[PHNUTR-L] Carotid Atherosclerosis,
Diabetes Mellitus and Vitamin D Concentrations
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Mon Feb 5 05:57:11 PST 2007
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Carotid Atherosclerosis, Diabetes Mellitus and Vitamin D Concentrations
Giovanni Targher, M.D.
Division of Internal Medicine and Diabetes Unit
Ospedale 'Sacro Cuore – don CalabriaVia Sempreboni 5
37024 Negrar (VR), Italy
+39 0456013713 (Phone/FAX)
targher at sacrocuore.it
“Serum 25-Hydroxyvitamin D3 Concentrations and Carotid Artery
Intima-Media Thickness Among Type 2 Diabetic Patients,”
Clin Endocrinol (Oxf). 2006 Nov;65(5):593-597. 45399 (1/2007)
Kirk Hamilton: Can you please share with us your educational
background and current position?
Giovanni Targher: I earned my MD degree in1991 at the University
School of Medicine of Verona; Specialty in Endocrinology and Metabolic
Diseases in 1996; from 1997-to present I have been a Senior Consultant
in Endocrinology and Diabetes, Division of Internal Medicine and
Diabetes Unit, “Sacro Cuore” Hospital of Negrar (Verona), Italy.
KH: What got you interested in studying the role of vitamin D and
carotid atherosclerosis in type II diabetics?
GT: In addition to its traditional calcium-related effects on the
skeleton, hypovitaminosis D3 has been now recognized to exert
non-skeletal adverse effects on several other organ systems. There is
accumulating experimental and clinical evidence suggesting that serum
concentrations of 25-hydroxyvitamin D3 [25(OH)D] may be inversely
associated with some cancers, metabolic syndrome, and cardiovascular
disease (CVD). Much remains to be learned, however, about the
associations between vitamin D status, metabolic syndrome, and CVD.
Because there is a lack of information currently on associations between
vitamin D status and carotid artery intima-media thickness (IMT) - a
reliable marker of early atherosclerosis - among type 2 diabetic
individuals, people in whom the incidence rates of CVD are very high, we
sought to estimate the prevalence of hypovitaminosis D3 and to assess
the relationship between serum 25(OH)D concentrations and carotid IMT in
type 2 diabetic adults.
KH: What is the physiology of vitamin D with regards to
atherosclerosis? How might an insufficiency of vitamin D increase the
risk to atherosclerosis?
GT: Although the published studies in humans arguing that vitamin D
deficiency/insufficiency may be a novel, underestimated, CVD risk factor
are conflicting, there is now accumulating evidence suggesting both
associative relationships and mechanisms for biologic plausibility. For
example, it has been reported that serum 25(OH)D concentrations are
remarkably lower in patients with acute myocardial infarction or
congestive heart failure than in healthy controls. A strong, inverse,
relationship between serum 25(OH)D concentrations and coronary artery
calcifications has been also reported. The following four potential,
biological, mechanisms might be important for the protective effects of
vitamin D3 against atherosclerosis: 1) vitamin D3 can inhibit various
aspects of inflammation, which have been established as a key pathogenic
mechanism in atherosclerosis; 2) vitamin D3 can exert an
anti-proliferative effect on vascular smooth muscle cells and myocardial
cell hypertrophy and proliferation, which underlies the pathogenesis of
congestive heart failure; 3) vitamin D3 can improve insulin
resistance/secretion, which is thought to play a causal role in
atherosclerosis; and 4) vitamin D3 can act as a negative endocrine
regulator for the renin-angiotensin system, which itself plays an
important independent role in hypertension and cardiovascular health.
KH: Do diabetics have a problem with vitamin D sufficiency?
GT: The prevalence of vitamin D deficiency/insufficiency among people
with type 2 diabetes is extremely common. In our recent study (published
in Diabetes Care, 2006), which was performed in 459 consecutive
outpatients with type 2 diabetes (aged 60 years), ~60% of them had a
serum 25(OH)D concentration ≤ 20 ng/ml (≤50 nmol/L), whereas ~35% of
them had a serum 25(OH)D concentration ≤ 15 ng/ml (≤37.5 nmol/l ).
KH: What is the best way to assess for vitamin D? What is the best
test? What are deficient, insufficient and optimal ranges for vitamin D?
GT: Vitamin D3 circulates in the blood stream largely as
25-hydroxyvitamin D3 [25(OH)D]. Although unhydroxylated vitamin D3 and
1,25-dihydroxyvitamin D3 can be measured in the circulation, the best
estimates of overall vitamin D status are provided by the measurement of
25(OH)D; this is due to its long serum half-life (~3 weeks) and because
the 25-hydroxylation step is unregulated, thus reflecting substrate
availability. Serum 25(OH)D concentration can be measured with several
laboratory methods: CPBA (competitive protein-binding assay); HPLC
(high-performance liquid chromatography); radio-immunoassay (RIA) and
mass spectrometry detection.
In our work, serum 25(OH)D concentrations were measured using an
automated chemiluminescence immunoassay (DiaSorin Liaison, Stillwater,
MN, USA). Measurement of 25OHD by immunoassay will remain the method of
choice for reasons of convenience, speed, turnaround and cost. For the
majority of the authors, vitamin D deficiency is defined as a serum
25(OH)D concentration ≤ 20 ng/ml (≤50 nmol/l); another commonly used
cut-off for defining vitamin D deficiency is a serum 25(OH)D
concentration ≤ 15 ng/ml (≤37.5 nmol/l ). For the majority of the
authors, the optimal ranges for vitamin D are defined as a serum 25(OH)D
concentration ranging from 30 to 50 ng/ml (75-125 nmol/l). Some argue
that the optimal serum 25(OH)D concentrations are those at which serum
parathyroid hormone (PTH) concentrations reach a minimum; maximal
suppression of serum PTH concentrations occurs at 30 ng/ml 25(OH)D in
KH: Is there a problem with vitamin D sufficiency in Western culture?
GT: Yes. We have recently measured serum 25(OH)D concentrations in 6,403
(M/F=1,299/5,104) medical in-patients and out-patients with a wide range
of age (6 months-103 years), who consecutively attended the laboratory
of Vicenza Hospital (a small town in Northern Italy) during the last 3
years. The mean (+SD) serum 25(OH)D concentration for the whole
population was 45+42 nmol/l (median 36; range 12.5-862). Among these
subjects, 52.5% (n=3,359) had a serum 25(OH)D concentration ≤15 ng/ml
(≤37.5 nmol/l) with percentages steadily increasing with advancing age
and ranging from 27% to 73% in men and from 39% to 75% in women,
respectively. Approximately 20% (n=1,299) of subjects had a very low
25(OH)D concentration (≤12.5 nmol/l or 5 ng/ml) with percentages ranging
from 11% to 40% in men and from 13% to 43% in women, respectively. Since
this is not a population-based study, these results do not apply to
non-institutionalized people, among whom vitamin D deficiency may be
(much) lower. Other previous studies have shown a prevalence of
hypovitaminosis D3 of 40 to 60% in elderly persons in community
settings. Even in the non-elderly, ~60% of hospitalized patients in
Boston had evidence of vitamin D3 deficiency. Finally, it has also been
reported that ~30% of healthy adults 18-29 years of age were vitamin D
deficient [25(OH)D < 50 nmol/l] at the end of the winter in Boston.
KH: Can you tell us about your study and the basic results?
GT: We compared winter serum 25(OH)D concentrations in 390 consecutive
type 2 diabetic patients and 390 non-diabetic controls who were
comparable for age and sex. Common carotid intima-media thickness (IMT),
as a reliable index of early atherosclerosis, was measured using
ultrasonography in patients with diabetes by a single operator blinded
to patient details. The prevalence of vitamin D3 deficiency [defined as
a serum 25(OH)D concentration ≤37.5 nmol/l] was higher in diabetic
patients (33.3 vs. 16.4%, P<0.001) than in controls. Among diabetic
patients, those with hypovitaminosis D had a marked increase in common
carotid IMT (1.10+0.15 vs. 0.87+0.14 mm, P<0.001) when compared with
their vitamin D-sufficient diabetic counterparts. These patients also
had higher hemoglobin A1c, fibrinogen and C-reactive protein (hs-CRP)
concentrations. In multivariate regression analysis, low 25(OH)D
concentrations independently predicted carotid IMT in people with type 2
diabetes after adjustment for traditional risk factors, diabetes
duration, HbA1c, calcium, estimated glomerular filtration rate,
inflammatory markers, current use of medications, and the components of
the metabolic syndrome. In conclusion, vitamin D3 deficiency is highly
prevalent in type 2 diabetic adults and is strongly and independently
associated with early signs of atherosclerosis.
KH: Is low vitamin D status associated with markers of inflammation,
such as C-reactive protein and fibrinogen, that are associated with
GT: In our study, patients with diabetes and hypovitaminosis D3 had
significantly higher plasma fibrinogen and hs-CRP concentrations than
diabetic patients with normal vitamin D3 concentrations. Similarly,
recent clinical studies have reported that vitamin D-deficient
individuals have increased plasma concentrations of CRP, interleukin-6
and other inflammatory markers, and that the supplementation of vitamin
D3 in these individuals may correct these abnormalities. Although in our
study low 25(OH)D concentrations predicted carotid IMT independent of
plasma inflammatory markers, it is possible to hypothesize that the
putative elevated CVD risk associated with hypovitaminosis D3 may be, at
least partially, mediated by the elevations in plasma inflammatory markers.
KH: What would be your recommendations to diabetics regarding
atherosclerosis and vitamin D status be? Do you think diabetics should
supplement with vitamin D?
GT: Because a lack of vitamin D3 can negatively affect bone health and
have other non-skeletal adverse effects on several organ systems, a
widespread screening for vitamin D deficiency or routine vitamin D3
supplementation should be seriously considered for people with type 2
KH: What is your therapeutic replenishment dose of vitamin D? What
type of vitamin D do you use? Do you give it daily? With or away from
food? In a single or divided dose?
GT: The treatment for hypovitaminosis D3 is supplementation with
vitamin D3 and calcium. Two methods are suggested here. Replacement with
50,000 IU vitamin D2 (given orally) once a week for eight weeks given
with supplemental calcium will restore tissue stores quickly and may be
more useful for patients with levels of 25(OH)D less than 15-20 ng/ml.
Oral supplementation with 800 IU/day of vitamin D3 and calcium (500-1000
mg/day) for those patients with levels of 25(OH)D between 20 and 30
ng/ml also is safe and effective. Family physicians should consider
screening for hypovitaminosis D3 in all patients who may be at risk,
regardless of age. Just as the blood concentration of cholesterol is
often measured on an annual basis, so too should the blood concentration
of 25(OH)D be measured. Elderly persons, and even children with dietary
lack and limited sun exposure, are vulnerable to vitamin D3 deficiency.
If an adult person has adequate exposure to sunlight, we recommend a
vitamin D3 intake of 400-600 UI per day. The American Academy of
Pediatrics recently recognized the continuing reports of rickets and
recommends 200 to 400 IU of daily vitamin D3 supplementation to all
children (to be continued throughout childhood and adolescence). Older
adults (>70 years) also may warrant vitamin D3 (400-600 IU/day) and
calcium supplementation without screening. Without exposure to sunlight,
a minimum of 1000 IU vitamin D3/day is generally required.
KH: Do you have any further comments you would like to make on this
GT: No further comments.
Kathrynne Holden, MS, RD < fivestar at nutritionucanlivewith.com >
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