title: Hyperinsulinemia and Insulin Resistance in Dopamine β-Hydroxylase Deficiency.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors: Department of Neural and Behavioral Sciences, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033.|Division of Clinical Pharmacology and.
authors: Amy C
authors: AC
authors: Arnold
authors: Division of Clinical Pharmacology and.
authors: Emily M
authors: EM
authors: Garland
authors: Division of Clinical Pharmacology and.
authors: Jorge E
authors: JE
authors: Celedonio
authors: Division of Clinical Pharmacology and.|Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta T2N 2T9, Canada.
authors: Satish R
authors: SR
authors: Raj
authors: Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232; and.
authors: Naji N
authors: NN
authors: Abumrad
authors: Division of Clinical Pharmacology and.
authors: Italo
authors: I
authors: Biaggioni
authors: Division of Clinical Pharmacology and.
authors: David
authors: D
authors: Robertson
authors: Division of Clinical Pharmacology and.
authors: James M
authors: JM
authors: Luther
authors: Division of Clinical Pharmacology and.
authors: Cyndya A
authors: CA
authors: Shibao
mesh_terms: D000293:Adolescent; D000818:Animals; D001342:Autonomic Nervous System Diseases / Q000150:complications*; D004299:Dopamine beta-Hydroxylase / Q000172:deficiency*; D015103:Droxidopa / Q000627:therapeutic use; D005260:Female; D006801:Humans; D006946:Hyperinsulinism / Q000175:diagnosis / Q000188:drug therapy / Q000209:etiology*; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D051379:Mice; D009638:Norepinephrine / Q000172:deficiency*; D011379:Prognosis
chemical_list: D007328:Insulin; D004299:Dopamine beta-Hydroxylase; D015103:Droxidopa; D009638:Norepinephrine