The number of adults with diabetes in the world is expected to grow to 380 million by the year 2025. Identifying drugs that prevent the development of diabetes in high-risk individuals, such as those with metabolic syndrome or impaired glucose tolerance (IGT), could have a major health impact. Based on published clinical trials and our preliminary data, we propose that inappropriately elevated aldosterone promotes diabetes in humans by impairing insulin sensitivity and insulin secretion. Targeting this system will provide a novel strategy for preventing metabolic complications in an obese, hypertensive population. Angiotensin I converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) reduce blood pressure and cardiovascular mortality. They also reduce the incidence of type 2 Diabetes Mellitus (T2DM) in retrospective analyses of clinical trials. The mechanism by which the renin-angiotensin-aldosterone system (RAAS) affects glucose control remains uncertain. We hypothesize that aldosterone reduction during ACE and ARB therapy mediates some of these beneficial effects. Because aldosterone concentrations increase back to baseline after prolonged ACE inhibitor and ARB treatment, this """"""""aldosterone breakthrough"""""""" could reduce the beneficial effect on blood glucose. Drugs which inhibit aldosterone synthesis are in development and will provide a specific approach to block this breakthrough response. We have found that endogenous aldosterone impairs glucose-stimulated insulin secretion in vivo in mice and ex vivo in perifused pancreatic islet cells. More recently, we have determined that renin-angiotensin- aldosterone system stimulation with low sodium intake attenuates insulin secretion in healthy humans (Preliminary Studies). Aldosterone is also increased, and insulin secretion is impaired in subjects with impaired versus normal glucose tolerance (Preliminary Studies). Plasma aldosterone inversely correlated with the acute insulin response to glucose. Prior studies demonstrate a detrimental effect of aldosterone on insulin sensitivity via mineralocorticoid receptor activation. These findings suggest that the RAAS, and particularly aldosterone, impair glucose homeostasis by altering insulin secretion and insulin sensitivity in mice and in humans. Our studies may help explain the variable beneficial effect of RAAS blockade on glucose tolerance in recent clinical studies. If the endogenous RAAS impairs insulin secretion and increase glucose concentrations in subjects with metabolic syndrome as we hypothesize, alternative strategies such as aldosterone synthase inhibition will provide an attractive therapy in the near future. We anticipate that targeted RAAS inhibition will minimize the adverse metabolic effects of dietary sodium restriction or diuretic administration, and improve glucose tolerance. In this proposal we will test the hypothesis that the endogenous RAAS impairs peripheral insulin sensitivity, hepatic insulin sensitivity, and insulin secretion in humans via aldosterone.
Twenty-nine percent of the United States population are hypertensive, and nearly thirty percent are obese. Aldosterone is inappropriately increased in obesity and ~10-15% of patients with resistant hypertension, and contributes significantly to cardiovascular disease. Our studies demonstrate that aldosterone may also provide a novel link between obesity, hypertension, and type 2 diabetes progression by impairing insulin secretion and insulin sensitivity.
|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|
|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|
|Luther, James M; Brown, Nancy J (2016) Epoxyeicosatrienoic acids and glucose homeostasis in mice and men. Prostaglandins Other Lipid Mediat 125:2-7|
|Luther, James M (2016) Aldosterone in vascular and metabolic dysfunction. Curr Opin Nephrol Hypertens 25:16-21|
|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|
|Ramirez, Claudia E; Nian, Hui; Yu, Chang et al. (2015) Treatment with Sildenafil Improves Insulin Sensitivity in Prediabetes: A Randomized, Controlled Trial. J Clin Endocrinol Metab 100:4533-40|
|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|
|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|
Showing the most recent 10 out of 13 publications