[PHNUTR-L] Carotid Atherosclerosis, Diabetes Mellitus and Vitamin D Concentrations

[Kathrynne Holden]

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Carotid Atherosclerosis, Diabetes Mellitus and Vitamin D Concentrations
http://www.vitasearch.com/CP/experts/GTargherAT12-28-06.htm
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 
most studies.



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 
atherosclerosis?

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 
diabetes.

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 
interesting research?

GT: No further comments.
-- 
Kathrynne Holden, MS, RD < fivestar at nutritionucanlivewith.com >
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