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Hindawi Publishing CorporationInternational Journal of EndocrinologyVolume 2010, Article ID 351385, 18 pagesdoi:10.1155/2010/351385
Review Article
Role of Vitamin D in Insulin Secretion andInsulin Sensitivity for Glucose Homeostasis
Jessica A. Alvarez1 and Ambika Ashraf2
1 Department of Nutrition Sciences, University of Alabama at Birmingham, AL 35233, USA2 Department of Pediatrics, Division of Pediatric Endocrinology and Metabolism, The Children’s Hospital,University of Alabama at Birmingham, AL 35233, USA
Correspondence should be addressed to Ambika Ashraf, aashraf@peds.uab.edu
Received 20 April 2009; Accepted 16 June 2009
Academic Editor: Vin Tangpricha
Copyright © 2010 J. A. Alvarez and A. Ashraf. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.
Vitamin D functions are not limited to skeletal health benefits and may extend to preservation of insulin secretion and insulinsensitivity. This review summarizes the literature related to potential vitamin D influences on glucose homeostasis and insulinsensitivity. Cross-sectional data provide some evidence that circulating 25-hydroxyvitamin D (25(OH)D) is inversely associatedwith insulin resistance, although direct measurements of insulin sensitivity are required for confirmation. Reported associationswith insulin secretion, however, are contradictory. Available prospective studies support a protective influence of high 25(OH)Dconcentrations on type 2 diabetes mellitus risk. There is a general lack of consistency in vitamin D intervention outcomes oninsulin secretion and sensitivity, likely due to differences in subject populations, length of interventions, and forms of vitaminD supplementation. Vitamin D receptor gene polymorphisms and vitamin D interactions with the insulin like growth factorsystem may further influence glucose homeostasis. The ambiguity of optimal vitamin D dosing regimens and optimal therapeuticconcentrations of serum 25(OH)D limit available intervention studies. Future studies, including cross-sectional and prospective,should be performed in populations at high risk for both vitamin D deficiency and type 2 diabetes mellitus. Well-designed,placebo-controlled, randomized intervention studies are required to establish a true protective influence of vitamin D on glucosehomeostasis.
1. Introduction
Over the last decade, numerous nonskeletal disease asso-ciations have been reported with vitamin D deficiency,including type 2 diabetes mellitus (T2DM). Circulating 25-hydroxyvitamin D (25(OH)D) concentrations are consid-ered an indicator of vitamin D status [1, 2]. Compared tohealthy controls, subjects with T2DM have been observed tohave significantly lower circulating 25(OH)D concentrations[3–5]. Perhaps not coincidently, both vitamin D deficiencyand T2DM share the same risk factors, including African-American, Asian, or Hispanic ethnicity, increased adiposity,age, and physical inactivity (which may translate to decreasedtime spent outdoors or reduced sun exposure) [6, 7].Seasonal variations in glucose and insulin concentrationshave been reported [8], which may correlate with seasonalvariations in 25(OH)D concentrations [9]. Although not
within the scope of this review, vitamin D has likewise beenimplicated in the development of type 1 diabetes mellitusdue to its modulation of the immune system [10]. T2DMis considered a state of insulin resistance (beta cell com-pensation) and insulinopenia (beta cell decompensation)and is characterized by progressive deterioration in betacell function and eventual loss of beta cell mass [11]. Themechanism by which vitamin D deficiency and T2DM arerelated is not well known.
We performed a computerized PubMed search of Englishlanguage original and review articles through March 2009using the terms “vitamin D”, “insulin”, “insulin sensitivity”,“insulin resistance”, “insulin secretion”, and other relatedterms. This review provides a comprehensive summaryof the literature available relating vitamin D to insulinsecretion and sensitivity, including the potential mechanismsmediating the vitamin D-glucose homeostasis relationship;
2 International Journal of Endocrinology
supportive or contradictory cross-sectional, prospective,and intervention studies; as well as potential interactionsof vitamin D with the insulin like growth factor (IGF)system and influences of vitamin D receptor (VDR) genepolymorphisms.
2. Potential Mechanisms of Effect ofVitamin D on Glucose Homeostasis
Pittas et al. [9] have summarized the biological evidenceimplicating a potential influence of vitamin D on glucosehomeostasis. The inferences for the manifold roles of vitaminD include the presence of specific vitamin D receptors(VDRs) on pancreatic β-cells [12], the expression of 1-α-hydroxylase enzyme in pancreatic β-cells which catalyzesthe conversion of 25(OH)D to 1, 25-dihydroxyvitamin D(1, 25(OH)2D) [13], the presence of a vitamin D responseelement in the human insulin gene promoter [14], andthe presence of VDR in skeletal muscle [15]. In addition,1, 25(OH)2D directly activates transcription of the humaninsulin receptor gene [16], activates peroxisome proliferatoractivator receptor-δ [17], stimulates the expression of insulinreceptor, and enhances insulin-mediated glucose transport invitro [18].
Animal and in vitro studies provide compelling evidencethat vitamin D may play a functional role in the preservationof glucose tolerance through its effects on insulin secretionand insulin sensitivity. Vitamin D deficient rabbits and micepresent with impaired insulin secretion, and supplementa-tion with vitamin D corrects the defect [19–22]. Mice withmutations in the VDR have impaired insulin secretion andlower glucose tolerance than those with functional receptors[23]. In vitro, 1, 25(OH)2D induces the biosynthesis ofinsulin in rat pancreatic islet cells [24], and in anotherstudy, inhibited free fatty acid-induced insulin resistance(i.e., improved glucose uptake) in cultured myocytes in adose-dependent manner. The insulin sensitizing effects weremediated by a reduction in JNK activation [25].
Although the skeletal effects of vitamin D occur via anendocrine mechanism, there may be an autocrine/paracrinerole of vitamin D in insulin target tissues. Pancreatic β-cellsexpress the vitamin D receptor (VDR) as well as the pivotalenzyme 1α-hydroxylase [12, 13]. VDR is also expressed byboth human skeletal muscle and adipose tissue [26, 27],which are the main determinants of peripheral insulinsensitivity. These tissues were shown to express the 1α-hydroxylase gene in male Wistar rats [28]. Notably, skeletalmuscle expression of VDR declines with age [29], as doesinsulin sensitivity.
Vitamin D deficiency may influence its effects on insulinsecretion and sensitivity via its effects on intracellularcalcium [9]. Elevated intracellular calcium impairs postre-ceptor binding insulin action, such as the dephosphorylationof glycogen synthase and of insulin regulatable glucosetransporter (GLUT-4) [30, 31]. Vitamin D deficiency resultsin elevated parathyroid hormone (PTH) [2], which in turn isknown to elevate intracellular calcium [31]. Sustained eleva-tions of intracellular calcium may inhibit insulin-target cells
from sensing the brisk intracellular calcium fluxes necessaryfor insulin action, such as glucose transport [32]. Pancreaticβ-cells also depend on an acute intracellular calcium increasefor insulin secretion [33], which may also be attenuated withelevated cytosolic calcium [34]. Another possible mechanismis that elevated intracellular calcium enhances calmodulinbinding to insulin receptor substrate-1 (IRS-1), whichinterferes with insulin-stimulated tyrosine phosphorylationand PI3-kinase activation [35–37]. Indeed, PTH has beenshown to be inversely associated with insulin sensitivity[38, 39]. On the other hand, Kamycheva et al. [40] did notfind significant differences in insulin or glucose metabolismin subjects with secondary hyperparathyroidism versuscontrols. Nevertheless, dichotomization based on serum25(OH)D concentrations appeared to determine differencesin insulin sensitivity. It is arguable that the insulin resistanceseen in vitamin D deficient subjects is not fully explained bythese aforementioned molecular mechanisms alone.
3. Cross-Sectional Data
Reports on associations between insulin secretion and25(OH)D have been inconsistent (Table 1(a)). The differ-ences in this relationship are likely due to differences insubject populations and disparate methods to determineinsulin secretion. Boucher et al. [41] reported a significantpositive association between 25(OH)D and oral glucosetolerance test- (OGTT-) induced insulin secretion in EastLondon Asians at risk for T2DM, although Orwoll et al.[42] reported no association between 25(OH)D and meal-induced insulin secretion in men with T2DM (mean glyco-sylated hemoglobin, HbA1c: 11.5 ± 3.5%). It is possible thatvitamin D is unable to augment insulin secretion in uncon-trolled T2DM subjects who have already exhausted theirinsulin secretory capacity. Analyses of the National Healthand Nutrition Examination Survey 1989–1994 (NHANESIII) disclosed that serum 25(OH)D was inversely associatedwith diabetes risk and measures of insulin resistance despitethere is no association between 25(OH)D concentrationsand the homeostasis model assessment of β-cell function(HOMA-β, an index of β-cell function derived from fastinginsulin and glucose concentrations) [5]. Significant inverseassociations have been reported between 25(OH)D andOGTT-induced insulin secretion in elderly Dutch men [4],hyperglycemic clamp-induced insulin response in glucosetolerant subjects of various ethnic backgrounds [43], andhyperglycemic clamp-induced insulin response in Norwe-gian subjects with secondary hyperparathyroidism [40].Although an inverse association between 25(OH)D andinsulin secretion may seem contradictory to the hypothesisthat vitamin D is necessary for β-cell synthesis of insulin,subjects with insulin resistance, but not T2DM, often expe-rience compensatory hyperinsulinemia [44]. Thus, inversestatistical associations of vitamin D with insulin secretionmay be mediated through vitamin D influences on insulinsensitivity, as shown by Chiu et al. [43].
In general, cross-sectional studies, including large-scalepopulation studies such as NHANES III [5, 45], have shown
International Journal of Endocrinology 3
a significant positive relationship between serum 25(OH)Dand measures of insulin sensitivity [4, 5, 40, 43, 45–48](Table 1(b)). This relationship has been corroborated ina variety of populations including pregnant and pediatricpopulations [49, 50].
A limitation to the available cross-sectional data is that,with the exception of few studies [40, 43, 51, 52], manystudies investigating relationships between 25(OH)D andinsulin secretion and sensitivity have used indirect proxymeasures, such as fasting insulin, fasting or postchallengeglucose, the homeostasis model assessment of insulinresistance (HOMA-IR), HOMA-β, the quantitative insulin-sensitivity index (QUICKI), postchallenge insulin, or HbA1c[4, 5, 42, 46–49, 53], instead of the paragon investigationand the hyperglycemic clamp. The accuracy of proxymeasures of insulin sensitivity may vary depending onobesity status or ethnicity [54]. In addition, the majorityof studies investigating the association between 25(OH)Dand insulin metabolism have used BMI, rather than adirect measure of adiposity as a covariate in analyses[4, 5, 40, 41, 43, 51, 53, 55]. The accuracy of BMI inreflecting adiposity has been questioned, and when studieshave used both dual energy X-ray absorptiometry-(DXA-) derived total body fat and BMI in models to predict25(OH)D, only total body fat emerged as an independentpredictor [56–58]. Also, many studies have not accountedfor confounders that may be mediating associations between25(OH)D and insulin sensitivity, such as physical activityand calcium intake [9], each of which has been shown tobe significantly associated with insulin sensitivity and may,thus, corrupt data analysis. Furthermore, inherent to thenature of the cross-sectional study design, studies using thisdesign are limited in their ability to infer causation.
Insulin sensitivity may not be influenced by circulating25(OH)D in some populations. Manco et al. [59] investi-gated the associations of 25(OH)D with insulin sensitivity(determined with a euglycemic-hyperinsulinemic clamp) inmorbidly obese Caucasian women. Serum 25(OH)D wasnot associated with insulin sensitivity in these subjectseither before bariatric surgery or 5 and 10 years post-surgery. Suggesting that the often found low serum 25(OH)Dconcentrations before and after bariatric surgery do notnegatively affect insulin sensitivity. Other anthropometricfactors, such as the extreme adiposity prior to surgery andthe improved metabolic and lipid profile postsurgery, likelyhad a greater impact than 25(OH)D on insulin sensitivity.NHANES III data did not show a significant relationshipbetween 25(OH)D and HOMA-IR in African Americansdespite there are significant results in Caucasian and Mex-ican Americans [5], and Alemzadeh et al. [50] reporteda significant relationship between serum 25(OH)D andHbA1c in Caucasian but not in African Americans. Similarly,in a meta-analysis of the association between 25(OH)Dand T2DM prevalence, Pittas et al. [9] found an OR of0.36 (95% CI: 0.16–0.08) for the highest concentrations of25(OH)D compared to the lowest, although this significantOR only appeared after African Americans were excludedfrom analyses. It is unclear whether disparate ethnicities havedifferent optimal serum concentrations of 25(OH)D, and the
relationships of serum 25(OH)D with glucose homeostasisshould be examined in African Americans using directmeasures of insulin sensitivity and secretion to confirm anugatory effect of 25(OH)D.
4. Prospective Studies
Few studies have examined the predictive value of 25(OH)Don future risk of T2DM [60–62]. Forouhi et al. [61] foundbaseline 25(OH)D to be inversely associated with fastingglucose, fasting insulin, and HOMA-IR at the 10-year follow-up of the Medical Research Council Ely Prospective Study(European-origin adults), independent of baseline outcomevalues. Similarly, in the Mini-Finland Health Study, therelative risk for T2DM was 0.60 in subjects with thehighest 25(OH)D quartiles (mean 70.9 nmol/L) comparedto those in the lowest quartile (mean 22.4 nmol/L, P =.01), after adjustment for age, sex, and month of blooddraw [60]. This observation, however, was subsequentlynegated to nonsignificance (P = .05–.07) after furtheradjustments for confounders such as BMI and leisure-time exercise. A pooled, nested case-control analysis of theMini-Finland Health Study and the Finnish Mobile ClinicHealth Examination Survey revealed an 82% reduced riskof T2DM incidence in men with the highest 25(OH)Dquartiles (mean 69.11 nmol/L) versus those with the lowestquartiles (mean 22.3 nmol/L, P < .001) after adjustmentfor BMI, physical activity, smoking, and education [62].A statistically significant reduced risk was not shown inwomen. Intermediate markers of T2DM risk, such as insulinresistance, were not reported in the latter studies. The roleof serum 25(OH)D in predicting the risk for T2DM andinsulin resistance in non-Caucasian ethnic populations, suchas those with African, Asian, and Indian-descent is worthinvestigating, as these populations are at high risk for T2DMand low 25(OH)D concentrations.
5. Intervention Studies
Table 2(a) summarizes results of available vitamin D inter-vention studies on insulin secretion. Gedik and Akalin [65]first reported impairment in insulin secretion in 4 relativelyhealthy subjects presenting with vitamin D deficiency, andtheir insulin secretion was normalized after 6 months ofvitamin D supplementation. Other studies have reportedsignificant improvement in insulin secretion after variabledoses and lengths of vitamin D3 supplementation in subjectswith or at risk for T2DM [41, 66], as did a study usingalphacalcidiol as the intervention [67]. Antithetically, studiesthat have used 1, 25(OH)2D to supplement have not shownsignificant improvement in insulin secretion [42, 68]. Insofaras the pancreatic β-cell is endowed with the ability to produce1, 25(OH)2D by an autocrine mechanism, supplementationwith vitamin D3 or D2 to produce a rise in circulating25(OH)D may be superior as 25(OH)D serves as the nec-essary substrate for extra-renal 1-α-hydroxylase [90, 91]. Ofnote, there was a tendency toward a better insulin secretoryresponse in recently diagnosed (within 3 years) T2DM sub-jects supplemented with 1, 25(OH)2D [42], supporting the
4 International Journal of Endocrinology
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.9±
4.1
kg/m
2
77.4±
31.2
nm
ol/L
Fast
ing
insu
linan
dgl
uco
se(H
OM
A-I
R)
Inve
rse
asso
ciat
ion
wit
hfa
stin
ggl
uco
se,f
asti
ng
insu
lin,a
nd
HO
MA
-IR
.On
lygl
uco
seh
eld
afte
rad
just
men
tfo
ral
lco
nfo
un
ders
.
Sex,
BM
I,ex
erci
se
No
mea
sure
ofdi
etar
yin
take
;in
dire
ctm
easu
res
ofad
ipos
ity
and
insu
linse
nsi
tivi
ty
6 International Journal of Endocrinology
Ta
ble
1:C
onti
nu
ed.
Au
thor
,yea
r(r
ef)
Subj
ects
’ch
arac
teri
stic
sM
ean
seru
m25
(OH
)DM
eth
odto
dete
rmin
ein
sulin
outc
omes
Ass
ocia
tion
of25
(OH
)Dw
ith
insu
linou
tcom
eC
ovar
iate
sM
ajor
limit
atio
ns
Clif
ton
-Blig
het
al.2
008
[49]
307
preg
nan
tw
omen
ofva
riou
set
hn
icit
ies,
mea
nag
e:32
.6ye
ars
53.8±
23.9
nm
ol/L
Fast
ing
insu
linan
dgl
uco
se(H
OM
A-I
R)
Inve
rse
asso
ciat
ion
wit
hfa
stin
gin
sulin
,glu
cose
,an
dH
OM
A-I
Rbu
tn
otaf
ter
adju
stm
ent
for
con
fou
nde
rs
Age
,BM
I,et
hn
icit
y
No
mea
sure
ofdi
etar
yin
take
orph
ysic
alac
tivi
ty;i
ndi
rect
mea
sure
sof
adip
osit
yan
din
sulin
sen
siti
vity
Ale
mza
deh
etal
.200
8[4
9]
127
child
ren
(Cau
casi
an,M
exic
an,
and
Afr
ican
Am
eric
an),
mea
nag
e:13
year
s,B
MI>
95th
per
cen
tile
for
age
59.9±
23.2
nm
ol/L
Fast
ing
insu
linan
dgl
uco
se(Q
UIC
KI)
,H
bA1c
Inve
rse
asso
ciat
ion
wit
hH
bA1c
,bu
tn
otaf
ter
adju
stm
ent
for
con
fou
nde
rs
Fat
mas
s(B
IA),
age,
sex,
eth
nic
ity,
seas
on
No
mea
sure
ofdi
etar
yin
take
orph
ysic
alac
tivi
ty;i
ndi
rect
mea
sure
sof
adip
osit
yan
din
sulin
sen
siti
vity
McG
illet
al.2
008
[46]
243
adu
lts
ofva
riou
set
hn
icit
ies
(New
Zea
lan
d),m
ean
age:
47.6
year
s,m
ean
BM
I:35
.4kg/m
2
62.2±
22.7
nm
ol/L
Fast
ing
glu
cose
and
HbA
1c
Inve
rse
asso
ciat
ion
wit
hH
bA1c
and
glu
cose
(neg
ated
afte
rre
mov
alof
3ou
tlie
rs)
Sex,
age,
eth
nic
ity,
seas
on,B
MI
No
mea
sure
ofdi
etar
yin
take
orph
ysic
alac
tivi
ty;i
ndi
rect
mea
sure
sof
adip
osit
yan
din
sulin
sen
siti
vity
Ford
etal
.200
5[5
3]
8421
NH
AN
ES
III
part
icip
ants
,age
s≥
20ye
ars,
mu
ltip
leet
hn
icit
ies
74n
mol
/L(r
ange
:8.
7–22
7.9
nm
ol/L
)Fa
stin
ggl
uco
seIn
vers
eas
soci
atio
nw
ith
fast
ing
glu
cose
Age
,sex
,et
hn
icit
y,ed
uca
tion
,sm
okin
g,co
tin
ine,
chol
este
rol,
abdo
min
alob
esit
y,tr
igly
ceri
dem
ia,
low
HD
L,h
igh
bloo
dpr
essu
re
No
mea
sure
ofdi
etar
yin
take
orph
ysic
alac
tivi
ty;i
ndi
rect
mea
sure
sof
adip
osit
yan
din
sulin
sen
siti
vity
Nee
det
al.2
005
[63]
753
post
men
opau
sal
Cau
casi
an(A
ust
ralia
n)
wom
en,
mea
nag
e:63
year
s,m
ean
BM
I:26
.5kg/m
2
62±
24.3
nm
ol/L
Fast
ing
glu
cose
Inve
rse
asso
ciat
ion
wit
hfa
stin
ggl
uco
seA
ge,B
MI
No
mea
sure
ofdi
etar
yin
take
orph
ysic
alac
tivi
ty;i
ndi
rect
mea
sure
sof
adip
osit
yan
din
sulin
sen
siti
vity
Hyp
pon
enet
al.2
008
[64]
6810
Bri
tish
Cau
casi
anad
ult
s,ag
e:45
year
s,B
MI
vari
able
53.8
nm
ol/L
(men
)51
.5n
mol
/L(w
omen
)H
bA1c
Inve
rse
asso
ciat
ion
wit
hH
bA1c
Sex,
mon
th,
IGF-
1,ph
ysic
alac
tivi
ty,
smok
ing,
alco
hol
,soc
ial
clas
s,ab
dom
inal
obes
ity,
BM
I
No
mea
sure
ofdi
etar
yin
take
;in
dire
ctm
easu
res
ofad
ipos
ity
and
insu
linse
nsi
tivi
ty
International Journal of Endocrinology 7
Ta
ble
1:C
onti
nu
ed.
Au
thor
,yea
r(r
ef)
Subj
ects
’ch
arac
teri
stic
sM
ean
seru
m25
(OH
)DM
eth
odto
dete
rmin
ein
sulin
outc
omes
Ass
ocia
tion
of25
(OH
)Dw
ith
insu
linou
tcom
eC
ovar
iate
sM
ajor
limit
atio
ns
Bay
nes
etal
.199
7[4
]14
2D
utc
hm
en,m
ean
age:
75.7
year
s42±
29.1
nm
ol/L
OG
TT
Inve
rse
asso
ciat
ion
wit
hfa
stin
gin
sulin
——
Ch
iuet
al.2
004
[43]
126
glu
cose
-tol
eran
tA
sian
,Afr
ican
,C
auca
sian
,an
dM
exic
anA
mer
ican
,m
ean
age
26±
6ye
ars,
mea
nB
MI:
24.7
kg/m
2
46.9
nm
ol/L
(Asi
anA
mer
ican
),47
.3n
mol
/L(A
A),
69.4
nm
ol/L
(CA
),50
.2n
mol
/L(M
A)
OG
TT
Hyp
ergl
ycem
iccl
amp
Inve
rse
asso
ciat
ion
wit
hpo
stch
alle
nge
glu
cose
;Pos
itiv
eas
soci
atio
nw
ith
insu
linse
nsi
tivi
tyin
dex
Age
,sex
,et
hn
icit
y,B
MI,
WH
R,b
lood
pres
sure
,sea
son
No
mea
sure
ofdi
etar
yin
take
orph
ysic
alac
tivi
ty;
indi
rect
mea
sure
ofad
ipos
ity
Kam
ych
eva
etal
.200
7[4
0]
15N
orw
egia
nsu
bjec
tsw
ith
seco
nda
ryhy
perp
arat
hyro
idis
m,
mea
nag
e:62
.9ye
ars,
mea
nB
MI:
27.1
kg/m
2an
d15
sex-
,age
-,an
dB
MI-
mat
ched
con
trol
s
58.4±
15.3
nm
ol/L
(pat
ien
ts)
61.9±
18.5
nm
ol/L
(con
trol
s)
Hyp
ergl
ycem
iccl
amp
Posi
tive
asso
ciat
ion
wit
hin
sulin
sen
siti
vity
inde
xam
ong
alls
ubj
ects
Sex,
age,
BM
I
No
mea
sure
ofdi
etar
yin
take
orph
ysic
alac
tivi
ty;
indi
rect
mea
sure
ofad
ipos
ity
Lin
det
al.1
995
[51]
34C
auca
sian
men
,m
ean
age:
63ye
ars
90±
19n
mol
/LE
ugl
ycem
iccl
amp
Posi
tive
asso
ciat
ion
wit
hin
sulin
sen
siti
vity
,inv
erse
asso
ciat
ion
wit
hfa
stin
gin
sulin
Age
,BM
I,W
HR
,ser
um
crea
tin
ine
No
mea
sure
ofdi
etar
yin
take
orph
ysic
alac
tivi
ty;
indi
rect
mea
sure
ofad
ipos
ity
Lin
det
al.1
989
[52]
10D
anis
hm
enw
ith
impa
ired
glu
cose
tole
ran
ce,a
ges
60–6
3ye
ars
107±
62n
mol
/LE
ugl
ycem
iccl
amp
Posi
tive
asso
ciat
ion
wit
hin
sulin
sen
siti
vity
Seru
mca
lciu
m,
phos
phat
e,m
agn
esiu
m,a
nd
oth
erm
iner
als
No
mea
sure
ofdi
etar
yin
take
orph
ysic
alac
tivi
ty;
no
adju
stm
ent
for
adip
osit
y
Man
coet
al.2
005
[59]
116
Cau
casi
an,
mor
bidl
yob
ese
(mea
nB
MI:
48.8
kg/m
2)
wom
enbe
fore
and
afte
rba
riat
ric
surg
ery,
ages
20–3
5ye
ars
Pre
-su
rger
y:39
.2±
22.3
nm
ol/L
,5ye
ars
post
surg
ery:
27.4±
16.4
nm
ol/L
,10
year
spo
stsu
rger
y:25
.1±
13.9
nm
ol/L
Eu
glyc
emic
clam
p
No
asso
ciat
ion
wit
hin
sulin
sen
siti
vity
befo
reor
afte
rba
riat
ric
surg
ery
Trig
lyce
ride
s,fa
tm
ass,
PT
H,
seru
mca
lciu
m,
phos
phor
us,
HD
L,LD
L,to
tal
chol
este
rol
No
mea
sure
ofdi
etar
yin
take
orph
ysic
alac
tivi
ty
8 International Journal of Endocrinology
Ta
ble
2:E
ffec
tsof
vita
min
Din
terv
enti
onon
insu
linse
cret
ion
and
sen
siti
vity
/res
ista
nce
.To
conv
ertn
mol
/Lto
ng/
mL,
divi
deby
2.49
6.25
(OH
)D:2
5-hy
drox
yvit
amin
D;O
GT
T:o
ralg
luco
seto
lera
nce
test
;IV
GT
T:i
ntr
aven
ous
glu
cose
tole
ran
cete
st;T
2DM
:typ
e2
diab
etes
mel
litu
s;1,
25(O
H) 2
D3:1
,25-
dihy
drox
yvit
amin
D3
orca
lcit
riol
;HO
MA
-β:h
omeo
stas
ism
odel
asse
ssm
ent
ofβ
-cel
lfu
nct
ion
;NFG
:nor
mal
fast
ing
glu
cose
;IFG
:im
pair
edfa
stin
ggl
uco
se;H
OM
A-I
R:h
omeo
stas
ism
odel
asse
ssm
ent
ofin
sulin
resi
stan
ce;H
bA1c
:gly
cosy
late
dh
emog
lobi
n.
Au
thor
,yea
r(r
ef)
Subj
ect
char
acte
rist
ics
Bas
elin
e25
(OH
)DD
eter
min
ant
ofin
sulin
/glu
cose
met
abol
ism
Rou
te,d
ose,
and
form
ofvi
tam
inD
adm
inis
trat
ion
Len
gth
ofin
terv
enti
onFo
llow
-up
25(O
H)D
Ou
tcom
eM
ajor
limit
atio
ns
(a)
Insu
linse
cret
ion
Ged
iket
al.1
986
[65]
4vi
tam
inD
defi
cien
tw
omen
(Tu
rkey
),m
ean
age:
32.7
year
s,m
ean
BM
I:22
.8kg
/m2
—O
GT
TO
ral,
2000
IU/d
chol
ecal
cife
rol
6m
onth
s—
Incr
ease
din
sulin
area
and
insu
linog
enic
inde
x
Not
ran
dom
ized
,pl
aceb
o-co
ntr
olle
d;25
(OH
)Dn
otas
sess
ed;s
mal
lsa
mpl
esi
ze
Bou
cher
etal
.199
5[4
1]
22 glu
cose
-in
tole
ran
tE
ast
Lon
don
Asi
ans,
mea
nag
e44
.9ye
ars,
mea
nB
MI:
25.9
kg/m
2)
9.0±
4.5
nm
ol/L
OG
TT
Intr
aven
ous,
100,
000
IUch
olec
alci
fero
l
Sin
gle
dose
,fo
llow
-up
8–12
wee
ksla
ter
33.7±
18.5
nm
ol/L
Incr
ease
inpo
stch
alle
nge
insu
linan
dC
-pep
tide
Not
ran
dom
ized
,pl
aceb
o-co
ntr
olle
d
Bor
isso
va20
03[6
6]
10B
ulg
aria
nw
omen
wit
hT
2DM
,mea
nag
e:53
.8ye
ars,
mea
nB
MI:
30.9
kg/m
2
35.3±
15.1
nm
ol/L
IVG
TT
Ora
l,13
32IU
chol
ecal
cife
rol/
d1
mon
th63
.3±
31n
mol
/LIn
crea
sed
firs
t-ph
ase
insu
linse
cret
ion
Not
ran
dom
ized
,pl
aceb
o-co
ntr
olle
d;sm
alls
ampl
esi
ze
Inom
ata
etal
.198
6[6
7]14
Japa
nes
eT
2DM
subj
ects
,mea
nag
e54
.3ye
ars
—O
GT
T2μ
g/d
alph
acal
cidi
olve
rsu
spl
aceb
o3
wee
ks—
Impr
oved
insu
linse
cret
ion
(are
au
nde
rth
ecu
rve)
and
redu
ced
free
fatt
yac
idco
nce
ntr
atio
ns
25(O
H)D
not
rep
orte
d;sm
all
sam
ple
size
Zof
kova
and
Stol
ba19
90[6
8]
13vi
tam
inD
-su
ffici
ent
adu
lts,
mea
nag
e:33
.4ye
ars
(eth
nic
ity
not
repo
rted
)
—IV
GT
TO
ral,
3μ
g/d
1,25
(OH
) 2D
34
days
—N
och
ange
inin
sulin
secr
etio
n
Not
ran
dom
ized
,pl
aceb
o-co
ntr
olle
d;25
(OH
)Dn
otre
por
ted;
smal
lsa
mpl
esi
ze
International Journal of Endocrinology 9
Ta
ble
2:C
onti
nu
ed.
Au
thor
,yea
r(r
ef)
Subj
ect
char
acte
rist
ics
Bas
elin
e25
(OH
)D
Det
erm
inan
tof
insu
lin/g
luco
sem
etab
olis
m
Rou
te,d
ose,
and
form
ofvi
tam
inD ad
min
istr
atio
n
Len
gth
ofin
terv
enti
onFo
llow
-up
25(O
H)D
Ou
tcom
eM
ajor
limit
atio
ns
Orw
olle
tal
.199
4[4
2]
35ad
ult
sw
ith
T2D
M,
mea
nag
e:61
year
s,m
ean
BM
I:29
.8kg/m
2(e
thn
icit
yn
otre
port
ed)
35±
7n
mol
/LM
ealc
hal
len
ge1μ
g/d
1,25
(OH
) 2D
vers
us
plac
ebo
4da
ys—
No
chan
ge,b
ut
ten
den
cyto
war
dsbe
tter
insu
linse
cret
ion
inre
cen
tly
diag
nos
edsu
bjec
ts(w
ith
in3
year
s)
Post
inte
rven
tion
25(O
H)D
not
asse
ssed
Jord
ean
dFi
gen
sch
au20
09[6
9]
32N
orw
egia
nad
ult
sw
ith
insu
linan
dm
etfo
rmin
-con
trol
led
T2D
M,a
ges
21–7
5,m
ean
BM
I:32
.8kg/m
2(t
reat
men
t),
31.3
kg/m
2(p
lace
bo)
60±
14n
mol
/L(t
reat
men
t)58
.5±
21n
mol
/L(p
lace
bo)
Fast
ing
insu
linan
dgl
uco
se(H
OM
A-β
)an
dc-
pept
ide
40,0
00IU
chol
e-ca
lcif
erol
/wk
vers
us
plac
ebo
6m
onth
s
118.
3n
mol
/L(t
reat
men
t)57
.2n
mol
/L(p
lace
bo)
No
chan
gein
insu
linse
cret
ion
Sam
ple
size
insu
ffici
ent
base
don
pow
erca
lcu
lati
ons;
indi
rect
mea
sure
ofin
sulin
secr
etio
n
Nag
pale
tal
.200
9[7
0]
100
Asi
anIn
dian
,ce
ntr
ally
-obe
sem
ales
,ag
e≥
35ye
ars,
BM
I:26
.7kg/m
2
(tre
atm
ent)
,26
kg/m
(pla
cebo
)
36.5±
14.6
nm
ol/L
(tre
atm
ent)
30±
12.5
nm
ol/L
(pla
cebo
)
Fast
ing
insu
linan
dgl
uco
se(H
OM
A-β
)
Ora
l,3
dose
sof
120,
000
IUch
olec
alci
fero
lfo
rtn
igh
tly
vers
us
plac
ebo
6w
eeks
71.6
nm
ol/L
(tre
atm
ent)
30.6
nm
ol/L
(pla
cebo
)
No
chan
gein
insu
linse
cret
ion
Indi
rect
mea
sure
ofin
sulin
secr
etio
n
(b)
Insu
linse
nsi
tivi
ty
De
Boe
ret
al.2
008
[71]
795–
866
post
men
opau
sal
wom
enof
vari
ous
eth
nic
itie
s,ag
es50
–79
year
s
43.7
nm
ol/L
(med
ian
)
Fast
ing
insu
linan
dgl
uco
se(H
OM
A-I
R)
Ora
l,40
0IU
chol
ecal
cife
rol+
1000
mg
calc
ium
vers
us
plac
ebo
6ye
ars
—
No
chan
gein
fast
ing
glu
cose
,in
sulin
,or
HO
MA
-IR
;no
chan
gein
diab
etes
risk
Post
inte
rven
tion
25(O
H)D
not
rep
orte
d;in
dire
ctm
easu
reof
insu
linse
nsi
tivi
ty
Nila
san
dC
hri
stia
nse
n19
84[7
2]
151
Dan
ish
post
men
opau
sal
wom
en,a
ges
45–5
4ye
ars
—B
lood
glu
cose
Ora
l,20
00IU
/dch
olec
alci
fero
l+50
0m
g/d
calc
ium
vers
us
0.25
μg/
dal
phac
alci
diol
+50
0m
g/d
calc
ium
vers
us
plac
ebo
2ye
ars
—N
och
ange
inbl
ood
glu
cose
25(O
H)D
not
rep
orte
d;in
dire
ctm
easu
reof
insu
linse
nsi
tivi
ty
10 International Journal of Endocrinology
Ta
ble
2:C
onti
nu
ed.
Au
thor
,yea
r(r
ef)
Subj
ect
char
acte
rist
ics
Bas
elin
e25
(OH
)D
Det
erm
inan
tof
insu
lin/g
luco
sem
etab
olis
m
Rou
te,d
ose,
and
form
ofvi
tam
inD ad
min
istr
atio
n
Len
gth
ofin
terv
enti
onFo
llow
-up
25(O
H)D
Ou
tcom
eM
ajor
limit
atio
ns
Jord
ean
dFi
gen
sch
au20
09[6
9]
32N
orw
egia
nad
ult
sw
ith
insu
linan
dm
etfo
rmin
-con
trol
led
T2D
M,a
ges
21–7
5,m
ean
BM
I:32
.8kg/m
2
(tre
atm
ent)
,31
.3kg/m
2(p
lace
bo)
60±
14n
mol
/L(t
reat
men
t)58
.5±
21n
mol
/L(p
lace
bo)
Fast
ing
insu
linan
dgl
uco
se(H
OM
A-I
R)
40,0
00IU
chol
e-ca
lcif
erol
/wk
vers
us
plac
ebo
6m
onth
s
118.
3n
mol
/L(t
reat
men
t)57
.2n
mol
/L(p
lace
bo)
No
chan
gein
fast
ing
glu
cose
,in
sulin
,H
OM
A-I
R,o
rH
bA1c
Sam
ple
size
insu
ffici
ent
base
don
pow
erca
lcu
lati
ons;
indi
rect
mea
sure
ofin
sulin
sen
siti
vity
Bor
isso
vaet
al.2
003
[66]
10B
ulg
aria
nw
omen
wit
hT
2DM
,mea
nag
e:53
.8ye
ars,
mea
nB
MI:
30.9
kg/m
2
35.3±
15.1
nm
ol/L
Fast
ing
insu
linan
dgl
uco
se(H
OM
A-I
R)
Ora
l,13
32IU
chol
ecal
cife
rol/
d1
mon
th63
.3±
31.0
nm
ol/L
Non
sign
ifica
nt
decr
ease
inH
OM
A-I
R
Not
ran
dom
ized
,pl
aceb
o-co
ntr
olle
d;in
dire
ctm
easu
reof
insu
linse
nsi
tivi
ty
Pit
tas
etal
.200
7[7
3]
314
Cau
casi
anA
mer
ican
adu
lts,
mea
nag
e:71
.2ye
ars,
mea
nB
MI:
26.7
kg/m
2
Trea
tmen
t:81
.4±
3.7
nm
ol/L
(NFG
),71
.2±
5.2
nm
ol/L
(IFG
);P
lace
bo:
70.6±
2.8
nm
ol/L
(NFG
),81
.2±
4.7
(IFG
)
Fast
ing
insu
linan
dgl
uco
se(H
OM
A-I
R)
Ora
l,70
0IU
chol
ecal
cife
rol+
500
mg
calc
ium
vers
us
plac
ebo
3ye
ars
Trea
tmen
t:11
1n
mol
/L(N
FG),
102.
4n
mol
/L(I
FG);
Pla
cebo
:69
.7n
mol
/L(N
FG),
73.4
nm
ol/L
(IFG
)
Impr
oved
HO
MA
-IR
insu
bjec
tsw
ith
IFG
Indi
rect
mea
sure
ofin
sulin
sen
siti
vity
Nag
pale
tal
.200
9[7
0]
100
Asi
anIn
dian
,ce
ntr
ally
-obe
sem
ales
,ag
e≥
35ye
ars,
BM
I:26
.7kg/m
(tre
atm
ent)
,26
kg/m
2
(pla
cebo
)
36.5±
14.6
nm
ol/L
(tre
atm
ent)
30±
12.5
nm
ol/L
(pla
cebo
)
OG
TT
Ora
l,3
dose
sof
120,
000
IUch
olec
alci
fero
lfo
rtn
igh
tly
vers
us
plac
ebo
6w
eeks
71.6
nm
ol/L
(tre
atm
ent)
30.6
nm
ol/L
(pla
cebo
)
Incr
ease
din
sulin
sen
siti
vity
(3-h
our
oral
glu
cose
insu
linse
nsi
tivi
tyin
dex)
;n
och
ange
inin
dice
sde
rive
dfr
omfa
stin
ggl
uco
sean
din
sulin
valu
es
Indi
rect
mea
sure
ofin
sulin
sen
siti
vity
International Journal of Endocrinology 11
Ta
ble
2:C
onti
nu
ed.
Au
thor
,yea
r(r
ef)
Subj
ect
char
acte
rist
ics
Bas
elin
e25
(OH
)D
Det
erm
inan
tof
insu
lin/g
luco
sem
etab
olis
m
Rou
te,d
ose,
and
form
ofvi
tam
inD
adm
inis
trat
ion
Len
gth
ofin
terv
enti
onFo
llow
-up
25(O
H)D
Ou
tcom
eM
ajor
limit
atio
ns
Taie
tal
.200
8[7
4]
33pr
imar
ilyC
auca
sian
adu
lts,
mea
nag
e55
year
s,m
ean
BM
I:24
.1kg/m
2
39.9±
8.6
nm
ol/L
OG
TT,
fast
ing
insu
linan
dgl
uco
se
Ora
l,2
dose
sof
100,
000
IUch
olec
alci
fero
l
1m
onth
(Fol
low
-up
2w
eeks
afte
r2n
ddo
se)
90.3±
4.3
nm
ol/L
No
chan
gein
fast
ing
glu
cose
,po
stch
alle
nge
insu
lin,
Avi
gnon
’sin
sulin
sen
siti
vity
,Q
UIC
KI,
orH
OM
A-I
R
Not
ran
dom
ized
,pl
aceb
o-co
ntr
olle
d;in
dire
ctm
easu
res
ofin
sulin
sen
siti
vity
Nyo
mba
etal
.198
6[7
5]
10B
elgi
ansu
bjec
tsw
ith
epile
psy
(mea
nag
e:56
year
s),a
nd
15el
derl
ysu
bjec
ts(m
ean
age:
78ye
ars)
17±
9.5
nm
ol/L
;19
±19
.4n
mol
/LO
GT
TO
ral,
25(O
H)D
load
ing
dose
of20
0μ
g+
10μ
g/d
2w
eeks
36±
6n
mol
/L35±
3n
mol
/L
Dec
reas
ein
fast
ing
insu
linan
dpo
stch
alle
nge
insu
linon
lyin
subj
ects
wit
hep
ileps
y
Not
ran
dom
ized
,pl
aceb
o-co
ntr
olle
d;sm
all
sam
ple
size
;in
dire
ctm
easu
reof
insu
linse
nsi
tivi
ty
Lin
det
al.1
989
[52]
14n
orm
al-w
eigh
t,D
anis
hm
enw
ith
impa
ired
glu
cose
tole
ran
ce,a
ges
60–6
3ye
ars
—IV
GT
TO
ral,
2μ
g/d
alph
acal
cidi
ol18
mon
ths
78±
43n
mol
/LN
och
ange
inin
sulin
sen
siti
vity
Not
ran
dom
ized
,pl
aceb
o-co
ntr
olle
d;ba
selin
e25
(OH
)Dn
otas
sess
ed;s
mal
lsa
mpl
esi
ze
Lju
ngh
alle
tal
.198
7[7
6]
65vi
tam
inD
suffi
cien
t,C
auca
sian
men
wit
him
pair
edgl
uco
seto
lera
nce
,ag
es61
–65
year
s,m
ean
BM
I:27
.5kg/m
2
(tre
atm
ent)
,28
.2kg/m
2
(pla
cebo
)
92.4±
23.5
nm
ol/L
(tre
atm
ent)
97.3
±72
.4n
mol
/L(p
lace
bo)
IVG
TT
Ora
l,0.
75μ
g/d
alph
acal
cidi
olve
rsu
spl
aceb
o3
mon
ths
104.
8±
20.7
nm
ol/L
(tre
atm
ent)
134.
8±
119.
8n
mol
/L(p
lace
bo)
No
chan
gein
insu
linse
nsi
tivi
ty—
Flis
eret
al.1
997
[77]
18h
ealt
hyG
erm
anm
ales
,mea
nag
e:26
year
s,m
ean
BM
I:22
.4kg/m
2
—E
ugl
ycem
iccl
amp
Ora
l,1.
5μ
g1,
25(O
H)D
/dve
rsu
spl
aceb
o7
days
—N
och
ange
inin
sulin
sen
siti
vity
25(O
H)D
not
rep
orte
d;sm
all
sam
ple
size
12 International Journal of Endocrinology
Ta
ble
3:A
ssoc
iati
ons
ofV
DR
poly
mor
phis
ms
wit
hin
sulin
secr
etio
n,
insu
linre
sist
ance
,an
dT
2DM
.V
DR
:vi
tam
inD
rece
ptor
;T
2DM
:ty
pe
2di
abet
esm
ellit
us;
OG
TT
:or
algl
uco
seto
lera
nce
test
;HD
L-C
:hig
hde
nsi
tylip
opro
tein
chol
este
rol;
HO
MA
-IR
:hom
eost
asis
mod
elas
sess
men
tofi
nsu
linre
sist
ance
;AU
C:a
rea
un
der
the
curv
e;W
HR
,wai
st-t
o-h
ipra
tio;
HO
MA
-β:
hom
eost
asis
mod
elas
sess
men
tof
β-c
ellf
un
ctio
n;L
DL-
C:l
owde
nsi
tylip
opro
tein
chol
este
rol;
OR
:odd
sra
tio;
HbA
1c:g
lyco
syla
ted
hem
oglo
bin
.
Au
thor
,yea
r(r
ef)
Subj
ect
Ch
arac
teri
stic
sV
DR
gen
ein
vest
igat
edM
easu
rem
ent
ofin
sulin
met
abol
ism
Mai
nou
tcom
eN
otes
(a)
Insu
linSe
cret
ion
Spee
ret
al.[
78]
2001
49C
auca
sian
sw
ith
T2D
M,2
9su
bjec
tsw
ith
obes
ity
but
no
T2D
M,
138
hea
lthy
con
trol
s
Bsm
IFa
stin
gan
dpo
stpr
andi
alC
-pep
tide
Hig
her
post
pran
dial
C-p
epti
dein
BB
gen
otyp
eam
ong
T2D
Man
dob
ese
subj
ects
Hig
hes
tp
ostp
ran
dial
C-p
epti
dein
subj
ects
wit
hB
Ban
des
trog
enre
cept
orpo
lym
orph
ism
Hit
man
etal
.199
8[7
9]17
1B
angl
ades
hiA
sian
sTa
qI,B
smI,
Apa
IO
GT
TH
igh
erin
sulin
secr
etio
nin
dex
inA
Age
not
ype
No
gen
otyp
edi
ffer
ence
sin
32,3
3sp
litpr
oin
sulin
Ogu
nko
lade
etal
.200
2[8
0]14
3h
ealt
hyB
angl
ades
hi
Asi
ans
TaqI
,Bsm
I,Fo
kl,A
paI
OG
TT
TaqI
gen
otyp
ein
depe
nde
ntl
ypr
edic
ted
insu
linse
cret
ion
inde
x;tt
gen
otyp
esh
adgr
eate
stin
sulin
secr
etio
nin
dex
—
(b)
Insu
linre
sist
ance
Filu
set
al.2
008
[81]
176
Polis
hm
enFo
kl,B
smI
Fast
ing
insu
linan
dgl
uco
se
FF/F
fgen
otyp
eas
soci
ated
wit
hgr
eate
rfa
stin
gin
sulin
than
ff
BB
gen
otyp
eas
soci
ated
wit
hgr
eate
rB
MI
and
wai
stci
rcu
mfe
ren
ce;F
Fge
not
ype
asso
ciat
edw
ith
low
erH
DL-
C
Ch
iuet
al.2
001
[82]
49gl
uco
se-t
oler
ant
Cau
casi
anA
mer
ican
sFo
kI
Fast
ing
insu
linan
dgl
uco
se
ff/F
fgen
otyp
esh
adh
igh
erfa
stin
gin
sulin
and
HO
MA
-IR
than
FF;
FokI
gen
otyp
ein
depe
nde
ntl
ypr
edic
ted
HO
MA
-IR
ff/F
fgen
otyp
esh
adh
igh
erp
ostc
hal
len
gein
sulin
AU
C;h
igh
erW
HR
inff
/Ffg
enot
ypes
;H
OM
A-β
did
not
diff
erbe
twee
nge
not
ypes
Oh
and
Bar
ret-
Con
nor
2002
[83]
1545
Cau
casi
anA
mer
ican
sTa
qI,B
smI,
Apa
IFa
stin
gin
sulin
and
glu
cose
Fast
ing
glu
cose
hig
her
inaa
gen
otyp
e(A
paI)
;H
OM
A-I
Rh
igh
erin
BB
gen
otyp
e(B
smI)
Tren
dto
war
dsh
igh
eraa
freq
uen
cyin
subj
ects
wit
hT
2DM
vers
us
thos
ew
ith
out
(P=.0
58)
Ort
lepp
etal
.200
3[8
4]15
39h
ealt
hy,m
ale
Ger
man
sold
iers
Bsm
IFa
stin
ggl
uco
se
Fast
ing
glu
cose
inde
pen
den
tly
asso
ciat
edw
ith
Bsm
IV
DR
(BB
gen
otyp
e)on
lyin
subj
ects
wit
hlo
wph
ysic
alac
tivi
ty
—
International Journal of Endocrinology 13
Ta
ble
3:C
onti
nu
ed.
Au
thor
,yea
r(r
ef)
Subj
ect
Ch
arac
teri
stic
sV
DR
gen
ein
vest
igat
edM
easu
rem
ent
ofin
sulin
met
abol
ism
Mai
nou
tcom
eN
otes
Twor
owsk
a-B
ardi
nsk
aet
al.2
008
[85]
350
hea
lthy
,Pol
ish
post
men
opau
salw
omen
Bsm
IFa
stin
gin
sulin
and
glu
cose
No
diff
eren
cein
fast
ing
insu
lin,g
luco
se,o
rfa
stin
gin
sulin
resi
stan
cein
dex
betw
een
gen
otyp
es
Gre
ater
LDL-
Cin
BB
gen
otyp
eam
ong
thos
ew
ith
cen
tral
obes
ity
(c)
Typ
e2
Dia
bete
s
Ort
lepp
etal
.200
3[8
4]29
3G
erm
anad
ult
sat
risk
for
coro
nar
yar
tery
dise
ase
Bsm
I—
Hig
her
T2D
Mpr
eval
ence
inB
Bve
rsu
sbb
gen
otyp
e;O
Rof
3.64
(CI:
1.53
–8.5
5)
Hig
her
coro
nar
yar
tery
dise
ase
prev
alen
cein
BB
gen
otyp
e
Dilm
ecet
al.2
009
[86]
72Tu
rkis
had
ult
sw
ith
T2D
Mve
rsu
s16
9h
ealt
hyco
ntr
ols
TaqI
,Apa
I—
No
stat
isti
cald
iffer
ence
inge
not
ype
freq
uen
cies
amon
gca
ses
vers
us
con
trol
s
No
diff
eren
cein
fast
ing
plas
ma
glu
cose
orH
bA1c
amon
gsu
bjec
tsw
ith
VD
Rpo
lym
orph
ism
sve
rsu
sth
ose
wit
hou
t
Mal
ecki
etal
.200
3[8
7]30
8Po
lish
adu
lts
wit
hT
2DM
vers
us
240
con
trol
sTa
qI,B
smI,
Fokl
,Apa
I—
No
stat
isti
cald
iffer
ence
inge
not
ype
freq
uen
cies
amon
gca
ses
vers
us
con
trol
s
—
Ye20
01et
al.[
88]
309
Cau
casi
ans
(Fre
nch
)w
ith
T2D
Mve
rsu
s14
3co
ntr
ols
TaqI
,Bsm
I,Tr
u9I,
Apa
I—
No
stat
isti
cald
iffer
ence
inge
not
ype
freq
uen
cies
amon
gca
ses
vers
us
con
trol
s
TT
(Taq
I)an
dbb
(Bsm
I)ge
not
ypes
asso
ciat
edw
ith
BM
Iam
ong
subj
ects
wit
hea
rly
onse
tT
2DM
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14 International Journal of Endocrinology
previous notion that vitamin D supplementation may not beuseful once β-cells are exhausted. Studies using HOMA-β, anindirect index of β-cell function derived from fasting valuesof glucose and insulin, as the insulin secretory outcome, havelikewise not shown significant changes in insulin secretion[69, 70]. The majority of available studies, regardless of apositive or negative outcome, are limited by their lack ofa randomized, placebo-controlled design [41, 65, 66, 68],and/or nonreporting of serum 25(OH)D to ensure attain-ment of sufficient vitamin D concentrations [42, 65, 67, 68].
With regards to insulin sensitivity, studies in subjectswith chronic renal disease have shown intravenous vitaminD administration to improve insulin sensitivity [92, 93].Human studies in relatively healthy populations withoutrenal disease have been inconsistent, particularly those usingindirect indices of insulin sensitivity (Table 2(b)). Studiesusing fasting values of glucose and insulin (e.g., HOMA-IR), which primarily reflect hepatic insulin sensitivity, havegenerally not shown significant improvements in insulin sen-sitivity after vitamin D intervention [66, 69, 71, 72]. Posthocanalyses, however, from a randomized placebo-controlledtrial revealed improved HOMA-IR after 3 years of 700 IUvitamin D3 plus 500 mg calcium citrate daily supplemen-tation in Caucasian subjects with impaired fasting glucose,but not normal fasting glucose [73]. This study could notdiscriminate the relative influences of vitamin D over cal-cium. Vitamin D supplementation is more likely to influenceperipheral insulin sensitivity, as shown by Nagpal et al.[70], whereby 3 doses of 120000 IU vitamin D3 fortnightlyversus placebo showed significant improvements in a 3-hour OGTT-derived insulin sensitivity index, but not indicesderived from fasting values, in Asian-Indian men. Additionalstudies that have used OGTT-derived indices are limited byrelatively small sample sizes, lack of randomized placebo-controlled design, and short-term supplementation [74, 75].
The few studies investigating vitamin D effects on directlymeasured insulin sensitivity using the euglycemic clamptechnique or intravenous glucose tolerance testing (IVGTT)have not shown improvements in insulin sensitivity withsupplementation [52, 76, 77] (Table 2(b)). The null effectsin 2 studies [52, 76] may, at least in part, be explainedby the vitamin D sufficiency of the subject populations. Assuggested by Jorde and Figenschau [69], supplementation ofvitamin D-sufficient populations may not incur additionalglucose regulating effects. In addition, all studies used theactive form of vitamin D (1, 25(OH)2D) or an analog of thishormone to supplement, and the increase in 25(OH)D wasminimal in one study [76] and unable to be evaluated in theothers [52, 77]. It is plausible that results would have differedin vitamin D deficient subjects supplemented with cholecal-ciferol or ergocalciferol to produce a rise in serum 25(OH)D.
There is no universally accepted definition for theoptimal serum concentration of 25(OH) D, thus compli-cating vitamin D supplementation trials. For prevention ofrickets or osteomalacia, a serum 25(OH)D concentration of25 mmol/L (10 ng/mL) is considered sufficient; yet to preventosteoporosis and maximize calcium absorption a concen-tration of 75 nmol/L (30 ng/mL) is suggested [1]. VitaminD deficiency is defined as serum 25(OH)D < 50 nmol/L
(<20 ng/mL) [94]. As summarized by Pepper et al. [94],there is also no universally accepted standard regimen for thecorrection of vitamin D deficiency. It is also unknown whatlength of intervention or duration of follow-up once vitaminD is replete is required to appreciate the effects of vitaminD on insulin sensitivity and secretion. Further confoundingconclusions are that the reported vitamin D interventionstudies are heterogeneous in their research design and length,form, and dosage of vitamin D supplementation. Many alsolack the demonstration of achieving a therapeutic level ofvitamin D. Additionally, the majority of intervention trialshave been performed in Caucasian subjects. There is a needfor more intervention studies in subjects of non-Caucasiandescent.
6. Vitamin D Receptor Polymorphisms
Polymorphisms in the VDR gene, namely, TaqI, BsmI, ApaI,and FokI, have been identified and may influence insulinsecretion and sensitivity, although relatively few studieshave been conducted and, results have varied (Table 3).Among a cohort of Bangladeshi Asians, the ApaI VDR genepolymorphism was associated with insulin secretion index[79]; however reanalysis of this cohort revealed TaqI to bethe independent predictor of the insulin secretion index [80].In contrast, the BsmI VDR gene polymorphism was asso-ciated with postprandial C-peptide concentrations amongCaucasian Hungarians [78]. The ApaI and BsmI VDR genepolymorphisms were also shown to be associated with fastingglucose and HOMA-IR, respectively, among a large cohortof Caucasian Americans [83], and BsmI was associated withfasting glucose in a large cohort of Germans [84]. Thelinkage disequilibrium that exists between the TaqI, BsmIand ApaI polymorphisms may partly explain the varyingresults [80, 88]. The FokI VDR polymorphism was alsoassociated with indices of insulin resistance among Polishmen [81] and among Caucasian Americans [82], althoughthe studies contradicted each other regarding the specificgenotype associated with insulin resistance (FF versus ff).
Despite the support for a VDR gene polymorphisminfluencing insulin secretion and resistance, case-controlstudies, in general, have not found statistical differencesin VDR gene polymorphism frequencies among subjectswith T2DM versus controls [86–89]. Ortlepp et al. [84]did, however, report a higher prevalence of T2DM amongGerman subjects with the BB genotype of the BsmI VDR genepolymorphism compared to those with the bb genotype. Theassociation between VDR gene polymorphisms and insulinsecretion and sensitivity should be confirmed using directmethods, such as IVGTT or clamp studies. In addition, theseassociations should be investigated in African Americans andother non-Caucasian ethnicities.
7. Vitamin D and the Insulin-Like GrowthFactor (IGF) System
There is some evidence to suggest that vitamin D statusmay interact with the IGF system to influence glucose
International Journal of Endocrinology 15
homeostasis [61, 64]. Analysis of the 1958 British BirthCohort revealed a lower risk for metabolic syndrome insubjects with the highest tertiles of both serum 25(OH)D andIGF-1 concentrations, although there was no statistical inter-action between 25(OH)D and IGF-1 in any of the individualcomponents of the metabolic syndrome and HbA1c [64].In a prospective study, Forouhi et al. [61] found an inverserelationship between baseline 25(OH)D and 10-year follow-up fasting and 2-hour glucose only in subjects with baselineIGF binding protein-1 (IGFBP-1) concentrations below themedian. An interaction between vitamin D and the IGF axisto influence glucose homeostasis seems conceivable as eachhas been shown to directly enhance the other [95, 96].
8. Summary and Conclusion
There is mechanistic support that vitamin D may influenceboth insulin secretion and insulin sensitivity and subse-quently T2DM incidence. In general, cross-sectional andprospective studies support the role of vitamin D in theprevention of T2DM. Despite the inherent limitations ofcross-sectional and prospective study designs, these typesof study designs are useful for preliminary research tosuggest which specific populations may respond to vitaminD interventions. Future cross-sectional and prospectivestudies should focus on non-Caucasian ethnicities witha high risk of both T2DM and vitamin D deficiency.Cross-sectional and prospective studies should account forpotential confounders of the vitamin D-T2DM relationship,including age, ethnicity, obesity, physical activity, and diet, aswell as use direct measures of adiposity, insulin sensitivity,and insulin secretion. Results of vitamin D interventionstudies are equivocal; yet many studies are flawed by lackof randomized, placebo-controlled design, use of indirectmeasures of insulin secretion and sensitivity, small samplesize, and inability to show relevant increases in serum25(OH)D. The lack of protocol for optimal dosing of vitaminD and lack of definition for optimal therapeutic concentra-tions of serum 25(OH)D further inhibit the application ofvitamin D intervention trials. One could also postulate thatinteractions with the IGF system, VDR gene polymorphisms,or other individual genotypes of subjects might becloudthe conflicting conclusions. It is plausible that vitamin Dhas a role in improving insulin secretion and sensitivity,but may not be effective in insulinopenic situations, or thatbeyond a certain concentration of vitamin D level, furthersupplementation of vitamin D sufficient subjects may not beof value in improving glucose homeostasis.
Based on a review of literature, a true, direct link betweenvitamin D and risk for T2DM has not yet been conclusivelyestablished, although several unknowns remain. It is notknown what the optimal concentration of vitamin D forglucose homeostasis should be and what duration of follow-up is necessary to appreciate the effects of vitamin D oninsulin secretion and sensitivity. It is also unclear if a serum25(OH)D threshold exists for which vitamin D does notincur additional benefits for glucose homeostasis, if vitaminD influences are ethnic-specific, or if there are differentoptimal thresholds for different ethnic groups. Large, well-
controlled, randomized studies are required to clarify theseimportant unknowns and define the relationship betweenvitamin D status and glucose homeostasis.
Acknowledgments
Jessica Alvarez is supported by the Alabama Louis StokesAlliance for Minority Participation and UAB Center for Clin-ical and Translational Science (NIH no. IUL1RR025777).Ambika Ashraf is supported from funds from Children’sCenter for Research and Innovation (CCRI Grants), Chil-dren’s Hospital, Birmingham, AL.
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