Hypoglycemia and the Mineralocorticoid Receptor (HypoMR)

Robert Wood Johnson Foundation, National Institutes of Health (NIH), National Heart, Lung, and Blood Institute (NHLBI)

The purpose of this study is to look at whether blockade of the mineralocorticoid receptor will result in changes in the cardiovascular and inflammatory response to hypoglycemia.

The effect of ongoing hypoglycemia on cardiovascular autonomic function is unclear and the focus of this protocol. In our preliminary studies, the investigators demonstrated that baroreflex sensitivity is impaired during hypoglycemia in healthy individuals. Treatment with eplerenone (200mg total administered in two doses in the 15 hours prior to the hypoglycemic clamp) prevented this impairment. The study is based on the overarching hypothesis that hypoglycemia leads to increases in aldosterone/mineralocorticoid receptor (MR) activity and increased cardiovascular injury. This study will address the following Specific Aims: To test the hypothesis that MR blockade will reduce the adverse effects of hypoglycemia on inflammation and on autonomic control of cardiovascular function. The investigators will determine the effects of hypoglycemia (50 mg/dl for 2.0 hours) on the blood inflammatory factor interleukin-6 levels, and on cardiovascular autonomic function (baroreflex sensitivity) in each subject under two conditions - pretreatment with MR blockade (eplerenone) and pretreatment with placebo.

hypoglycemia (50 mg/dl) with pretreatment with two doses of eplerenone (100 mg of eplerenone per dose)

Modified oxford procedures was performed in duplicate immediately prior to start of the hypoglycemic clamp and during the last 30 min of the clamp (i.e. during the last 30 min of exposure to 2 hours of hypoglycemia).. We calculated the baroreflex sensitivity (the relationship between RR interval and change in systolic blood pressure defined as the change in the inter-beat cardiac interval in milliseconds per unit change in blood pressure in mmHg) at each time point and then the change in baroreflex sensitivity (BRS during hypoglycemia minus BRS at baseline)

Inclusion Criteria: Healthy volunteers Males and females age 18 to 40 years Exclusion Criteria: Pregnancy Lactation Menopause Any medical condition other than treated hypothyroidism. Alcoholism Active tobacco use In all subjects, any individuals on oral, injected, inhaled or topical corticosteroids within the last year or oral contraceptives within the past 3 months will be excluded. Use of medications other than physiological thyroxine replacement Serum potassium >5.0 mmol/L Estimated glomerular filtration rate < 60 mL/min

Rao AD, Bonyhay I, Dankwa J, Baimas-George M, Kneen L, Ballatori S, Freeman R, Adler GK. Baroreflex Sensitivity Impairment During Hypoglycemia: Implications for Cardiovascular Control. Diabetes. 2016 Jan;65(1):209-15. doi: 10.2337/db15-0871. Epub 2015 Oct 5.