, but not with LPA. Interestingly,
platelet-derived growth factor treatment of cells activated
Akt but not eNOS. Results from human vascular endothelial
cells were qualitatively similar to those obtained in
transfected NIH-3T3IR cells, although the magnitude of the
responses was smaller. We conclude that insulin regulates
eNOS activity using a Ca2-independent mechanism requiring
phosphorylation of eNOS by Akt. Importantly,
phosphorylation-dependent mechanisms that enhance
eNOS activity can operate independently from Ca2-dependent
mechanisms
Cardiovascular actions of insulin RID B-1970-2008
No full textInsulin has important vascular actions to stimulate production
of nitric oxide from endothelium. This leads to capillary
recruitment, vasodilation, increased blood flow, and subsequent
augmentation of glucose disposal in classical insulin
target tissues (e.g., skeletal muscle). Phosphatidylinositol
3-kinase-dependent insulin-signaling pathways regulating
endothelial production of nitric oxide share striking parallels
with metabolic insulin-signaling pathways. Distinct MAPKdependent
insulin-signaling pathways (largely unrelated to
metabolic actions of insulin) regulate secretion of the vasoconstrictor
endothelin-1 from endothelium. These and other
cardiovascular actions of insulin contribute to coupling metabolic
and hemodynamic homeostasis under healthy conditions.
Cardiovascular diseases are the leading cause of morbidity
and mortality in insulin-resistant individuals. Insulin
resistance is typically defined as decreased sensitivity and/or
responsiveness to metabolic actions of insulin. This cardinal
feature of diabetes, obesity, and dyslipidemia is also a prominent
component of hypertension, coronary heart disease, and
atherosclerosis that are all characterized by endothelial dysfunction.
Conversely, endothelial dysfunction is often present
in metabolic diseases. Insulin resistance is characterized by
pathway-specific impairment in phosphatidylinositol 3-kinase-
dependent signaling that in vascular endothelium contributes
to a reciprocal relationship between insulin resistance
and endothelial dysfunction. The clinical relevance of
this coupling is highlighted by the findings that specific therapeutic
interventions targeting insulin resistance often also
ameliorate endothelial dysfunction (and vice versa). In this
review, we discuss molecular mechanisms underlying cardiovascular
actions of insulin, the reciprocal relationships between
insulin resistance and endothelial dysfunction, and implications
for developing beneficial therapeutic strategies
that simultaneously target metabolic and cardiovascular
diseases
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