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Article ; Online: Critical Role for 24-Hydroxylation in Homeostatic Regulation of Vitamin D Metabolism.

Shahidzadeh Yazdi, Zhinous / Streeten, Elizabeth A / Whitlatch, Hilary B / Montasser, May E / Beitelshees, Amber L / Taylor, Simeon I

The Journal of clinical endocrinology and metabolism

2024

Abstract: ... 24-hydroxylase activity (h) (ρ=-0.85; p=0.001) compared to total plasma 25(OH)D (ρ=0.51; p=0.01) and ... dihydroxyvitamin D [1,25(OH)2D] within narrow physiological ranges. Clinical guidelines emphasize important ... regulation of vitamin D (VitD) metabolism and to apply mechanistic insights to improve clinical assessment ...

Abstract	Context: The body has evolved homeostatic mechanisms to maintain free levels of Ca+2 and 1,25-dihydroxyvitamin D [1,25(OH)2D] within narrow physiological ranges. Clinical guidelines emphasize important contributions of PTH in maintaining this homeostasis. Objective: To investigate mechanisms of homeostatic regulation of vitamin D (VitD) metabolism and to apply mechanistic insights to improve clinical assessment of VitD status. Design: Crossover clinical trial studying participants before and after VitD3-supplementation. Setting: Community. Participants: 11 otherwise healthy individuals with VitD-deficiency (25-hydroxyvitamin D [25(OH)D] ≤20 ng/mL). Interventions: VitD3-supplements (50,000 IU once or twice a week depending on BMI, for 4-6 weeks) were administered to achieve 25(OH)D≥30 ng/mL. Results: VitD3-supplementation significantly increased mean 25(OH)D by 2.7-fold and 24,25-dihydroxyvitamin D [24,25(OH)2D] by 4.3-fold. In contrast, mean levels of PTH, FGF23, and 1,25(OH)2D did not change. Mathematical modeling suggested that 24-hydroxylase activity was maximal for 25(OH)D≥50 ng/mL and achieved a minimum (∼90% suppression) with 25(OH)D<10-20 ng/mL. The 1,25(OH)2D/24,25(OH)2D ratio better predicted modeled 24-hydroxylase activity (h) (ρ=-0.85; p=0.001) compared to total plasma 25(OH)D (ρ=0.51; p=0.01) and the 24,25(OH)2D/25(OH)D ratio (ρ=0.37; p=0.3). Conclusions: Suppression of 24-hydroxylase provides a first line of defense against symptomatic VitD-deficiency by decreasing metabolic clearance of 1,25(OH)2D. The 1,25(OH)2D/24,25(OH)2D ratio provides a useful index of VitD status since it incorporates 24,25(OH)2D levels and therefore, provides insight into 24-hydroxylase activity. When VitD availability is limited, this suppresses 24-hydroxylase activity - thereby decreasing the level of 24,25(OH)2D and increasing the 1,25(OH)2D/24,25(OH)2D ratio. Thus, an increased 1,25(OH)2D/24,25(OH)2D ratio signifies triggering of homeostatic regulation, which occurs at early stages of VitD-deficiency.
Language	English
Publishing date	2024-03-14
Publishing country	United States
Document type	Journal Article
ZDB-ID	3029-6
ISSN	1945-7197 ; 0021-972X
ISSN (online)	1945-7197
ISSN	0021-972X
DOI	10.1210/clinem/dgae156
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Article: Acute pharmacodynamic responses to exenatide: Drug-induced increases in insulin secretion and glucose effectiveness.

Taylor, Simeon I / Montasser, May E / Yuen, Ashley H / Fan, Hubert / Yazdi, Zhinoosossadat Shahidzadeh / Whitlatch, Hilary B / Mitchell, Braxton D / Shuldiner, Alan R / Muniyappa, Ranganath / Streeten, Elizabeth A / Beitelshees, Amber L

medRxiv : the preprint server for health sciences

2023

Abstract: Background: GLP1R agonists provide multiple benefits to patients with type 2 diabetes - including improved glycemic control, weight loss, and decreased risk of major adverse cardiovascular events. Because drug responses vary among individuals, we ... ...

Abstract	Background: GLP1R agonists provide multiple benefits to patients with type 2 diabetes - including improved glycemic control, weight loss, and decreased risk of major adverse cardiovascular events. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses. Methods: Exenatide (5 µg, sc) or saline (0.2 mL, sc) was administered to 62 healthy volunteers. Frequently sampled intravenous glucose tolerance tests were conducted to assess the impact of exenatide on insulin secretion and insulin action. This pilot study was designed as a crossover study in which participants received exenatide and saline in random order. Results: Exenatide increased first phase insulin secretion 1.9-fold (p=1.9×10 Conclusions: This pilot study provides validation for the value of an FSIGT (including minimal model analysis) to provide primary data for our ongoing pharmacogenomic study of pharmacodynamic effects of semaglutide ( NCT05071898 ). Three endpoints provide quantitative assessments of GLP1R agonists' effects on glucose metabolism: first phase insulin secretion, glucose disappearance rates, and glucose effectiveness. Registration: NCT02462421 (clinicaltrials.gov). Funding: American Diabetes Association (1-16-ICTS-112); National Institute of Diabetes and Digestive and Kidney Disease (R01DK130238, T32DK098107, P30DK072488).
Language	English
Publishing date	2023-05-03
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.03.15.23287166
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Article ; Online: Acute pharmacodynamic responses to exenatide: Drug-induced increases in insulin secretion and glucose effectiveness.

Diabetes, obesity & metabolism

2023 Volume 25, Issue 9, Page(s) 2586–2594

Abstract: Aim: Glucagon-like peptide-1 receptor agonists provide multiple benefits to patients with type 2 diabetes, including improved glycaemic control, weight loss and decreased risk of major adverse cardiovascular events. Because drug responses vary among ... ...

Abstract	Aim: Glucagon-like peptide-1 receptor agonists provide multiple benefits to patients with type 2 diabetes, including improved glycaemic control, weight loss and decreased risk of major adverse cardiovascular events. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses. Methods: Exenatide (5 μg, subcutaneously) or saline (0.2 ml, subcutaneously) was administered to 62 healthy volunteers. Frequently sampled intravenous glucose tolerance tests were conducted to assess the impact of exenatide on insulin secretion and insulin action. This pilot study was a crossover design in which participants received exenatide and saline in random order. Results: Exenatide increased first phase insulin secretion 1.9-fold (p = 1.9 × 10 Conclusions: This pilot study provides validation for the value of a frequently sampled intravenous glucose tolerance test (including minimal model analysis) to provide primary data for our ongoing pharmacogenomic study of pharmacodynamic effects of semaglutide (NCT05071898). Three endpoints provide quantitative assessments of the effects of glucagon-like peptide-1 receptor agonists on glucose metabolism: first phase insulin secretion, glucose disappearance rates and glucose effectiveness.
MeSH term(s)	Humans ; Exenatide/therapeutic use ; Diabetes Mellitus, Type 2/drug therapy ; Glucose/therapeutic use ; Insulin Secretion ; Hypoglycemic Agents/adverse effects ; Glucagon-Like Peptide-1 Receptor/therapeutic use ; Pilot Projects ; Glucagon-Like Peptide 1/therapeutic use ; Insulin/therapeutic use ; Peptides/pharmacology ; Peptides/therapeutic use ; Venoms/adverse effects ; Blood Glucose
Chemical Substances	Exenatide (9P1872D4OL) ; Glucose (IY9XDZ35W2) ; Hypoglycemic Agents ; Glucagon-Like Peptide-1 Receptor ; Glucagon-Like Peptide 1 (89750-14-1) ; Insulin ; Peptides ; Venoms ; Blood Glucose
Language	English
Publishing date	2023-06-01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1454944-x
ISSN	1463-1326 ; 1462-8902
ISSN (online)	1463-1326
ISSN	1462-8902
DOI	10.1111/dom.15143
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Article: Role of impaired lower-limb venous innervation in the pathogenesis of the chronic fatigue syndrome.

Streeten, D H

The American journal of the medical sciences

2001 Volume 321, Issue 3, Page(s) 163–167

Abstract: Background: In patients with acute orthostatic hypotension, there is excessive pooling of blood in the legs, which may result from the strikingly subnormal compliance that is demonstrable in the pedal veins during norepinephrine infusion. The common ... ...

Abstract	Background: In patients with acute orthostatic hypotension, there is excessive pooling of blood in the legs, which may result from the strikingly subnormal compliance that is demonstrable in the pedal veins during norepinephrine infusion. The common occurrence of delayed orthostatic hypotension and/or tachycardia in the chronic fatigue syndrome (CFS) led to the present studies of foot vein compliance in CFS patients with a linear variable differential transformer. Methods: Seven patients with CFS were compared with 7 age- and gender matched healthy control subjects in their blood pressure, heart-rate, and plasma norepinephrine responses to prolonged standing and in measurements of their foot vein contractile responses to intravenous norepinephrine infusions with the linear variable differential transformer. Results: Excessive, delayed (usually after 10 min) orthostatic reductions in systolic and diastolic blood pressure (P < 0.01) and inconsistently excessive increases in heart rate were found in the CFS patients, in whom venous compliance in response to infused norepinephrine was significantly reduced (P < 0.05). Conclusions: In these patients with CFS, delayed orthostatic hypotension was clearly demonstrable, and, as in previously reported patients with orthostatic hypotension of acute onset, this was associated with reduced pedal vein compliance during norepinephrine infusion, implying impaired sympathetic innervation of foot veins. The rapid symptomatic improvement demonstrated in previous studies of CFS patients during correction of orthostatic venous pooling by inflation of military antishock trousers (MAST) to 35 mm Hg may suggest that excessive lower body venous pooling, perhaps by reducing cerebral perfusion, is involved in the orthostatic component of fatigue in these patients.
MeSH term(s)	Adult ; Blood Pressure ; Compliance/drug effects ; Fatigue Syndrome, Chronic/etiology ; Female ; Foot/blood supply ; Foot/innervation ; Heart Rate ; Humans ; Hypotension, Orthostatic/etiology ; Male ; Middle Aged ; Norepinephrine/pharmacology ; Vasoconstriction/physiology ; Veins/innervation ; Veins/physiology
Chemical Substances	Norepinephrine (X4W3ENH1CV)
Language	English
Publishing date	2001-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	82078-7
ISSN	1538-2990 ; 0002-9629
ISSN (online)	1538-2990
ISSN	0002-9629
DOI	10.1097/00000441-200103000-00001
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Article: What test for hypothalamic-pituitary-adrenocortical insufficiency?

Streeten, D H

Lancet (London, England)

1999 Volume 354, Issue 9174, Page(s) 179–180

MeSH term(s)	Adrenal Gland Diseases/diagnosis ; Adrenocorticotropic Hormone/administration & dosage ; Adrenocorticotropic Hormone/deficiency ; Anti-Inflammatory Agents, Non-Steroidal/blood ; Cholecystectomy ; Humans ; Hydrocortisone/blood
Chemical Substances	Anti-Inflammatory Agents, Non-Steroidal ; Adrenocorticotropic Hormone (9002-60-2) ; Hydrocortisone (WI4X0X7BPJ)
Language	English
Publishing date	1999-07-17
Publishing country	England
Document type	Journal Article
ZDB-ID	3306-6
ISSN	1474-547X ; 0140-6736 ; 0023-7507
ISSN (online)	1474-547X
ISSN	0140-6736 ; 0023-7507
DOI	10.1016/s0140-6736(98)00318-3
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Zs.MG 94: Show issues

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Article: Shortcomings in the low-dose (1 microg) ACTH test for the diagnosis of ACTH deficiency states.

Streeten, D H

The Journal of clinical endocrinology and metabolism

1999 Volume 84, Issue 3, Page(s) 835–837

MeSH term(s)	Adrenocorticotropic Hormone/administration & dosage ; Adrenocorticotropic Hormone/deficiency ; Dose-Response Relationship, Drug ; Evaluation Studies as Topic ; Humans ; Hydrocortisone/blood
Chemical Substances	Adrenocorticotropic Hormone (9002-60-2) ; Hydrocortisone (WI4X0X7BPJ)
Language	English
Publishing date	1999-03
Publishing country	United States
Document type	Comment ; Editorial ; Review
ZDB-ID	3029-6
ISSN	1945-7197 ; 0021-972X
ISSN (online)	1945-7197
ISSN	0021-972X
DOI	10.1210/jcem.84.3.5581
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Article: Orthostatic intolerance. A historical introduction to the pathophysiological mechanisms.

Streeten, D H

The American journal of the medical sciences

1999 Volume 317, Issue 2, Page(s) 78–87

Abstract: Several of the pathophysiological mechanisms resulting in orthostatic intolerance (ie, tachycardia) have been recognized individually over the course of the past 100 years or more. More recent definitions of the normal ranges of orthostatic blood ... ...

Abstract	Several of the pathophysiological mechanisms resulting in orthostatic intolerance (ie, tachycardia) have been recognized individually over the course of the past 100 years or more. More recent definitions of the normal ranges of orthostatic blood pressure and heart rate changes have facilitated the recognition of pathogenetic disorders that are probably shared in various proportions between orthostatic intolerance and various types of orthostatic hypotension. These include autonomic dysfunction of (1) the leg veins almost invariably causing excessive gravitational blood pooling, usually associated with (2) hypovolemia of circulating erythrocytes and plasma that is probably attributable to impaired autonomic stimulation of erythropoietin production, renin release, and (less consistently) aldosterone secretion. Improved understanding of these apparent results of lower body dysautonomia should facilitate more effective therapy in the future.
MeSH term(s)	History, 19th Century ; History, 20th Century ; Humans ; Hypotension, Orthostatic/history ; Hypotension, Orthostatic/physiopathology ; Posture ; Tachycardia/history ; Tachycardia/physiopathology
Language	English
Publishing date	1999-02
Publishing country	United States
Document type	Historical Article ; Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	82078-7
ISSN	1538-2990 ; 0002-9629
ISSN (online)	1538-2990
ISSN	0002-9629
DOI	10.1097/00000441-199902000-00002
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Article: The nature of chronic fatigue.

Streeten, D H

JAMA

1998 Volume 280, Issue 12, Page(s) 1094–1095

MeSH term(s)	Fatigue Syndrome, Chronic/etiology ; Fatigue Syndrome, Chronic/therapy ; Humans ; Hydrocortisone/metabolism ; Hydrocortisone/therapeutic use ; Hypotension, Orthostatic/complications ; Hypothalamo-Hypophyseal System/physiology ; Pituitary-Adrenal System/physiology
Chemical Substances	Hydrocortisone (WI4X0X7BPJ)
Language	English
Publishing date	1998-09
Publishing country	United States
Document type	Editorial
ZDB-ID	2958-0
ISSN	1538-3598 ; 0098-7484 ; 0254-9077 ; 0002-9955
ISSN (online)	1538-3598
ISSN	0098-7484 ; 0254-9077 ; 0002-9955
DOI	10.1001/jama.280.12.1094
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Article ; Online: The burden of pathogenic variants in clinically actionable genes in a founder population.

Lynch, Megan T / Maloney, Kristin A / Pollin, Toni I / Streeten, Elizabeth A / Xu, Huichun / Shuldiner, Alan R / Van Hout, Cristopher V / Gonzaga-Jauregui, Claudia / Mitchell, Braxton D

American journal of medical genetics. Part A

2021 Volume 185, Issue 11, Page(s) 3476–3484

Abstract: Founder populations may be enriched with certain genetic variants of high clinical impact compared to nonfounder populations due to bottleneck events and genetic drift. Using exome sequencing (ES), we quantified the load of pathogenic variants that may ... ...

Abstract	Founder populations may be enriched with certain genetic variants of high clinical impact compared to nonfounder populations due to bottleneck events and genetic drift. Using exome sequencing (ES), we quantified the load of pathogenic variants that may be clinically actionable in 6136 apparently healthy adults living in the Lancaster, PA Old Order Amish settlement. We focused on variants in 78 genes deemed clinically actionable by the American College of Medical Genetics and Genomics (ACMG) or Geisinger's MyCode Health Initiative. ES revealed 3191 total variants among these genes including 480 nonsynonymous variants. After quality control and filtering, we applied the ACMG/AMP guidelines for variant interpretation and classified seven variants, across seven genes, as either pathogenic or likely pathogenic. Through genetic drift, all seven variants, are highly enriched in the Amish compared to nonfounder populations. In total, 14.7% of Lancaster Amish individuals carry at least one of these variants, largely explained by the 13% who harbor a copy of a single variant in APOB. Other studies report combined frequencies of pathogenic/likely pathogenic (P/LP) variants in actionable genes between 2.0% and 6.2% in outbred populations. The Amish population harbors fewer actionable variants compared to similarly characterized nonfounder populations but have a higher frequency of each variant identified, offering opportunities for efficient and cost-effective targeted precision medicine.
MeSH term(s)	Adult ; Amish/genetics ; Exome/genetics ; Female ; Genetic Diseases, Inborn/diagnosis ; Genetic Diseases, Inborn/epidemiology ; Genetic Diseases, Inborn/genetics ; Genetic Predisposition to Disease ; Genetic Testing ; Genetic Variation/genetics ; Genomics ; Humans ; Male ; Middle Aged ; Precision Medicine ; Whole Exome Sequencing
Language	English
Publishing date	2021-08-31
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2108614-X
ISSN	1552-4833 ; 0148-7299 ; 1552-4825
ISSN (online)	1552-4833
ISSN	0148-7299 ; 1552-4825
DOI	10.1002/ajmg.a.62472
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Article: Idiopathic edema.

Streeten, D H

Current therapy in endocrinology and metabolism

1997 Volume 6, Page(s) 203–206

MeSH term(s)	Bandages ; Diuretics/therapeutic use ; Edema/drug therapy ; Edema/physiopathology ; Edema/therapy ; Humans
Chemical Substances	Diuretics
Language	English
Publishing date	1997
Publishing country	Canada
Document type	Journal Article ; Review
ISSN	0831-652X
ISSN	0831-652X
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