Hyperinsulinemia and insulin resistance in dopamine b-hydroxylase deficiency

Amy Arnold, Emily M. Garland, Jorge E. Celedonio, Satish R. Raj, Naji N. Abumrad, Italo Biaggioni, David Robertson, James M. Luther, Cyndya A. Shibao

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Context: Dopamine b-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 (232 mm Hg supine to seated). She had high adiposity (41%) and fasting plasma insulin levels (25 mU/mL), with normal glucose (91 mg/dL). Hyperglycemic clamp revealed increased glucosestimulated 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 DBHdeficient 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.

Original languageEnglish (US)
Pages (from-to)10-14
Number of pages5
JournalJournal of Clinical Endocrinology and Metabolism
Volume102
Issue number1
DOIs
StatePublished - Jan 1 2017

Fingerprint

Hyperinsulinism
Mixed Function Oxygenases
Insulin Resistance
Dopamine
Droxidopa
Insulin
Norepinephrine
Glucose
Orthostatic Hypotension
Plasmas
Genetic Testing
Clamping devices
Homeostasis
Testing
Therapeutics
Inborn Genetic Diseases
Metabolome
Adiposity
Prodrugs
dopamine beta hydroxylase deficiency

All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical

Cite this

Arnold, A., Garland, E. M., Celedonio, J. E., Raj, S. R., Abumrad, N. N., Biaggioni, I., ... Shibao, C. A. (2017). Hyperinsulinemia and insulin resistance in dopamine b-hydroxylase deficiency. Journal of Clinical Endocrinology and Metabolism, 102(1), 10-14. https://doi.org/10.1210/jc.2016-3274
Arnold, Amy ; Garland, Emily M. ; Celedonio, Jorge E. ; Raj, Satish R. ; Abumrad, Naji N. ; Biaggioni, Italo ; Robertson, David ; Luther, James M. ; Shibao, Cyndya A. / Hyperinsulinemia and insulin resistance in dopamine b-hydroxylase deficiency. In: Journal of Clinical Endocrinology and Metabolism. 2017 ; Vol. 102, No. 1. pp. 10-14.
@article{816942e5b5714c65870c000e77fa5680,
title = "Hyperinsulinemia and insulin resistance in dopamine b-hydroxylase deficiency",
abstract = "Context: Dopamine b-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 (232 mm Hg supine to seated). She had high adiposity (41{\%}) and fasting plasma insulin levels (25 mU/mL), with normal glucose (91 mg/dL). Hyperglycemic clamp revealed increased glucosestimulated 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 DBHdeficient 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.",
author = "Amy Arnold and Garland, {Emily M.} and Celedonio, {Jorge E.} and Raj, {Satish R.} and Abumrad, {Naji N.} and Italo Biaggioni and David Robertson and Luther, {James M.} and Shibao, {Cyndya A.}",
year = "2017",
month = "1",
day = "1",
doi = "10.1210/jc.2016-3274",
language = "English (US)",
volume = "102",
pages = "10--14",
journal = "Journal of Clinical Endocrinology and Metabolism",
issn = "0021-972X",
publisher = "The Endocrine Society",
number = "1",

}

Arnold, A, Garland, EM, Celedonio, JE, Raj, SR, Abumrad, NN, Biaggioni, I, Robertson, D, Luther, JM & Shibao, CA 2017, 'Hyperinsulinemia and insulin resistance in dopamine b-hydroxylase deficiency', Journal of Clinical Endocrinology and Metabolism, vol. 102, no. 1, pp. 10-14. https://doi.org/10.1210/jc.2016-3274

Hyperinsulinemia and insulin resistance in dopamine b-hydroxylase deficiency. / Arnold, Amy; Garland, Emily M.; Celedonio, Jorge E.; Raj, Satish R.; Abumrad, Naji N.; Biaggioni, Italo; Robertson, David; Luther, James M.; Shibao, Cyndya A.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 102, No. 1, 01.01.2017, p. 10-14.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Hyperinsulinemia and insulin resistance in dopamine b-hydroxylase deficiency

AU - Arnold, Amy

AU - Garland, Emily M.

AU - Celedonio, Jorge E.

AU - Raj, Satish R.

AU - Abumrad, Naji N.

AU - Biaggioni, Italo

AU - Robertson, David

AU - Luther, James M.

AU - Shibao, Cyndya A.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Context: Dopamine b-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 (232 mm Hg supine to seated). She had high adiposity (41%) and fasting plasma insulin levels (25 mU/mL), with normal glucose (91 mg/dL). Hyperglycemic clamp revealed increased glucosestimulated 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 DBHdeficient 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.

AB - Context: Dopamine b-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 (232 mm Hg supine to seated). She had high adiposity (41%) and fasting plasma insulin levels (25 mU/mL), with normal glucose (91 mg/dL). Hyperglycemic clamp revealed increased glucosestimulated 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 DBHdeficient 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.

UR - http://www.scopus.com/inward/record.url?scp=85010387213&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85010387213&partnerID=8YFLogxK

U2 - 10.1210/jc.2016-3274

DO - 10.1210/jc.2016-3274

M3 - Article

VL - 102

SP - 10

EP - 14

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 1

ER -