Possibility of Distinct Insulin-Signaling Pathways Beyond Phosphatidylinositol 3-Kinase-Mediating Glucose Transport and Lipogenesis

Diabetes ◽  
1998 ◽  
Vol 47 (2) ◽  
pp. 179-185 ◽  
Author(s):  
R. W. Stevenson ◽  
D. K. Kreutter ◽  
K. M. Andrews ◽  
P. E. Genereux ◽  
E. M. Gibbs
Keyword(s):  
Signaling Pathways ◽  
Glucose Transport ◽  
Insulin Signaling ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3

Possibility of distinct insulin-signaling pathways beyond phosphatidylinositol 3-kinase-mediating glucose transport and lipogenesis

Diabetes ◽  
1998 ◽  
Vol 47 (2) ◽  
pp. 179-185 ◽  
Author(s):  
R. W. Stevenson ◽  
D. K. Kreutter ◽  
K. M. Andrews ◽  
P. E. Genereux ◽  
E. M. Gibbs
Keyword(s):  
Signaling Pathways ◽  
Glucose Transport ◽  
Insulin Signaling ◽  
Phosphatidylinositol 3 Kinase ◽  
Phosphatidylinositol 3

scholarly journals Cardiovascular Actions of Insulin

2007 ◽  
Vol 28 (5) ◽  
pp. 463-491 ◽  
Author(s):  
Ranganath Muniyappa ◽  
Monica Montagnani ◽  
Kwang Kon Koh ◽  
Michael J. Quon
Keyword(s):  
Nitric Oxide ◽  
Insulin Resistance ◽  
Cardiovascular Diseases ◽  
Endothelial Dysfunction ◽  
Signaling Pathways ◽  
Insulin Signaling ◽  
Reciprocal Relationship ◽  
Phosphatidylinositol 3 Kinase ◽  
Cardiovascular Actions ◽  
Phosphatidylinositol 3

Insulin 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 MAPK-dependent 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.

Phosphatidylinositol 3-Kinase and Prostaglandylinositol Cyclic Phosphate (Cyclic PIP), a Mediator of Insulin Action, in the Signal Transduction of Insulin

2000 ◽  
Vol 381 (11) ◽  
pp. 1139-1141 ◽  
Author(s):  
A. Gypakis ◽  
H.K. Wasner
Keyword(s):  
Insulin Receptor ◽  
Glucose Transport ◽  
Functional Role ◽  
Specific Inhibitor ◽  
Insulin Receptor Substrate ◽  
Phosphatidylinositol 3 Kinase ◽  
Downstream Signaling ◽  
Cyclic Phosphate ◽  
Phosphatidylinositol 3

Abstract It has been suggested that downstream signaling from the insulin receptor to the level of the protein kinases and protein phosphatases is accomplished by prostaglandylinositol cyclic phosphate (cyclic PIP), a proposed second messenger of insulin. However, evidence points also to both phosphatidylinositol 3-kinase, which binds to the tyrosine phosphorylated insulin receptor substrate-1, and the Ras complex in insulin's downstream signaling. We have examined whether a correlation exists between these various observations. It was found that wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase, prevented insulin-induced, as well as cyclic PIP-induced activation of glucose transport, indicating that PI 3-kinase action on glucose transport involves downstream signaling of both insulin and cyclic PIP. Wortmannin has no effect on cyclic PIP synthase activity nor on the substrate production for cyclic PIP synthesis either, indicating that the functional role of PI 3-kinase is exclusively downstream of cyclic PIP.

scholarly journals Persistent insulin signaling coupled with restricted PI3K activation causes insulin-induced vasoconstriction

2019 ◽  
Vol 317 (5) ◽  
pp. H1166-H1172 ◽  
Author(s):  
T. Dylan Olver ◽  
Zachary I. Grunewald ◽  
Thaysa Ghiarone ◽  
Robert M. Restaino ◽  
Allan R. K. Sales ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Insulin Signaling ◽  
Relative Increase ◽  
Resistance Arteries ◽  
Phosphatidylinositol 3 Kinase ◽  
Insulin Stimulation ◽  
Receptor Antagonism ◽  
Endothelin 1 ◽  
Pi3k Activation ◽  
Obese Subjects

Insulin modulates vasomotor tone through vasodilator and vasoconstrictor signaling pathways. The purpose of the present work was to determine whether insulin-stimulated vasoconstriction is a pathophysiological phenomenon that can result from a combination of persistent insulin signaling, suppressed phosphatidylinositol-3 kinase (PI3K) activation, and an ensuing relative increase in MAPK/endothelin-1 (ET-1) activity. First, we examined previously published work from our group where we assessed changes in lower-limb blood flow in response to an oral glucose tolerance test (endogenous insulin stimulation) in lean and obese subjects. The new analyses showed that the peak rise in vascular resistance during the postprandial state was greater in obese compared with lean subjects. We next extended on these findings by demonstrating that insulin-induced vasoconstriction in isolated resistance arteries from obese subjects was attenuated with ET-1 receptor antagonism, thus implicating ET-1 signaling in this constriction response. Last, we examined in isolated resistance arteries from pigs the dual roles of persistent insulin signaling and blunted PI3K activation in modulating vasomotor responses to insulin. We found that prolonged insulin stimulation did not alter vasomotor responses to insulin when insulin-signaling pathways remained unrestricted. However, prolonged insulinization along with pharmacological suppression of PI3K activity resulted in insulin-induced vasoconstriction, rather than vasodilation. Notably, such aberrant vascular response was rescued with either MAPK inhibition or ET-1 receptor antagonism. In summary, we demonstrate that insulin-induced vasoconstriction is a pathophysiological phenomenon that can be recapitulated when sustained insulin signaling is coupled with depressed PI3K activation and the concomitant relative increase in MAPK/ET-1 activity. NEW & NOTEWORTHY This study reveals that insulin-induced vasoconstriction is a pathophysiological phenomenon. We also provide evidence that in the setting of persistent insulin signaling, impaired phosphatidylinositol-3 kinase activation appears to be a requisite feature precipitating MAPK/endothelin 1-dependent insulin-induced vasoconstriction.

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