Review Article - Hindawimuscle expression of VDR declines with age [29], as does insulin sensitivity. Vitamin D deficiency may influence its effects on insulin secretion and sensitivity

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, [email protected]

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


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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


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


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


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


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


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


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


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

—


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

Bou

llu-S

anch

iset

al.1

999

[89]

89m

igra

nt

Indi

ans

ofG

uad

elou

pew

ith

T2D

Mve

rsu

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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


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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Review Article - Hindawimuscle expression of VDR declines with age [29], as does insulin sensitivity. Vitamin D deficiency may influence its effects on insulin secretion and sensitivity