SUN-255 - Increase in fasting and postprandial plama aldosterone and renin concentrations in women with prediabetes is associated with adipose tissue metabolic dysfunction

Introduction: Excess visceral adipose tissue (VAT) has been linked to increased activation of the renin-angiotensine-aldosterone system (RAAS), especially in women. A number of mechanisms have been proposed including renin and angiotensine II production by adipose tissues, sympathetic nervous system activation, and direct stimulation of aldosterone synthase expression in the adrenal glands by leptin. One major mechanism linking cardiometabolic complications with visceral obesity is increased release of plasma nonesterified fatty acids (NEFA) and abnormal dietary fatty acid (DFA) uptake in adipose tissues (i.e. adipose tissue metabolic dysfunction) leading to enhanced fatty acid flux to lean organs and ectopic fat deposition.

Research

Objective: Evaluate the association between direct renin concentration (DRC) and plasma aldosterone concentration (PAC) and adipose tissue metabolic dysfunction in prediabetes.

Methods: We measured fasting and postprandial (i.e. each hour x 6 hours) DRC and PAC in a cohort of 21 men (10 with normal glucose tolerance [NGT] and 11 with impaired glucose tolerance [IGT]) and 19 women (10 NGT and 9 IGT). All participants underwent a meal test with oral and intravenous stable isotope palmitate tracers followed by positron emission tomography (PET) with intravenous [11C]-palmitate and oral [18F]-fluoro-thiaheptadecanoic acid to determine systemic and organ-specific DFA partitioning and uptake and NEFA fluxes and organ-specific uptake and metabolism. Glucose, total NEFA, plasma lipoprotein, triglycerides, insulin, C-peptide, incretin hormones, adiponectine, leptin, plasma oleate, palmitate, and linoleate, cardiac function (PET ventriculography), liver fat content (computed tomography), VAT volume, body composition, abdominal subcutaneous adipocyte size (fat biopsy) were also measured.

Results: Women with IGT had higher fasting PAC (p=0.0027), postprandial area under the curve (AUC) PAC (p=0.0017), fasting DRC (p=0.0674) and AUC DRC (p=0.0676) than women with NGT. In the entire cohort, multivariate regression models revealed a positive correlation between fasting PAC and VAT DFA partitioning (p=0.008), VAT unsaturated DFA partitioning (p < 0.004) and plasma palmitate appearance rate (p < 0.002). Fasting DRC was positively correlated with NEFA appearance rate (p < 0.002) and NEFA AUC (p < 0.03) whereas DRC AUC was positively correlated with fasting NEFA (p < 0.001). Principal components analysis across > 150 metabolic variables in our dataset demonstrated associations between AUC PAC and two clusters enriched with adipose tissue DFA metabolism, NEFA spillover, postprandial fatty acid fluxes and ectopic fat components. These associations were independent of sex and NGT/IGT status.

Conclusion: Fasting and postprandial PAC and DRC are increased in women with IGT. These changes appear driven by adipose tissue metabolic dysfunction.

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