Clinical trial NCT00491322: Vitamin D Deficiency, Insulin Resistance and FGF-23
Official title: Impact of Vitamin D Deficiency on Insulin Resistance and the Regulation of FGF-23
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Vitamin D Deficiency
Keywords: Vitamin D
Vitamin D deficiency
Insulin resistance
Diabetes
Diabetes mellitus
FGF-23
FGF23
Phosphate
Lead sponsor: Massachusetts General Hospital
Sponsor class: OTHER
Collaborators: name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
First posted: 2007-06-26
Enrollment: 92
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this project is to determine if treating vitamin D deficiency decreases insulin resistance and improves insulin secretion in healthy volunteers. Additionally, this project will investigate if treating vitamin D deficiency affects a new phosphate-regulating hormone called FGF-23.

Detailed description: Vitamin D deficiency or hypovitaminosis D, defined as serum 25 hydroxyvitamin D \< or = 20 ng/mL, is prevalent in several populations in the United States, specifically minorities and the elderly. Causes of vitamin D deficiency include lack of exposure to sunlight, malnutrition, and drugs that alter vitamin D metabolism and absorption.

Vitamin D is an essential factor for many organ systems. Data suggest that vitamin D is required for normal insulin secretion by the pancreas. Specifically, animal studies demonstrate that treatment of vitamin D deficiency improves insulin secretion. In humans, there is less consensus about the impact of vitamin D deficiency on insulin resistance. In one study of middle-aged patients with Type 2 diabetes mellitus, no association was seen between serum 25 hydroxyvitamin D levels and a measure of insulin resistance. However, in a larger study of younger glucose tolerant subjects, serum 25 hydroxyvitamin D levels were associated with both insulin secretion and insulin resistance. These data suggest that treatment of vitamin D deficiency may delay or prevent the development of insulin resistance, and thus diabetes mellitus type 2. Repletion of this common vitamin deficiency could therefore have major public health implications for the prevention of diabetes mellitus.

Fibroblast growth factor 23 (FGF-23) is a newly discovered phosphaturic hormone that is regulated by both dietary and serum phosphate. Hormonal regulation of FGF-23, however, is largely unknown. Recent data suggest that vitamin D plays an important role in the regulation of FGF-23. Some groups have shown that inactivation of the vitamin D receptor gene decreases serum FGF-23 levels in mice; administration of 1,25 dihydroxyvitamin D stimulates the transcription of the FGF-23 gene in vitro. Little is known, however, about the regulation of FGF-23 by vitamin D in humans.

Phosphate is critical for bone mineralization, muscle function, signal transduction, and the creation and utilization of energy. Vitamin D deficiency can result in phosphate malabsorption, osteomalacia and increased risk of fractures. Enhanced understanding of the regulation of this new phosphate-regulating hormone, FGF-23, will advance the field of phosphate metabolism.

Eligibility criteria: Inclusion Criteria:

* Age 18 to 45 yrs
* Serum 25-OHD \< or = 20 ng/mL
* At least 1 menses in the last 3 months (females) and normal serum testosterone (males)

Exclusion Criteria:

* Significant cardiac, hepatic, oncologic, or psychiatric disease
* History of diabetes mellitus, malabsorption, kidney stones, or recent alcohol excess/abuse (15 drinks per week in the last month)
* Fasting glucose \> 126 mg/dl or 2 hour OGTT \> 200 mg/dl
* Use of medications known to affect serum phosphate levels including phosphate-binding antacids, sodium etidronate, calcitonin, excessive doses of vitamin D (\> 1000 units per day), excessive doses of vitamin A (\> 20,000 units/day), calcitriol, growth hormone, or anti-convulsants
* Use of metformin or insulin sensitizing agents
* Serum calcium \< 8 or \> 11 mg/dL, creatinine \> 1.5 mg/dL, or Hgb \< 11 gm/dL
* Liver function tests \> 2 times the upper limit of normal
* TSH \< 0.1 or \> 7 uU/mL
* WBC \< 2,000 or \> 15,000/cmm
* Platelet count \< 100,000 or \> 500,000/cum
* Hormone replacement therapy or testosterone use
* Urine uhCG positive (females), testosterone \< 270 ng/dL (males)

Primary outcomes:
measure: Fibroblast Growth Factor 23 (FGF23) After 12 Weeks of Weekly Ergocalciferol 50000 Units
timeFrame: 12 weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
Study officials:
affiliation: Massachusetts General Hospital
name: Sherri-Ann M Burnett-Bowie, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Burnett SM, Gunawardene SC, Bringhurst FR, Juppner H, Lee H, Finkelstein JS. Regulation of C-terminal and intact FGF-23 by dietary phosphate in men and women. J Bone Miner Res. 2006 Aug;21(8):1187-96. doi: 10.1359/jbmr.060507.
citation: Burnett-Bowie SM, Mendoza N, Leder BZ. Effects of gonadal steroid withdrawal on serum phosphate and FGF-23 levels in men. Bone. 2007 Apr;40(4):913-8. doi: 10.1016/j.bone.2006.10.016. Epub 2006 Dec 8.
citation: Burnett-Bowie SA, Leder BZ, Henao MP, Baldwin CM, Hayden DL, Finkelstein JS. Randomized trial assessing the effects of ergocalciferol administration on circulating FGF23. Clin J Am Soc Nephrol. 2012 Apr;7(4):624-31. doi: 10.2215/CJN.10030911. Epub 2012 Feb 2.
citation: Mitchell DM, Leder BZ, Cagliero E, Mendoza N, Henao MP, Hayden DL, Finkelstein JS, Burnett-Bowie SA. Insulin secretion and sensitivity in healthy adults with low vitamin D are not affected by high-dose ergocalciferol administration: a randomized controlled trial. Am J Clin Nutr. 2015 Aug;102(2):385-92. doi: 10.3945/ajcn.115.111682. Epub 2015 Jul 8.