Impaired glucose homeostasis, as measured by worsened insulin resistance and insulin secretory capacity, accompanies obesity and the metabolic syndrome, ultimately producing hyperglycemia and overt diabetes mellitus. The Framingham Offspring Study recently demonstrated that basal aldosterone concentrations predict the development of the metabolic syndrome, which is associated with increased cardiovascular risk. We have observed that fasting glucose concentrations are decreased in aldosterone synthase-deficient (AS-/-) mice, and that AS-/- mice demonstrate enhanced glucose-stimulated insulin secretion through a potassium-independent mechanism. This proposal tests the central hypothesis that aldosterone attenuates insulin secretion in humans via a mineralocorticoid receptor (MR)-dependent mechanism. The applicant will collaborate with experienced clinical and basic science investigators to gain expertise in the regulation of the rennin-angiotensin-aldosterone system and the field of diabetes, while investigating the following three specific aims:
SPECIFIC AIM 1 Test the hypothesis that exogenous aldosterone increases fasting glucose concentrations in humans by attenuating glucose-stimulated insulin secretion.
SPECIFIC AIM 2 Test the hypothesis that endogenous aldosterone increases fasting glucose and decreases insulin secretion in individuals with the metabolic syndrome via an MR-dependent mechanism.
SPECIFIC AIM 3 Test the hypothesis that MR antagonism and angiotensin II type-1 receptor (AT1) antagonism will cause synergistic beneficial effects on fasting blood glucose and insulin secretion. We will utilize previously-developed protocols for aldosterone infusion and hyperglycemic clamp to assess the effect of aldosterone on insulin secretion in normal subjects. We will then study subjects with the metabolic syndrome, a group at high risk for diabetes, to similarly assess the effects of treatment with MR and AT1 antagonism. These studies will have immediate clinical relevance to preventing the development of diabetes in individuals with the metabolic syndrome.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23DK081662-03
Application #
7880777
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2008-09-01
Project End
2013-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
3
Fiscal Year
2010
Total Cost
$172,390
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Sausville, Lindsay N; Gangadhariah, Mahesha H; Chiusa, Manuel et al. (2018) The Cytochrome P450 Slow Metabolizers CYP2C9*2 and CYP2C9*3 Directly Regulate Tumorigenesis via Reduced Epoxyeicosatrienoic Acid Production. Cancer Res 78:4865-4877
Arnold, Amy C; Garland, Emily M; Celedonio, Jorge E et al. (2017) Hyperinsulinemia and Insulin Resistance in Dopamine ?-Hydroxylase Deficiency. J Clin Endocrinol Metab 102:10-14
Gangadhariah, Mahesha H; Dieckmann, Blake W; Lantier, Louise et al. (2017) Cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids contribute to insulin sensitivity in mice and in humans. Diabetologia 60:1066-1075
Luther, James M (2016) Aldosterone in vascular and metabolic dysfunction. Curr Opin Nephrol Hypertens 25:16-21
Luther, James M; Brown, Nancy J (2016) Epoxyeicosatrienoic acids and glucose homeostasis in mice and men. Prostaglandins Other Lipid Mediat 125:2-7
Shah, Sapna S; Ramirez, Claudia E; Powers, Alvin C et al. (2016) Hyperglycemic clamp-derived disposition index is negatively associated with metabolic syndrome severity in obese subjects. Metabolism 65:835-42
Qi, Ying; Wang, Xiaojing; Rose, Kristie L et al. (2016) Activation of the Endogenous Renin-Angiotensin-Aldosterone System or Aldosterone Administration Increases Urinary Exosomal Sodium Channel Excretion. J Am Soc Nephrol 27:646-56
Schey, Kevin L; Luther, J Matthew; Rose, Kristie L (2015) Proteomics characterization of exosome cargo. Methods 87:75-82
Gangadhariah, Mahesha H; Luther, James M; Garcia, Victor et al. (2015) Hypertension is a major contributor to 20-hydroxyeicosatetraenoic acid-mediated kidney injury in diabetic nephropathy. J Am Soc Nephrol 26:597-610
Luther, James M (2014) Is there a new dawn for selective mineralocorticoid receptor antagonism? Curr Opin Nephrol Hypertens 23:456-61

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