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 #
5K23DK081662-05
Application #
8281716
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
Project Start
2008-09-01
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$172,104
Indirect Cost
$12,748
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
Luther, James M; Byrne, Loretta M; Yu, Chang et al. (2014) Dietary sodium restriction decreases insulin secretion without affecting insulin sensitivity in humans. J Clin Endocrinol Metab 99:E1895-902
Luther, James M (2014) Is there a new dawn for selective mineralocorticoid receptor antagonism? Curr Opin Nephrol Hypertens 23:456-61
Brown, Jenifer M; Williams, Jonathan S; Luther, James M et al. (2014) Human interventions to characterize novel relationships between the renin-angiotensin-aldosterone system and parathyroid hormone. Hypertension 63:273-80
Luther, James M (2014) Effects of aldosterone on insulin sensitivity and secretion. Steroids 91:54-60
Gilbert, Kimberly; Nian, Hui; Yu, Chang et al. (2013) Fenofibrate lowers blood pressure in salt-sensitive but not salt-resistant hypertension. J Hypertens 31:820-9
Luo, P; Dematteo, A; Wang, Z et al. (2013) Aldosterone deficiency prevents high-fat-feeding-induced hyperglycaemia and adipocyte dysfunction in mice. Diabetologia 56:901-10
Wang, Zhen; Hill, Salisha; Luther, James M et al. (2012) Proteomic analysis of urine exosomes by multidimensional protein identification technology (MudPIT). Proteomics 12:329-38
Luther, James M (2012) Sodium intake, ACE inhibition, and progression to ESRD. J Am Soc Nephrol 23:10-2
Martinerie, Laetitia; Viengchareun, Say; Meduri, Geri et al. (2011) Aldosterone postnatally, but not at birth, is required for optimal induction of renal mineralocorticoid receptor expression and sodium reabsorption. Endocrinology 152:2483-91
Luther, James Matthew; Brown, Nancy J (2011) The renin-angiotensin-aldosterone system and glucose homeostasis. Trends Pharmacol Sci 32:734-9

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