Association of serum 25-hydroxyvitamin D withtype 2 diabetes and markers of insulin resistance ina general older population in Finland

Anne-Riina HurskainenJyrki K. Virtanen*Tomi-Pekka TuomainenTarja NurmiSari Voutilainen

The Institute of Public Health andClinical Nutrition,University of Eastern Finland,PO Box 1627,70211 Kuopio, Finland

*Correspondence to:Jyrki K. Virtanen, The Institute ofPublic Health and Clinical Nutrition,University of Eastern Finland,PO Box 1627, 70211 Kuopio, Finland.E-mail: jyrki.virtanen@uef.fi

Abstract

Background Vitamin D insufficiency and type 2 diabetes are both commonin Finland, and low vitamin D status has been suggested as a risk factorfor type 2 diabetes. Our aim was to study the associations between serum25-hydroxyvitamin D [25(OH)D], a marker of vitamin D status, and glucosehomeostasis and type 2 diabetes in a general population sample in EasternFinland.

Methods Cross-sectional analysis in the Kuopio Ischaemic Heart Disease RiskFactor Study. A total of 850 men and 906 women, aged 53–73 years, wereanalysed. Relative risk (RR) of prevalent diabetes was estimated as odds ratiosby logistic regression. Associations between serum 25(OH)D and markers ofimpaired glucose metabolism in tertiles of serum 25(OH)D concentration wereassessed by linear regression.

Results The mean serum 25(OH)D concentration was 43.4 nmol/L (SD 17.6,range 8.5–122.8 nmol/L) in the study population. Serum 25(OH)D concentra-tion <50 nmol/L were observed in 65.5% of the participants. Serum 25(OH)Dwas inversely associated with fasting serum insulin, fasting blood glucose andoral glucose tolerance test (OGTT) 2-h glucose levels after adjustment for age,gender and examination year. Association with the OGTT 2-h glucose remainedstatistically significant after multivariate adjustments. The RR (95% confidenceinterval) for type 2 diabetes in tertiles of serum 25(OH)D were 1, 1.26 (0.86,1.85) and 1.44 (0.96, 2.15) after multivariate adjustments (p for trend=0.08).

Conclusions Our results suggest that low serum 25(OH)D is associated with im-paired glucose and insulin metabolism. Copyright © 2012 John Wiley & Sons, Ltd.

Keywords vitamin D; calcidiol; type 2 diabetes; glucose homeostasis; insulinresistance

Introduction

Vitamin D deficiency is a worldwide health problem, and recently, vitaminD deficiency has been linked to many chronic diseases, such as diabetes,cardiovascular disease (CVD) and cancer [1]. Several cross-sectional studieshave also reported an inverse association between vitamin D and impairedglucose tolerance, but some studies failed to show such an association [2].Observational studies have shown that glycemic control in patients with type2 diabetes has a seasonal variation, being worse in the winter [3]. This varia-tion may in part be explained by seasonal fluctuations in concentrations of

RESEARCH ARTICLE

Received: 22 November 2011Revised: 23 January 2012Accepted: 23 January 2012

Copyright © 2012 John Wiley & Sons, Ltd.

DIABETES/METABOLISM RESEARCH AND REVIEWSDiabetes Metab Res Rev 2012; 28: 418–423.Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/dmrr.2286

serum 25-hydroxyvitamin D [25(OH)D], a marker ofvitamin D status of the body. However, findings fromobservational studies have not been consistent regardingthe association between lower serum 25(OH)D concentra-tion and type 2 diabetes or insulin resistance [4]. Somerandomized trials have reported that in participantswith impaired fasting glucose at baseline, combined dailyvitamin D3 and calcium supplementation attenuated theincrease in fasting glycemia [4,5]. Most trials performedwith participants with normal glucose tolerance at baselinereported no effect of vitamin D supplementation on fastingplasma glucose level [4,5].

The major source of vitamin D for most humans is expo-sure to ultraviolet B-radiation of the sun [1]. However,several factors influence cutaneous vitamin D production,such as latitude, season, time of day and aging [1].Because of the seasonal variation, the serum levels fallsignificantly in the winter and early spring in the northernlatitudes. This is evident also in our Kuopio IschaemicHeart Disease Risk Factor (KIHD) study population [6].In the diet, there are only few foods, mainly fish, wherevitamin D is naturally found in significant amounts.Although some foods, such as liquid milk and milkproducts, and margarine, are fortified with vitamin D inFinland, a large proportion still has insufficient serum 25(OH)D levels (<50 nmol/L) [6,7].

The aim of our study was to evaluate the associationbetween serum 25(OH)D and risk of type 2 diabetes andmarkers of glucose homeostasis in a general aging popula-tion in Finland.

Materials and methods

The KIHD study is an ongoing population-based studydesigned to investigate risk factors for CVD and otherchronic diseases in middle-aged men and women inEastern Finland [8]. The study protocol was approved bythe Research Ethics committee of the University ofKuopio. All subjects gave their written informed consent.The baseline examinations of the KIHD study wereconducted between 1984 and 1989 to a random sampleof men living in the city of Kuopio and neighbouring ruralcommunities. A total of 2682 men who were 42, 48, 54 or60 years old at baseline (82.9% of those eligible) wererecruited in two cohorts. The first cohort consisted of1166 men who were 54 years old, enrolled between1984 and 1986, and the second cohort included 1516men who were 42, 48, 54 or 60 years old, enrolled be-tween 1986 and 1989. During the years 1998–2001, allmen from the second cohort were invited to the 11-yearre-examinations of the study, and 854 men (95.0% ofthose eligible) participated. The 11-year examinationswere also the baseline for 920 post-menopausalwomen (78.4% of those eligible) from the same area,aged 53–73 years. These 854 men and 920 women wereused as the study population, and the 11-year examina-tions was the baseline in the current study. We excluded

those without data on serum 25(OH)D (n=18), leaving850 men and 906 women, a total of 1756 participantsfor the analyses of prevalent diabetes. Data on blood glu-cose, serum insulin and OGTT 2-h glucose were availablefor 702 men and 798 women without diabetes. During2005–2008, all eligible men from the first and secondcohorts from 1984 to 1989, and all eligible women fromthe 11-year examinations were invited to the 20-yearre-examinations, and 1241 men (79.7%) and 634 women(81.0%) participated. For the analyses of incident diabetesbetween the 11-year and 20-year examinations, weincluded 503 men and 579 women who did not havediabetes at the 11-year examinations and for whom dataon diabetes status at the 20-year examinations was available.

The subjects gave fasting blood samples between 8:00and 10:00 in the morning. They were instructed to abstainfrom ingesting alcohol for 3 days and from smokingand eating for 12 h prior to giving sample. Detaileddescriptions of the assessment of lipids and lipoproteins,serum fatty acids, assessment of medical history andmedications, family history of diseases, smoking, alcoholconsumption and blood pressure have been pub-lished [9,10]. Education was assessed in years by usingself-administrated questionnaire. Physical activity wasassessed using the KIHD 12-Month Leisure-Time PhysicalActivity Questionnaire [11]. Body mass index (BMI) wascomputed as the ratio of weight in kilogrammes to thesquare of height in metres. Dietary intake of foods andnutrients was assessed at the time of blood sampling using4-day food recording [12].

Blood glucose was measured by glucose dehydrogenasemethod (Merck, Darmstadt, FRG) after precipitation ofproteins by trichloro acetic acid. The between-batchcoefficient of variation was 2.4% for Seronom and 3.6%for Panthonorm control specimens. Insulin was measuredwith a radioimmunoassay kit (Novo Nordisk, Denmark)from the serum samples stored at �80 �C. A 2-h oralglucose tolerance test (OGTT) was performed with a75-g glucose load after at least 12 h of overnight fasting.Blood glucose was measured from fresh whole blood priorto, and 2 hours after, the glucose load by using theglucose dehyrogenase method, after precipitation ofproteins with trichloroacetic acid. Diabetes was definedas fasting blood glucose of ≥6.1 mmol/L or OGTT2-h blood glucose ≥10.0 mmol/L or a clinical diagnosisof diabetes with either dietary, oral or insulin treatment.

Blood samples for 25(OH)D analysis were taken intoserum gel tubes at common laboratory conditions. After30 min time for clotting, serum was separated and storedat �70 �C for 9–11 years prior to 25(OH)D measurement.Serum 25(OH)D3 and 25(OH)D2 concentrations weredetermined with a high-performance liquid chromatogra-phy (Shimadzu, Kyoto, Japan) by using a diode arraydetector (Beckman, CA, USA) as previously described [6].The limit of detection for both 25(OH)D3 and D2 was1.5 nmol/L, and the limit of quantification was 5 nmol/L.The few concentrations of 25-hydroxyvitamin D2 detectedwere mainly below the quantification limit. Therefore,results for 25-hydroxyvitamin D3 are reported only.

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Intra-assay and inter-assay variation was monitored byanalysing in each assay duplicates of two controlsamples, a self-made serum pool 1 or 2, and a vitamin Dcontrol serum (Chromsystems GmbH, Germany). Inter-assay variation for serum pool 1 (53 nmol/L) was 15% andfor vitamin D control serum (68 nmol/L) 16%. Variation forserum pool 2 (99 nmol/L) was 8.7%.

Relative risk (RR) of prevalent and incident diabetes wasestimated as odds ratios by logistic regression, and linearregression was used to assess the associations betweenserum 25(OH)D and markers of impaired glucose metab-olism in tertiles of serum 25(OH)D concentration. Themultivariable-adjusted models included age, gender, exam-ination year, examination month, BMI, waist-to-hip ratio(WHR), smoking (never, previous, current), leisure-timephysical activity, intake of fruits, berries and vegetables,and diabetes history in family. In addition, serum long-chain omega-3 fatty acids, systolic and diastolic blood pres-sure, calcium intake, multivitamin use or post-menopausalhormone medication in women were tested for entry inthe models, but they did not change the association(change in RR <5%). Cohort mean was used to replacemissing values in covariates (<2.7%). Statistical signifi-cance of the interactions on a multiplicative scale wasassessed by likelihood ratio tests using a cross-productterm. Tests of linear trend were conducted by assigningthe median values for each category of exposure variableand treating those as a single continuous variable. Linear(for continuous variables) or logistic (for binary variables)regression was used to evaluate the trend. All p-valueswere two-tailed (a=0.05). Data were analysed using SPSS

14.0 for Windows (SPSS Inc., Chicago, IL, USA).

Results

Participant characteristics

The mean age of the study population was 62.9 years(SD 6.5, range 53.4–73.8 years). The mean serum 25(OH)D concentration was 43.4 nmol/L (SD 17.6, range

8.5–122.8 nmol/L) in the whole population, 42.0 nmol/L(SD 17.6) in men and 44.8 nmol/L (SD 17.6) in women.Serum 25(OH)D concentrations <25 nmol/L wereobserved in 15.1% of the participants, 65.5% had concen-trations <50 nmol/l and 4.9% had concentrations≥75 nmol/L. The mean serum 25(OH)D concentrationwas 41.4 nmol/L (SD 17.4) among those who had type 2diabetes and 43.7 nmol/L (SD 17.7) among those who didnot have diabetes (p for difference=0.07).

Subjects with higher serum 25(OH)D concentrationwere more likely to be women, have lower WHR andBMI, lower intake of alcohol and saturated fatty acids,higher dietary vitamin D intake, higher leisure-timephysical activity and higher fruit and vegetable intake(Table 1). They were also less likely to smoke and morelikely to use multivitamins and have their blood samplestaken in summer months (Table 1).

Association of serum 25(OH)D withmarkers of glucose metabolism

Age, gender and examination year adjusted serum 25(OH)D was inversely associated with fasting seruminsulin, fasting blood glucose and OGTT 2-h glucose(Model 1 in Table 2). These associations were attenuatedafter further multivariable adjustments but remainedstatistically significant for the OGTT 2-h glucose (Model2). No significant effect modification was observed withage, gender, smoking, BMI, WHR or leisure-time physicalactivity (p for interactions >0.05).

Association of serum 25(OH)D withprevalence of type 2 diabetes

There were 214 (12.2%) diabetes cases in the wholepopulation, 119 (14.0%) cases among men and 95(10.5%) cases among women. After adjustment for age,gender and examination year, the risk of type 2 diabeteswas increased by 36% in the lowest versus the highestserum 25(OH)D tertile, but the result was not statistically

Table 1. Characteristics of the 1756 participants by tertiles of plasma25(OH)D in theKuopio IschaemicHeart Disease Risk Factor Study

Plasma 25(OH)D tertile (nmol/L) 1 (8.5–33.9) 2 (34.0–50.4) 3 (50.5–112.8) p for trend

Participants (n) 585 586 585Plasma 25(OH)D (nmol/L) 24.7�6.4 42.2�4.7 63.4�11.0Sample taken in summer (%) 8.7 18.1 34.4 <0.001Age (year) 62.6�6.7 63.2�6.4 62.9�6.4 0.56Women (%) 45.5 52.2 57.1 <0.001Waist-to-hip ratio 0.92�0.09 0.91�0.09 0.89�0.09 <0.001Body mass index (kg/m2) 28.3�4.6 28.0�4.5 27.2�4.2 <0.001Current smoker (%) 17.3 12.6 9.1 <0.001Leisure-time physical activity (kcal/day) 165�185 175�176 207�230 <0.001Diabetes in family (%) 32.1 33.8 36.6 0.11Alcohol intake (g/week) 57.4�127.2 44.0�81.3 42.4�79.4 0.01Total energy intake (kcal/day) 1864�582 1825�594 1831�560 0.35Vitamin D intake (mg/day) 5.9�6.0 6.4�6.2 7.1�5.9 0.001Calcium intake (mg/day) 1006�327 1017�335 988�327 0.18Fruit, berry & vegetable intake (g/day) 297�185 292�178 327�193 0.005Multivitamin use (%) 3.4 7.7 10.8 <0.001

Values are means� SD or percentages.

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significant (95% CI �6, 95%, p for trend acrosstertiles=0.10) (Table 3). The association did not appreciablychange after further adjustment for the potentialconfounding factors BMI,WHR, smoking, physical activity, in-take of fruits and vegetables, and diabetes history in family(Table 3). When comparing those with serum 25(OH)D≤50 nmol/L (65.5%of participants) to thosewith higher con-centrations, the multivariate-adjusted RR was 1.34 (95% CI0.95, 1.89). Again, no significant effect modification wasobserved with age, gender, smoking, BMI, WHR or leisure-time physical activity (p for interactions >0.05).

Association of serum 25(OH)D withincidence of type 2 diabetes

At the 20-year examinations, 140 out of the total 1082participants (12.9%, 78 men and 62 women) free ofdiabetes at the 11-year examinations were diagnosed withtype 2 diabetes. The mean serum 25(OH)D concentrationwas 41.8 nmol/L (SD 18.3) among those diagnosed withincident type 2 diabetes and 45.0 nmol/L (SD 17.6)among others (p for difference=0.05). After adjustmentfor age, gender and examination year, the RR in themiddle and highest tertile of serum 25(OH)D were 1.02(95% CI 0.62, 1.62) and 1.65 (95% CI 1.06, 2.57),as compared with the lowest tertile (p for trend=0.02).The multivariate-adjusted (Model 2 in Table 3) RRsin tertiles of serum 25(OH)D were 1, 0.95 (95% CI 0.58,1.55) and 1.39 (95% CI 0.85, 2.27), p for trend=0.17. The

RR was 1.05 (95% CI 0.69, 1.59) when those with serum25(OH)D ≤50 nmol/L (62.8%) were compared to thosewith higher concentrations. Age, gender, smoking, BMI,WHR or leisure-time physical activity did not modify theassociation (p for interactions >0.05).

Discussion

The results of this study showed that low concentration ofserum 25(OH)D, a marker of vitamin D status of the body,was associated with impaired glucose metabolism, mainlywith OGTT 2-h glucose.

Our findings are consistent with previous epidemiolog-ical studies that suggest an inverse association between 25(OH)D and insulin resistance [4]. For example, in thelarge cross-sectional study, the Third National Healthand Nutrition Examination Survey (NHANES III), multi-variate-adjusted serum 25(OH)D concentration wasinversely associated with fasting and 2-h glucose andfasting insulin and type 2 diabetes prevalence [13]. Ourresults support these findings. In many, but not all studies,patients with type 2 diabetes or glucose intolerance havebeen found to have a lower serum 25(OH)D concentra-tion, compared with controls without diabetes [2]. Theevidence from longitudinal observational studies is sparseand inconclusive [4]. For example, in a Finnish nestedcase–control study, high serum 25(OH)D concentrationwas related to a reduced incidence of type 2 diabetes inmen, but not in women [14]. On the other hand, in the

Table 2. Association between serum 25(OH)D and markers of glucose homeostasis in 1500 non-diabetic participants in theKuopio Ischaemic Heart Disease Risk Factor Study

Plasma 25(OH)D tertile (nmol/L)1 (8.5–34.3) 2 (34.4–50.9) 3 (51.0–112.8)

Mean 95% CI Mean 95% CI Mean 95% CI p for trend

Fasting serum insulin (mU/l)Model 1 8.82 8.10, 9.74 7.69 6.88, 8.50 7.34 6.52, 8.16 0.009Model 2 8.64 7.82, 9.47 7.56 6.77, 8.35 7.75 6.93, 8.57 0.17

Fasting blood glucose (mmol/L)Model 1 4.85 4.81, 4.89 4.77 4.73, 4.81 4.78 4.74, 4.82 0.02Model 2 4.84 4.81, 4.88 4.76 4.72, 4.80 4.80 4.76, 4.84 0.13

OGTT 2-h glucose (mmol/L)Model 1 5.79 5.67, 5.91 5.56 5.44, 5.68 5.49 5.36, 5.61 0.001Model 2 5.75 5.63, 5.87 5.55 5.43, 5.66 5.53 5.41, 5.65 0.02

Model 1: adjusted for age, gender and examination year.Model 2: adjusted for model 1 and body mass index, waist-to-hip ratio, smoking, leisure-time physical activity, intake of fruits, berries andvegetables, diabetes in family and examination month.OGTT 2-h glucose, 2-hour post-oral glucose tolerance test.

Table 3. Risk of type 2 diabetes in tertiles of serum 25(OH)D in 1756 participants in the Kuopio Ischaemic Heart Disease RiskFactor Study

Serum 25(OH)D tertile (nmol/L) 1 (8.6–34.0) 2 (34.1–50.5) 3 (50.6–112.8) p for trend

Type 2 diabetes cases, n (%) 81 (37.9) 73 (34.1) 60 (28.0)Odds ratio 95% CI Odds ratio 95% CI Odds ratio 95% CI

Model 1 1.36 0.94, 1.95 1.21 0.84, 1.74 1.00 Ref. 0.10Model 2 1.44 0.96, 2.15 1.26 0.86, 1.85 1.00 Ref. 0.08

Model 1: adjusted for age, gender and examination year.Model 2: adjusted for model 1 and body mass index, waist-to-hip ratio, smoking, leisure-time physical activity, intake of fruits, berries andvegetables, diabetes in family and examination month.

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large prospective cohort study, The Nurses’ Health Study,there was an inverse association between vitamin D intakeand risk of incident type 2 diabetes in women [15]. In arecent prospective study, higher serum 25(OH)D levelswere associated with reduced risk of type 2 diabetesincidence during the 5-year follow up [16]. In majorityof randomized controlled trial studies that providedvitamin D supplements, no effect on glycemic measureshave been found [4]. However, in a recent trial amongsubjects with insulin resistance and vitamin D deficiency,100 mg/day of vitamin D3 reduced insulin resistance[17]. Null results from the trials may be due to the lowdoses of the supplemented vitamin D in most studies. Itis also possible that study populations have been too smallor study durations too short to observe an effect.

The possible role of vitamin D in the pathogenesis oftype 2 diabetes is not completely understood. Mechanismsby which vitamin D deficiency may play a role might bethrough actions on systemic inflammation, insulin secre-tion, insulin resistance and pancreatic b-cell function[3,15]. Type 2 diabetes and obesity are conditions ofincreased inflammatory reaction, and systemic inflamma-tion has been found to increase insulin resistance [18].Vitamin D may also reduce the insulin resistance by itsimmunomodulatory and anti-inflammatory effects [3,19].There is evidence that vitamin D affects b-cells by increasinginsulin response to glucose stimulation, but it does notaffect basal insulin secretion [20]. Several vitamin D-relatedgenes have also shown associations with different pathoge-netic traits of the type 2 diabetes [21].

According to The National FINDIET 2007 survey, theintake of vitamin D is below the recommendations amongadult Finnish population, even though the fortification ofliquid milk products and spreads has increased thevitamin D intake and improved vitamin D status [7,22].However, even the currently recommended vitamin Dintakes have been criticized for being inadequate to main-tain serum 25(OH)D concentrations in the absence ofsubstantial cutaneous production of vitamin D [23]. Ithas been suggested that vitamin D doses of 100 mg/dayare needed to reach the suggested optimal 25(OH)Dconcentrations of 75–110 nmol/L [24]. In contrast, recently,the Institute of Medicine in the USA concluded that50 nmol/L is sufficient for most people and set the vitaminD recommendations at 15 mg/day for those ≤70 years oldand at 20 mg/day for those >71 years [25]. However,currently, there are no long-term intervention studies onthe benefits and possible risks of high-dose vitamin D.

Strengths of our study are the population-based recruit-ment and high participation rate. Some limitations should

also be noted. The measured serum 25(OH)D concentra-tions were relatively low, so it was not possible to explorea larger scale of serum 25(OH)D and to investigatewhether additional benefits could be observed withhigher serum 25(OH)D levels. Sunlight in summer andfish consumption are major sources of vitamin D inFinland. Low serum 25(OH)D concentration may thusonly be a marker of low physical activity outdoors or lowintake of long-chain omega-3 polyunsaturated fatty acidsfrom fish, which have been associated with lower risk oftype 2 diabetes. However, adjustment for these factorsdid not appreciably change the associations. Low cal-cium intake has been associated with impaired glucosemetabolism and type 2 diabetes [2]. However, adjust-ment for calcium intake did not have an effect on theassociations with serum 25(OH)D. We did not haveinformation on serum calcium. Another limitation is thatas a cross-sectional study, measured serum 25(OH)D in par-ticipants with glucose intolerance or type 2 diabetes maynot reflect vitamin D status before diagnosis, thus prevent-ing assessment of causality. Therefore, the inverse associa-tions seenwithmarkers of glucose homeostasis in this studymay be due to reverse causation. On the other hand, theassociation of the serum 25(OH)D with the risk of type 2diabetes was similar in both cross-sectional and longitudi-nal analyses. We did not have information on plasmaparathyroid hormone (PTH) levels. Low serum 25(OH)Dis associated with increased plasma PTH levels, and PTHhas been shown to be inversely associated with insulinsensitivity [26]. However, the association between serum25(OH)D and insulin resistance has been found to be inde-pendent of PTH [27].

In conclusion, our findings support the earlier resultsthat vitamin D deficiency is associated with increasedrisk of disturbances in glucose metabolism. In order tomore fully establish an association between vitamin Dinsufficiency and diabetes, one will need to demonstratethat vitamin D supplementation alone to newly diag-nosed diabetes in those with low vitamin D levels hasa beneficial effect on glycemic control. Overall, the roleof vitamin D supplementation in the prevention andtreatment of diabetes and insulin resistance requiresfurther exploration in large-scale randomized clinicaltrials.

Conflict of interest

The authors have no conflicts of interest.

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