Our novel, preliminary data have lead to the hypothesis that "insulin is an important regulator of the cerebral circulation and that the magnitude of this effect is impaired with aging and the metabolic syndrome." This important research area is totally unexplored. Our data show for the first time that insulin, at levels which are equivalent to those reached in blood several times each day during meals, is able to have dramatic effects on cerebral vascular tone and cerebral blood flow (CBF). In addition, the effect of insulin at very high levels which are associated with replacement therapy in diabetic patients has never been investigated. Furthermore, many of the initial elements of the insulin signaling cascade in cerebral arteries are similar to those that we have found to promote neuronal preconditioning;leading to speculation that insulin has a normal, protective effect against stress-related damage in the cerebral vasculature. Our preliminary data also indicate that insulin-dependent effects on the cerebral vasculature are greatly reduced by insulin resistance (IR), a major component of the metabolic syndrome, or by aging. However, mechanisms and possible therapeutic approaches for the restoration of normal cerebral vascular responsiveness to insulin are unknown. We will address two specific aims.
Specific Aim 1. Determination of the effects of insulin on cerebral arteries. First, we will characterize the effects of physiological and therapeutic doses of insulin on cerebral arteries of normal Sprague Dawley (SD) rats. Second, we will examine the roles of endothelium and smooth muscle on the integrative changes in vascular tone. Third, we will examine the signaling cascades following activation of insulin receptors. Fourth, we will examine the nature of vasoactive substances mediating insulin effects on the cerebral arteries. Fifth, we will examine whether insulin protects cerebral vascular cells against lethal stress.
Specific Aim 2. Determination of the effects of insulin on cerebral arteries during aging and insulin resistance. First, we will characterize responses in cerebral arteries in aged (12-24 month) SD rats. Second, we will characterize responses in cerebral arteries from SD rats suffering from insulin resistance due to consumption of a diet high in fructose. Third, we will elucidate the mechanisms of altered responses in aged and insulin resistant animals. Fourth, we will examine therapeutic approaches for the restoration of normal cerebral arterial responses to insulin in the presence of IR or aging.

Public Health Relevance

Chronic cerebral vascular insufficiency as occurs in IR and in aging and leads to neurological diseases such as non-specific cognitive deficiency, Alzheimer's Disease and strokes but the potential role of insulin has not been studied. Current treatment regimens are not optimal and we expect that the results of our studies will lead to new and improved therapies to prevent or slow the onset of neurological diseases in an obese and aging population.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL077731-08
Application #
8249384
Study Section
Special Emphasis Panel (ZRG1-VH-G (03))
Program Officer
OH, Youngsuk
Project Start
2004-09-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
8
Fiscal Year
2012
Total Cost
$371,238
Indirect Cost
$123,738
Name
Tulane University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Katakam, Prasad V G; Gordon, Angellica O; Sure, Venkata N L R et al. (2014) Diversity of mitochondria-dependent dilator mechanisms in vascular smooth muscle of cerebral arteries from normal and insulin-resistant rats. Am J Physiol Heart Circ Physiol 307:H493-503
Busija, David W; Katakam, Prasad V (2014) Mitochondrial mechanisms in cerebral vascular control: shared signaling pathways with preconditioning. J Vasc Res 51:175-89
Rutkai, Ibolya; Katakam, Prasad V G; Dutta, Somhrita et al. (2014) Sustained mitochondrial functioning in cerebral arteries after transient ischemic stress in the rat: a potential target for therapies. Am J Physiol Heart Circ Physiol 307:H958-66
Carvalho, Cristina; Katz, Paige S; Dutta, Somhrita et al. (2014) Increased susceptibility to amyloid-? toxicity in rat brain microvascular endothelial cells under hyperglycemic conditions. J Alzheimers Dis 38:75-83
Katakam, Prasad V G; Wappler, Edina A; Katz, Paige S et al. (2013) Depolarization of mitochondria in endothelial cells promotes cerebral artery vasodilation by activation of nitric oxide synthase. Arterioscler Thromb Vasc Biol 33:752-9
Wappler, Edina A; Institoris, Adam; Dutta, Somhrita et al. (2013) Mitochondrial dynamics associated with oxygen-glucose deprivation in rat primary neuronal cultures. PLoS One 8:e63206
Katakam, Prasad V G; Snipes, James A; Steed, Mesia M et al. (2012) Insulin-induced generation of reactive oxygen species and uncoupling of nitric oxide synthase underlie the cerebrovascular insulin resistance in obese rats. J Cereb Blood Flow Metab 32:792-804
Institoris, Adam; Snipes, James A; Katakam, Prasad V et al. (2011) Impaired vascular responses of insulin-resistant rats after mild subarachnoid hemorrhage. Am J Physiol Heart Circ Physiol 300:H2080-7
Domoki, Ferenc; Kis, Bela; Gaspar, Tamas et al. (2010) Rosuvastatin induces delayed preconditioning against L-glutamate excitotoxicity in cultured cortical neurons. Neurochem Int 56:404-9
Gaspar, Tamas; Domoki, Ferenc; Lenti, Laura et al. (2009) Immediate neuronal preconditioning by NS1619. Brain Res 1285:196-207

Showing the most recent 10 out of 48 publications