Effects of vitamin D on insulin secretion

1α,25-Dihydroxyvitamin D3 is considered to be a
modulator of insulin secretion because vitamin D
defi ciency in rats is associated with marked impairment
of insulin secretion (Chertow et al., 1983) and
the insulin-secreting β-cells of the pancreas contain
the vitamin D-regulated protein calbindin-D28k
(Buffa et al., 1989) as well as the VDR (Clark et al.,
1980). Lee et al. (1994) speculated that 1α,25(OH)2D3
may primarily affect intracellular calcium mobilization,
resulting in an inhibition or stimulation of insulin
secretion depending on the vitamin D status and
other biochemical variables.
8.9 Vitamin D-related diseases
8.9.1 Rickets and osteomalacia
Rickets
Rickets, a word from the Anglo-Saxon wrikken (to
twist) is the classic vitamin D defi ciency disease in
children. The disease is characterized by bow legs or
knock knees, curvature of the spine, and pelvic and
thoracic bone deformities. These deformities result
from the mechanical stresses of body weight and muscular
activity applied to the soft uncalcifi ed bone.
Without vitamin D, the cartilaginous growth plate
of the growing child fails to calcify. With this defect,
the cartilage cannot be replaced by bone on the diaphyseal
side and the growth plate becomes progressively
thicker. This results in enlargement of the joints
in the knees, wrists and ankles.
The prevalence of rickets among city-dwelling
children during the industrial revolution was attributable
to a limited exposure to sunlight and a lack of
suffi cient vitamin D in the diet. The narrow streets
and alleys in which the children lived and the smokepolluted
atmosphere were responsible for the lack of
sunlight. During the 1930s, the practice of adding
provitamin D to milk followed by UV irradiation
drastically reduced the incidence of rickets in the
222 Vitamins: their role in the human body
United States and some European countries. Later,
the commercial production of crystalline vitamin D2
led to its use in the fortifi cation of foods. Nowadays,
rickets is a rare disease among the indigenous populations
of the United States and Europe, but it is still evident
among the children of immigrants, particularly
Asians in Europe.
Osteomalacia
In adults, when the skeleton is fully developed, vitamin
D is still necessary for the continuous remodelling
of bone. During prolonged vitamin D defi ciency,
the newly formed, uncalcifi ed bone tissue gradually
takes the place of the older bone tissue and the weakened
bone structure is easily prone to fracture. This
condition, osteomalacia, should not be confused with
osteoporosis in which the ratio of mineral to osteoid
is unchanged. In osteomalacia, the epiphyses do not
swell, as they do in rickets, because the epiphyseal
growth plates no longer exist. Patients with osteomalacia
frequently suffer from muscle weakness and
bone tenderness or pain in the spine, shoulder, ribs or
pelvis. Pelvic deformation can occur causing potential
problems with childbirth. Women with low vitamin
D status may develop osteomalacia after several pregnancies
because they are unable to replace the calcium
lost from their bone reserves to the fetus in utero and
in lactation.
8.9.2 Vitamin D-dependent rickets
Vitamin D-dependent rickets is a rare inherited disorder
in which clinical and biochemical features of rickets
are evident despite an adequate intake of vitamin D.
This disorder is classifi ed into type I and type II disease
states, both of which appear to follow an autosomal
recessive pattern of inheritance (Brown et al., 2000).
Type I
Type I vitamin D-dependent rickets arises from impaired
renal synthesis of 1α,25(OH)2D3, which may
be due to a mutation in the gene encoding 25(OH)D-
1α-hydroxylase. The disease is diagnosed by normal
blood levels of 25(OH)D and profoundly decreased
levels of 1α,25(OH)2D3. At birth, affected children
appear healthy, but during the fi rst year or two of life
severe hypocalcaemia with tetany becomes evident.
The hypocalcaemia leads to secondary hyperparathyroidism
with elevated PTH levels and hypophosphataemia.
The calcium and phosphate defi ciencies
result in impaired mineralization of newly forming
bone, producing the classical symptoms of rickets.
The treatment of type I vitamin D-dependent rickets
is long-term administration of physiological doses of
1α,25(OH)2D3.
Type II
Type II vitamin D-dependent rickets, now more
commonly called hereditary vitamin D-resistant
rickets (HVDRR), arises from a lack of responsiveness
of target tissues to 1α,25(OH)2D3 and in almost
all cases is due to a mutation in the gene encoding
the VDR. Some mutations lead to defective ligand
binding, while others lead to defective binding of the
hormone–receptor complex to the DNA. Hewison et
al. (1993) described an exceptional case attributable
not to a mutation of the VDR gene, but to a defect in
VDR translocation to the nucleus. Whereas the type
I disease state is characterized by depressed levels
of 1α,25(OH)2D3, this metabolite is elevated in the
type II state. Impaired hormonal function at the intestine
and bone causes defi ciencies in calcium and
phosphate, leading to rickets within months of birth.
Affl icted children are often growth retarded and suffer
convulsions due to tetany. Some children have total
scalp and body alopecia, including eyebrows and, in
some cases, eyelashes. The treatment of type II vitamin
D-defi cient rickets is supra-physiological doses
of 1α,25(OH)2D3 (Malloy et al., 1999).
8.9.3 Vitamin D-resistant rickets
Vitamin D-resistant rickets is a group of hereditable
abnormalities of renal phosphate transport, the most
common of which is X-linked hypophosphataemia.
The rickets cannot be explained solely by the severe
hypophosphataemia that is present and the undefi ned
pathological mechanism may involve both abnormal
phosphate transport and renal 1-hydroxylase function.
Treatment entails a combination of oral phosphate
and 1α,25(OH)2D3 (Brown et al., 2000).
8.10 Therapeutic applications of vitamin
D analogues
There have been several trials to assess the effi cacy of
vitamin D compounds in the treatment of postmeno-
Vitamin D 223
pausal osteoporosis. The most critical parameter for
successful treatment, a decrease in fracture rate, was
observed in some, but not all, studies (Brown et al.,
2000). In one Japanese study (Shiraki et al., 1996),
new fracture occurrence in the group treated with
1α(OH)D3 was around one-third of that in the placebo
group. The ideal vitamin D analogue would be one
which promotes bone formation and slow resorption,
yet has less tendency than 1α,25(OH)2D3 to produce
hypercalcaemia.
When cultured human epidermal keratinocytes
are exposed to physiological concentrations of
1α,25(OH)2D3, the cells cease to proliferate and start
to differentiate (Smith et al., 1986). The inhibition of
proliferation has been utilized in the treatment of hyperproliferative
diseases of the skin. Psoriasis, for example,
can be effectively treated by topical application
of the vitamin D analogue calcipotriol, which is about
200 times less potent than 1α,25(OH)2D3 in its effects
on calcium metabolism, although similar in receptor
affi nity (Kragballe, 1992). Non-toxic derivatives of
1α,25(OH)2D3 also have potential for the treatment
of some cancers and a variety of autoimmune disorders
(Holick, 1995a).
8.11 Toxicity
An excessive chronic intake of vitamin D can result
in toxicity with a fatal outcome. As in vitamin A
toxicity, hypervitaminosis D results from the excessive
consumption of vitamin D supplements, and
not from the consumption of usual diets. Toxic
concentrations of vitamin D have not resulted from
unlimited exposure to sunshine. Vitamin D intoxication
can be a concern in patients with specifi c diseases
being treated with unusual amounts of vitamin D or
analogues of the vitamin. In Great Britain, during
the 1940s and early 1950s, an epidemic of ‘idiopathic
hypercalcaemia’ broke out in newborn infants, who
failed to thrive and exhibited symptoms of toxicity.
This epidemic was eventually traced to over-supplementation
of commercial infant milk formulas
with vitamin D. The government policy was to supplement
milk with up to 2000 IU (50 μg) of vitamin
D to compensate for nutritional deprivation that
British children had suffered during World War II. To
allow for anticipated degradation of vitamin D during
processing and storage, some manufacturers put
1.5 to 2 times the correct amount of vitamin D into
the pre-processed milk.
Vitamin D toxicity is due primarily to the hypercalcaemia
caused by the increased intestinal absorption
of calcium, together with increased resorption of
bone. The cause of the hypercalcaemia is therefore
a drastic exaggeration of the normal physiological
action of vitamin D. The increased serum calcium
level can lead to a variety of non-specifi c symptoms,
such as anorexia, nausea, vomiting, muscle weakness
and constipation. Polyuria and polydipsia result from
the failure of the kidney to concentrate the urine.
The hypercalciuria that accompanies hypercalcaemia
encourages the formation of kidney stones in
the renal tubules. Chronic hypercalcaemia results in
irreversible calcifi cation of the kidneys (nephrocalcinosis),
causing permanent damage to the glomeruli
and renal tubules. Calcium salts may be deposited in
other extra-skeletal tissues as well, such as the heart,
blood vessels and lungs. The renal damage results in
a decrease in the glomerular fi ltration rate and severe
hypertension. In long-term hypervitaminosis D, the
excessive bone resorption results in part of the bone
being replaced by fi brous tissue. Where hypervitaminosis
D is fatal, the usual cause of death is renal
insuffi ciency.
High amounts of 25(OH)D3 can promote calcium
translocation in intestine and bone in vitro, suggesting
that overwhelming concentrations of 25(OH)D3
can displace 1α,25(OH)2D3 from the VDR and
directly elicit the biological responses. Brumbaugh
& Haussler (1973) predicted from their data that
25(OH)D3 must be present in 150 times the concentration
of 1α,25(OH)2D3 to displace the physiological
hormone. Hypervitaminosis D patients typically
exhibit a 15-fold increase in plasma 25(OH)D concentrations
compared to normal individuals, but
their 1α,25(OH)2D levels are not substantially altered
(Hughes et al., 1976). These observations have led to
the general conclusion that 25(OH)D, rather than
1α,25(OH)2D, is responsible for vitamin D toxicity.
An alternative hypothesis, presented by Vieth
(1990), is that 1α,25(OH)2D is, in fact, the agent
causing toxicity. This hypothesis is based on the differential
binding affi nities of the various vitamin D
metabolites for the DBP in the plasma. The 25(OH)D
metabolite binds much more tightly to the DBP than
does 1α,25(OH)2D. Therefore, when the plasma concentration
of 25(OH)D increases many-fold, a certain
224 Vitamins: their role in the human body
fraction of the circulating 1α,25(OH)2D will be displaced
from the DBP by 25(OH)D, thereby increasing
the concentration of free 1α,25(OH)2D. The liberated
hormone is now able to interact with a greater than
normal number of VDRs in target cells and elicit an
exaggerated response.
Hypercalcaemia resulting from excessive intake of
the parent vitamin D can persist for weeks or months
after intake has ceased, because of the accumulation of
this vitamin in adipose tissue and its gradual release
into the circulation. Treatment must therefore be
continued for a long time to counteract the hypercalcaemic
response. The treatment includes drugs to
enhance urinary excretion of calcium and drugs to
diminish the calcium effl ux from bone and absorption
of calcium from the intestine. The duration of
the patient’s toxic episode is brief if the administered
agent is 1α,25(OH)2D, because the half-life of this
hormone is only 4–6 h.