Hyperinsulinemia and Insulin Resistance in Dopamine β-Hydroxylase Deficiency

Abstract

Context: Dopamine β-hydroxylase (DBH) deficiency is a rare genetic disorder characterized by failure to convert dopamine to norepinephrine. DBH-deficient patients lack sympathetic adrenergic function and are therefore predisposed to orthostatic hypotension. DBH-deficient mice exhibit hyperinsulinemia, lower plasma glucose levels, and insulin resistance due to loss of tonic sympathetic inhibition of insulin secretion. The impact of DBH deficiency on glucose homeostasis in humans is unknown.

Case description: We describe the metabolic profile of an adolescent female DBH-deficient patient. The patient underwent genetic testing, cardiovascular autonomic function testing, and evaluation of insulin secretion and sensitivity with hyperglycemic clamp under treatment-naive conditions. All procedures were repeated after 1 year of treatment with the norepinephrine prodrug droxidopa (300 mg, 3 times a day). Genetic testing showed a homozygous mutation in the DBH gene (rs74853476). Under treatment-naive conditions, she had undetectable plasma epinephrine and norepinephrine levels, resulting in sympathetic noradrenergic failure and orthostatic hypotension (-32 mm Hg supine to seated). She had high adiposity (41%) and fasting plasma insulin levels (25 μU/mL), with normal glucose (91 mg/dL). Hyperglycemic clamp revealed increased glucose-stimulated insulin secretion and insulin resistance. Droxidopa restored plasma norepinephrine and improved orthostatic tolerance, with modest effects on glucose homeostasis.

Conclusions: We provide evidence for impairment in cardiovascular autonomic regulation, hyperinsulinemia, enhanced glucose-stimulated insulin secretion, and insulin resistance in a DBH-deficient patient. These metabolic derangements were not corrected by chronic droxidopa treatment. These findings provide insight into the pathophysiology and treatment of DBH deficiency and into the importance of catecholaminergic mechanisms to resting metabolism.

Trial registration: ClinicalTrials.gov NCT00748059.

Copyright © 2017 by the Endocrine Society

Figures

Figure 1.

β-Cell function and insulin sensitivity in a DBH-deficient patient under treatment-naive conditions (baseline) and after norepinephrine replacement (droxidopa). (A) Plasma glucose was similarly clamped at ∼200 mg/dL during hyperglycemic clamps in the DBH-deficient patient (at baseline) and in healthy female control subjects (n = 5). (B) Plasma glucose was similarly clamped at ∼200 mg/dL during hyperglycemic clamps on baseline and droxidopa study days. (C) There was a greater increase in plasma insulin in response to hyperglycemia in the DBH-deficient patient at baseline. (D) Droxidopa did not alter the exaggerated increase in plasma insulin in response to hyperglycemia. (E) The glucose infusion rate (GIR) required to maintain hyperglycemia, a measure of insulin sensitivity, was lower in the DBH-deficient patient compared with healthy control subjects at baseline. (F) Droxidopa did not alter the GIR in the patient with DBH deficiency. Acute glucose-stimulated insulin response (times 0–10 min, hatched area); late glucose-stimulated insulin response (90–120 minutes, gray area)