Primary Aldosteronism Decreases Insulin Secretion and Increases Insulin Clearance in Humans

Abstract

Primary aldosteronism is a frequent cause of resistant hypertension and is associated with an increased risk of developing diabetes mellitus. Aldosterone impairs insulin secretion in isolated islets, and insulin secretion is increased in aldosterone synthase-deficient mice. We hypothesized that treatment for primary aldosteronism increases insulin secretion and insulin sensitivity in humans. We conducted a prospective cohort study in patients with primary aldosteronism, with assessment of glucose metabolism before and 3 to 12 months after treatment. Participants underwent treatment for primary aldosteronism with adrenalectomy or a mineralocorticoid receptor antagonist at the discretion of their treating physician. We assessed insulin secretion and insulin sensitivity by hyperglycemic and hyperinsulinemic-euglycemic clamps, respectively, on 2 study days after a 5-day standardized diet. After treatment, the C-peptide and insulin response during the hyperglycemic clamp increased compared with pretreatment (ΔC-peptide at 90-120 minutes +530.5±384.1 pmol/L, P=0.004; Δinsulin 90-120 minutes +183.0±122.6, P=0.004). During hyperinsulinemic-euglycemic clamps, insulin sensitivity decreased after treatment (insulin sensitivity index 30.7±6.2 versus 18.5±4.7 nmol·kg-1·min-1·pmol-1·L; P=0.02). Insulin clearance decreased after treatment (872.8±207.6 versus 632.3±178.6 mL/min; P=0.03), and disposition index was unchanged. We conclude that the insulin response to glucose increases and insulin clearance decreases after treatment for primary aldosteronism, and these effects were not due to alterations in creatinine clearance or plasma cortisol. These studies may provide further insight into the mechanism of increased diabetes mellitus risk in primary aldosteronism.

Keywords: aldosterone; hypertension; insulin resistance; insulin secretion; mineralocorticoids.

Figures

Figure 1.

Summary data from hyperglycemic clamps to assess glucose- and L-arginine-stimulated insulin secretion in participants with primary aldosteronism before treatment (●) and post-treatment (▽). Glucose was infused at a similar rate and glucose was maintained at 200mg/dL in both treatment periods. Insulin increased to a greater extent in participants post-treatment in response to hyperglycemia (A) and after L-arginine administration (B). C-peptide increased to a greater extent after treatment in response to hyperglycemia (C, D). The acute insulin response during the initial 0–10 minutes of the clamp is expanded (D). *p<0.05, **p<0.01, ***p<0.001. Group mean and SEM are shown.

Figure 2.

Summary data from the hyperinsulinemic euglycemic clamps to assess insulin sensitivity in participants with primary aldosteronism before treatment (●) and post-treatment (▽). Glucose was infused to maintain euglycemia ~5.28 mmol/L (95 mg/dL) during low and high insulin infusion rates (20 and 120 mU/m2/min) (A). Glucose infusion rates (GIR, B) required to maintain euglycemia were similar on both study days (B). Achieved insulin concentrations during the clamp were increased after treatment compared to baseline assessment, despite identical insulin infusion rates (C). The resulting glucose infusion rate versus achieved plasma insulin curve was shifted rightward, indicating insulin resistance after treatment (D). Group mean and SEM are shown. *p<0.05, **p<0.01, ***p<0.001