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.
|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|
|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|
|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|
|Luther, James M (2014) Effects of aldosterone on insulin sensitivity and secretion. Steroids 91:54-60|
|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|
|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|
|Ramirez, Claudia E; Shuey, Megan M; Milne, Ginger L et al. (2014) Arg287Gln variant of EPHX2 and epoxyeicosatrienoic acids are associated with insulin sensitivity in humans. Prostaglandins Other Lipid Mediat 113-115:38-44|
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