Vitamin D Deficiency, Insulin Resistance and FGF-23

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.

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)