Abstract
The purpose of this study is to look at these relationships in non-diabetic Korean adults. This study was based on data from the KNHANES V-1, which is representative of the population of Korea. A total of 5,492 participants (≥20 years in age) without type 1 or type 2 diabetes, assessed for serum 25-hydroxyvitamin D [25(OH)D], fasting blood glucose and insulin, as well as anthropometric variables, were included in the analyses. The key study results were as follows: First, vitamin D status [vitamin D deficient, 25(OH)D <25 nM; vitamin D insufficient, 25(OH)D ≥25, <50 nM; vitamin D sufficient, 25(OH)D ≥50 nM] was inversely associated with homeostasis model assessment of insulin resistance (HOMA-IR) and beta cell function (HOMA-B) in model 2 (adjusted for age and gender) and 3 (further adjusted for smoking, alcohol drinking, regular exercise, systolic and diastolic blood pressure, waist circumference, and body mass index). Second, in model 4, when further adjusted for total cholesterol, triglycerides, and HDL-C, vitamin D status was inversely associated with HOMA-B. However, association of vitamin D status and HOMA-IR was no longer significant. In conclusion, vitamin D was inversely associated with beta cell function in non-diabetic Korean adults but was not associated with insulin resistance.
Keywords: vitamin D, HOMA-IR, HOMA-B, non-diabetic adult
Introduction
Diabetes, a disease that results from the interaction of genetic factors and environmental factors, is one of the most common endocrine diseases worldwide.(1,2) Increased insulin resistance and decreased beta cell function are known to play a role in the pathogenesis of type 2 diabetes.(3)
Vitamin D is involved in calcium and phosphate absorption in the intestines, which maintains sufficient concentrations of circulating calcium and phosphate levels and normal mineralization of bone by providing the minerals to bone-forming sites.(4,5) Recently, vitamin D has also received greater attention to additional functions that concerning its effect on insulin secretion and resistance.(6–8)
However, the association of vitamin D and beta cell function and insulin resistance differs among ethnic groups and countries, and its mechanism of action remains unclear. For example, some studies have shown that vitamin D was inversely associated with insulin resistance,(9–11) beta cell function,(12,13) or both.(14) Some studies have shown that vitamin D was positively associated with beta cell function.(15,16) Some studies have shown that vitamin D was not associated with insulin resistance,(17) beta cell function,(9,18) or both.(19,20) In addition, most of the studies were designed to target populations with diseases, such as metabolic syndrome, obesity and especially diabetes.
The Republic of Korea has recently been known as a country that has a severe vitamin D deficiency problem. Among Koreans (age ≥10 years), 65.9% of men and 77.7% of women were deficient [25(OH)D ≤25 nM] or insufficient [25(OH)D ≥25, <50 nM] of vitamin D. In particular, vitamin D deficient or insufficient is serious in the twenties (men, 78.8%; women, 88.3%).(21) However, there still remains a lack of studies on the association of vitamin D with insulin resistance and beta cell function in the population of Korea. Therefore, our objective was to assess the association between vitamin D concentrations and both insulin resistance and beta cell function in non-diabetic Korean adults using data from the fifth Korea National Health and Nutrition Examination Survey (KNHANES), which is representative of the population of Korea.(22)
Materials and Methods
Subjects
This study was based on data from the KNHANES V-1 (2010), which is the most recent data that measured homeostasis model assessment (HOMA) among the KNHANES. The KNHANES is a cross-sectional survey conducted nationwide by the Division of Korean National Health and Welfare. The KNHANES V-1 (2010) was performed from January 2010 to December 2010. The survey includes a representative national sample of the Korean population, selecting from recorded households in the Population and Housing Census in Korea. The survey section is arranged by district and housing type characteristics. Twenty households were selected from each survey section using a stratified, multistage probability cluster sampling method that considers geographical area, age, and gender. In the KNHANES V-1 (2010), 8,958 individuals over 1 year of age were sampled for the survey. Among the 6,665 subjects who participated in the KNHANES V-1, we limited the analyses to adults aged ≥20 years. We excluded 778 subjects whose data were missing important analytic variables, such as serum 25(OH)D levels, various blood chemistry tests, and information about lifestyle. After the exclusion of those individuals with missing values or who suffered from diabetes (395 subjects diagnosed with type 1 or 2 diabetes or with fasting plasma glucose level ≥126 mg/dl), 5,492 adults were included in the analyses. The KNHANES V-1 (2010) study has been conducted according to the principles expressed in the Declaration of Helsinki. (Institutional Review Board No. 2010-02CON-21-C). All participants in the survey signed an informed written consent form. Further information can be found in “The KNHANES V-1 (2010) Sample”, which is available on the KNHANES website.(22) The data from KNHANES is available on request by email if the applicant logs onto the “Korea National Health and Nutrition Examination Survey” website.
General characteristics and blood chemistry
Research subjects were classified by sex (men or women), smoking (non-smoker or ex-smoker or current smoker), alcohol drinking (yes or no), and regular exercise (yes or no). In the smoking category, participants who smoked more than one cigarette a day, those who had previously smoked but do not presently smoke, and those who never smoked were classified into the current-smoker, ex-smoker, and non-smoker groups, respectively. Alcohol drinking was indicated as “yes” for participants who had consumed at least one glass of alcohol every month over the last year. Regular exercise was indicated as “yes” for participants who had exercised on a regular basis regardless of indoor or outdoor exercise. (Regular exercises was defined as 30 min at a time and 5 times/week in the case of moderate exercise, such as swimming slowly, doubles tennis, volleyball, badminton, table tennis, and carrying light objects; and for 20 min at a time and 3 times/week in the case of vigorous exercise, such as running, climbing, cycling fast, swimming fast, football, basketball, jump rope, squash, singles tennis, and carrying heavy objects). Anthropometric measurements included measurement of body mass index (BMI) and waist circumference (WC), as well as final measurements of systolic blood pressure (SBP) and diastolic blood pressure (DBP). Blood chemistries included measurements of total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), triglycerides (TGs), fasting plasma glucose (FPG), fasting insulin, and 25-hydroxyvitamin D [25(OH)D].
Serum 25(OH)D assessments
Blood samples were collected through an antecubital vein after 10–12 h of fasting to assess serum levels of biochemical markers. Serum levels of 25(OH)D were measured with a radioimmunoassay (25-hydroxy-vitamin D 125I RIA Kit; DiaSorin, Still Water, MN) using a 1470 Wizard Gamma Counter (Perkin Elmer, Turku, Finland). To minimize the analytical variation, serum 25(OH)D levels were analyzed by the same institute, which carried out a quality assurance program through the analysis period. The inter-assay coefficients of variation were 1.9–6.1% for the samples. Serum 25(OH)D levels were classified as either vitamin D deficient [25(OH)D <25 nM], vitamin D insufficient [25(OH)D ≥25, <50 nM], or vitamin D sufficient [25(OH)D ≥50 nM].(23)
HOMA-IR and HOMA-B
The homeostasis model assessment of insulin resistance (HOMA-IR) and beta cell function (HOMA-B) constitute a method for assessing beta cell function and IR from basal glucose and insulin concentrations.(24) HOMA-IR and HOMA-B are also significantly associated with diabetes risk across ethnic groups.(18) The formulas are as follows: HOMA-IR = [fasting insulin (µU/ml) × fasting plasma glucose (mg/dl)]/405; HOMA-B = 20 × fasting insulin (µU/ml)/[fasting plasma glucose (mg/dl) – 63].(24)
Data analysis
The collected data were statistically analyzed using SPSS WIN (ver. 18.0). The distributions of the participant characteristics were converted into percentages, and the successive data were presented as averages with standard deviations. The average difference in HOMA-IR and HOMA-B for general characteristics and blood chemistries were calculated using an analysis of variance and independent t tests. In the case of analysis of covariance test (ANCOVA), the 4 models constructed were: 1) Serum 25(OH)D; 2) Serum 25(OH)D, age, gender; 3) Serum 25(OH)D, age, gender, smoking, alcohol drinking, regular exercise, SBP, DBP, WC, and BMI; and 4) Serum 25(OH)D, age, gender, smoking, alcohol drinking, regular exercise, SBP, DBP, WC, BMI, TC, TGs, and HDL-C. The significance level for all of the statistical data was set as p<0.05.
Results
General characteristics of research subjects
General characteristics of the research subjects are shown in Table 1. Among the total set of subjects (5,492 subjects), the serum 25(OH)D, HOMA-IR, and HOMA-B levels were 44.95 ± 16.73 nM, 2.39 ± 1.30, and 133.09 ± 70.39, respectively. In the males (2,339 subjects), the mean of serum 25(OH)D levels was 48.68 ± 16.95 nM. According to the classification of vitamin D status, 117 (5.0%), 1,232 (52.7%), and 990 (42.3%) subjects were classified as vitamin D deficient, vitamin D insufficient, and vitamin D sufficient, respectively. The mean values of HOMA-IR and HOMA-B for males were 2.45 ± 1.51 and 125.50 ± 66.27, respectively. In the females (3,153 subjects), the mean of serum 25(OH)D levels was 42.21 ± 16.02 nM. According to the classification of vitamin D status, 341 (10.8%), 2,005 (63.6%), and 807 (25.6%) subjects were classified as vitamin D deficient, vitamin D insufficient, and vitamin D sufficient, respectively. The mean values of HOMA-IR and HOMA-B for females were 2.36 ± 1.13 and 138.72 ± 72.80, respectively.
Table 1.
General characteristics
| N (%), mean ± SD, (n = 5,492) | |||||
|---|---|---|---|---|---|
| Variables | Category | Total (n = 5,492) | Males (n = 2,339) | Females (n = 3,153) | p value |
| Age (years) | 20–29 | 668 (12.2) | 265 (11.3) | 403 (12.8) | 0.001 |
| 30–39 | 1,184 (21.6) | 494 (21.1) | 690 (21.9) | ||
| 40–49 | 1,084 (19.7) | 493 (21.1) | 591 (18.7) | ||
| 50–59 | 1,041 (19.0) | 399 (17.1) | 642 (20.4) | ||
| ≥60 | 1,515 (27.6) | 688 (29.4) | 827 (26.2) | ||
| Smoking | Non-smoker | 3,230 (58.8) | 433 (18.5) | 2,797 (88.7) | <0.001 |
| Ex-smoker | 1,086 (19.8) | 898 (38.4) | 188 (6.0) | ||
| Current smoker | 1,176 (21.4) | 1,008 (43.1) | 168 (5.3) | ||
| Alcohol drinking | No | 3,086 (56.2) | 789 (33.7) | 2,297 (72.9) | <0.001 |
| Yes | 2,406 (43.8) | 1,550 (66.3) | 856 (27.1) | ||
| Regular exercise | No | 4,661 (84.9) | 1,947 (83.2) | 2,714 (86.1) | 0.004 |
| Yes | 831 (15.1) | 392 (16.8) | 439 (13.9) | ||
| ω25(OH)D (nM) | <25 | 458 (8.3) | 117 (5.0) | 341 (10.8) | <0.001 |
| ≥25, <50 | 3,237 (58.9) | 1,232 (52.7) | 2,005 (63.6) | ||
| ≥50 | 1,797 (32.7) | 990 (42.3) | 807 (25.6) | ||
| 44.95 ± 16.73 | 48.68 ± 16.95 | 42.21 ± 16.02 | 0.008 | ||
| αWC (cm) | 80.69 ± 13.78 | 84.50 ± 17.16 | 77.85 ± 9.67 | <0.001 | |
| βBMI (kg/m2) | 23.51 ± 3.30 | 23.92 ± 3.10 | 23.21 ± 3.41 | <0.001 | |
| γSBP (mmHg) | 120.46 ± 17.57 | 123.50 ± 16.11 | 118.21 ± 18.25 | <0.001 | |
| δDBP (mmHg) | 77.27 ± 10.67 | 80.51 ± 10.50 | 74.87 ± 10.15 | <0.001 | |
| εTC (mg/dl) | 188.46 ± 36.42 | 187.83 ± 37.03 | 188.92 ± 35.97 | 0.272 | |
| ζTGs (mg/dl) | 128.96 ± 103.46 | 155.48 ± 132.08 | 109.29 ± 69.27 | <0.001 | |
| ηHDL-C (mg/dl) | 53.13 ± 12.88 | 49.65 ± 12.18 | 55.71 ± 12.77 | <0.001 | |
| θFPG (mg/dl) | 93.08 ± 9.85 | 94.75 ± 9.99 | 91.85 ± 9.56 | <0.001 | |
| µHOMA-IR | 2.39 ± 1.30 | 2.45 ± 1.51 | 2.36 ± 1.13 | 0.015 | |
| ψHOMA-B | 133.09 ± 70.39 | 125.50 ± 66.27 | 138.72 ± 72.80 | <0.001 | |
| §Insulin (µU/ml) | 10.30 ± 4.91 | 10.33 ± 5.58 | 10.27 ± 4.35 | 0.626 | |
ω25(OH)D, 25-hydroxyvitamin D; αWC, waist circumference; βBMI, body mass index; γSBP, systolic blood pressure; δDBP, diastolic blood pressure; εTC, total cholesterol; ζTGs, triglycerides; ηHDL-C, HDL-cholesterol; θFPG, fasting plasma glucose; µHOMA-IR, homeostasis model assessment of insulin resistance; ψHOMA-B, homeostasis model assessment of beta cell function; §Insulin, fasting insulin.
HOMA-IR and HOMA-B levels by subject characteristics
HOMA-IR and HOMA-B levels by subject characteristics are shown in Table 2 and 3. Variables showing a significant difference in the mean of HOMA-IR was age (p<0.001), gender (p = 0.015), regular exercise (p = 0.010), WC (p<0.001), BMI (p<0.001), SBP (p = 0.003), DBP (p<0.001), TC (p<0.001), TGs (p<0.001), HDL-C (p<0.001), and FPG (p<0.001). However, smoking (p = 0.057) and alcohol drinking (p = 0.191) showed no significant difference in the mean differences of HOMA-IR. Variables showing a significant difference in the mean of HOMA-B was age (p<0.001), gender (p<0.001), smoking (p = 0.018), alcohol drinking (p<0.001), WC (p<0.001), BMI (p<0.001), SBP (p<0.001), TGs (p<0.001), HDL-C (p<0.001), and FPG (p<0.001). However, regular exercise (p = 0.215), DBP (p = 0.126), and TC (p = 0.185) showed no significant difference in the mean differences of HOMA-B.
Table 2.
HOMA-IR and HOMA-B levels according to general characteristics in non-diabetic subjects
| mean ± SD, (n = 5,492) | |||||
|---|---|---|---|---|---|
| Variables | Category | HOMA-IR | p value | HOMA-B | p value |
| Gender | Males | 2.45 ± 1.51 | 0.015 | 125.50 ± 66.27 | <0.001 |
| Females | 2.36 ± 1.13 | 138.72 ± 72.80 | |||
| Age (years) | 20–29 | 2.27 ± 1.13 | <0.001 | 165.74 ± 69.87 | <0.001 |
| 30–39 | 2.35 ± 1.55 | 146.17 ± 70.96 | |||
| 40–49 | 2.36 ± 1.20 | 128.30 ± 57.74 | |||
| 50–59 | 2.37 ± 1.11 | 118.48 ± 54.81 | |||
| ≥60 | 2.52 ± 1.36 | 121.95 ± 80.90 | |||
| Smoking | Non-smoker | 2.36 ± 1.18 | 0.057 | 134.62 ± 62.09 | 0.018 |
| Ex-smoker | 2.47 ± 1.23 | 127.68 ± 86.23 | |||
| Current smoker | 2.42 ± 1.65 | 133.89 ± 75.23 | |||
| Alcohol drinking | No | 2.42 ± 1.29 | 0.191 | 137.09 ± 77.18 | <0.001 |
| Yes | 2.37 ± 1.32 | 129.95 ± 64.33 | |||
| Regular exercise | No | 2.41 ± 1.33 | 0.01 | 133.71 ± 71.36 | 0.215 |
| Yes | 2.26 ± 1.05 | 129.92 ± 63.85 | |||
Table 3.
HOMA-IR and HOMA-B levels according to anthropometric and blood chemistry tests in non-diabetic subjects
| mean ± SD, (n = 5,492) | |||||
|---|---|---|---|---|---|
| Variables | Category | HOMA-IR | p value | HOMA-B | p value |
| αWC (cm) | Males <90 or Females <80 | 2.13 ± 1.14 | <0.001 | 128.98 ± 63.26 | <0.001 |
| Males ≥90 or Females ≥80 | 2.92 ± 1.46 | 140.54 ± 73.19 | |||
| βBMI (kg/m2) | <25 | 2.14 ± 1.15 | <0.001 | 128.81 ± 68.04 | <0.001 |
| ≥25 | 2.96 ± 1.45 | 142.27 ± 73.52 | |||
| γSBP (mmHg) | <140 | 2.38 ± 1.32 | 0.003 | 135.01 ± 71.79 | <0.001 |
| ≥140 | 2.55 ± 1.13 | 117.03 ± 54.89 | |||
| δDBP (mmHg) | <90 | 2.37 ± 1.30 | <0.001 | 133.49 ± 71.19 | 0.126 |
| ≥90 | 2.65 ± 1.32 | 127.81 ± 58.81 | |||
| εTC (mg/dl) | <200 | 2.37 ± 1.29 | <0.001 | 132.80 ± 65.57 | 0.185 |
| ≥200 | 2.75 ± 1.55 | 138.42 ± 83.80 | |||
| ζTGs (mg/dl) | <150 | 2.22 ± 1.07 | <0.001 | 131.26 ± 65.76 | 0.002 |
| ≥150 | 2.86 ± 1.70 | 138.03 ± 81.40 | |||
| ηHDL-C (mg/dl) | Males ≥40 or Females ≥50 | 2.22 ± 0.95 | <0.001 | 128.03 ± 57.94 | <0.001 |
| Males <40 or Females <50 | 2.57 ± 1.34 | 137.87 ± 79.89 | |||
| θFPG (mg/dl) | <100 | 2.16 ± 0.91 | <0.001 | 142.90 ± 71.17 | <0.001 |
| ≥100 | 3.22 ± 1.99 | 98.32 ± 54.91 | |||
ω25(OH)D, 25-hydroxyvitamin D; αWC, waist circumference; βBMI, body mass index; γSBP, systolic blood pressure; δDBP, diastolic blood pressure; εTC, total cholesterol; ζTGs, triglycerides; ηHDL-C, HDL-cholesterol; θFPG, fasting plasma glucose; µHOMA-IR, homeostasis model assessment of insulin resistance; ψHOMA-B, homeostasis model assessment of beta cell function; §Insulin, fasting insulin.
Comparisons of HOMA-IR and HOMA-B levels according to vitamin D status
Comparisons of HOMA-IR and HOMA-B levels according to vitamin D status are shown in Table 4. Vitamin D status [vitamin D deficient, 25(OH)D <25 nM; vitamin D insufficient, 25(OH)D ≥25, <50 nM; vitamin D sufficient, 25(OH)D ≥50 nM] was inversely associated with HOMA-B (p<0.001) in model 1. However, association of vitamin D status and HOMA-IR was not significant (p = 0.211). In model 2, when adjusted for age and gender, Vitamin D status was inversely associated with HOMA-B (p<0.001) and HOMA-IR (p = 0.010). In model 3, when further adjusted for smoking, alcohol drinking, regular exercise, SBP, DBP, WC, and BMI, vitamin D status was inversely associated with HOMA-B (p = 0.002) and HOMA-IR (p = 0.035). In model 4, when further adjusted for TC, TGs, and HDL-C, vitamin D status was inversely associated with HOMA-B (p = 0.006). However, association of vitamin D status and HOMA-IR was no longer significant (p = 0.335).
Table 4.
Comparisons of HOMA-IR and HOMA-B levels according to serum 25(OH)D in non-diabetic subjects
| (n = 5,492) | ||||
|---|---|---|---|---|
| Serum 25(OH)D |
p value | |||
| <25.0 nmol/L | ≥25.0, <50.0 nmol/L | ≥50.0 nmol/L | ||
| HOMA-IR | ||||
| Model 1 | 2.37 ± 1.15 (2.26–2.47) | 2.42 ± 1.33 (2.37–2.47) | 2.35 ± 1.29 (2.36–2.43) | 0.211 |
| Model 2 | 2.44 ± 0.06 (2.28–2.52) | 2.44 ± 0.02 (2.39–2.48) | 2.32 ± 0.03 (2.25–2.38) | 0.010 |
| Model 3 | 2.47 ± 0.06 (2.36–2.59) | 2.41 ± 0.02 (2.37–2.46) | 2.33 ± 0.03 (2.76–2.39) | 0.035 |
| Model 4 | 2.41 ± 0.05 (2.31–2.50) | 2.37 ± 0.05 (2.31–2.50) | 2.34 ± 0.03 (2.31–2.50) | 0.335 |
| HOMA-B | ||||
| Model 1 | 145.93 ± 103.50 (136.43–155.44) | 136.94 ± 68.51 (134.59–139.31) | 122.88 ± 61.61 (120.03–125.73) | <0.001 |
| Model 2 | 141.50 ± 3.24 (135.16–147.84) | 134.95 ± 1.22 (132.57–137.34) | 127.60 ± 1.66 (124.35–130.85) | <0.001 |
| Model 3 | 138.63 ± 3.04 (132.67–144.60) | 134.34 ± 1.14 (132.11–136.58) | 128.66 ± 1.56 (125.61–131.71) | 0.002 |
| Model 4 | 138.09 ± 3.04 (132.14–144.05) | 134.24 ± 1.14 (132.02–136.46) | 128.99 ± 1.55 (125.95–132.03) | 0.006 |
Model 1 [mean ± SD (95% CI)], Non-adjusted; Model 2 [mean ± SE (95% CI)], adjusted for age and gender; Model 3 [mean ± SE (95% CI)], adjusted for age, gender, smoking, alcohol drinking, regular exercise, SBP, DBP, WC, and BMI; Model 4 [mean ± SE (95% CI)], adjusted for age, gender, smoking, alcohol drinking, regular exercise, SBP, DBP, WC, BMI, TC, TGs, and HDL-C.
Discussion
In our study population involving non-diabetic Korean adults, vitamin D status was inversely associated with beta cell function indices (HOMA-B) and insulin resistance (HOMA-IR) after adjusting for variables (age, gender, smoking, alcohol drinking, regular exercise, SBP, DBP, WC, and BMI). However, when further adjusted for TC, TGs, and HDL-C, vitamin D status was inversely associated with HOMA-B, but was not significantly associated with HOMA-IR.
Previous studies found inconsistent results in the association between vitamin D and insulin resistance in non diabetic subject (Table 5). These inconsistent results may be caused by different populations due to ethnic groups and countries. In studies on the association between vitamin D and insulin resistance among the healthy subjects, some studies have suggested that insulin resistance is inversely associated with vitamin D level.(11,14,25,26) Ding and his colleagues evaluated the association between serum vitamin D and insulin resistance among Chinese subjects without diabetes mellitus.(11) After adjusting for age, gender, and BMI, they suggested that independent inverse associations existed between the serum level of 25(OH)D and log (HOMA-IR) (p<0.001). Tao and his colleagues evaluated the association between 25(OH)D level and insulin resistance among a healthy Chinese female population.(14) After adjusting for age, parathyroid hormone, Ca2+, and BMI, they suggested that independent inverse associations existed between the serum level of 25(OH)D and HOMA-IR (p<0.001). On the other hand, some previous studies(17,19,27) did not observe an association between serum 25(OH)D and insulin resistance. Gobbo and his colleagues(19) evaluated the association between serum 25(OH)D levels and insulin resistance in non-diabetic Canadian Cree. They suggested that the serum 25(OH)D level was not associated with HOMA-IR in models adjusted for age, gender, physical activity, education, alcohol consumption, smoking, and BMI (p = 0.572). Song and her colleagues evaluated the association between serum 25(OH)D levels and insulin resistance in a Korean rural population.(17) After adjusting for potential confounders, such as age, gender, BMI, smoking status, alcohol intake, and regular exercise, vitamin D was not independently associated with insulin resistance (p = 0.247). In addition, there is a study that the association between vitamin D and HOMA-IR differ in the results according to gender. Choi and his colleagues(28) evaluated the association between 25(OH)D level and insulin resistance among an apparently healthy Korean adolescent population. In male adolescents, after adjusting for age, body mass index, smoking, drinking, and regular exercise, the lowest 25(OH)D quartile was significantly associated with increased insulin resistance (odds ratio 3.54; 95% CI 1.01 to 12.41). Continuous measure (per 10 ng/ml decrease) of 25(OH)D level was also significantly (p = 0.003) and inversely associated with insulin resistance among male participants. However, this association was not observed among female participants (p = 0.752). In the present study, when adjusted for age, gender, smoking, alcohol drinking, regular exercise, SBP, DBP, WC, and BMI, our results are consistent with previous studies(11,14,25,26) that serum 25(OH)D levels were inversely associated with HOMA-IR levels. However, in the results after adjustments for TC, TGs, and HDL-C, association of vitamin D status and HOMA-IR was no longer significant (Table 4). These results was similar the results of Gulseth and colleagues.(29) They evaluated the relation between serum concentration of 25(OH)D and insulin action and secretion. In multiple linear analyses, when adjusted for age, gender, geographic location, 25(OH)D concentrations were inversely associated with HOMA-IR (p = 0.016). However, when further adjusted for all of the variables, the association of 25(OH)D concentrations and HOMA-IR was no longer significant (p = 0.240). Dyslipidemia, such as decrease of HDL-C or increase of total cholesterol and triglycerides, is a consistently strong risk factors of insulin resistance, and is associated with the reduction of vitamin D. In the present results, we conclude that insulin resistance and reduction of vitamin D were increased by effect of the serum lipid contents in the non-diabetic Korean adults. Therefore, when further adjusted for serum lipid contents, such significance has disappeared.
Table 5.
Studies reporting an association between vitamin D status, insulin resistance, and beta cell function in non-diabetic subjects
| Study (country of origin) | Gender (M/F) | Outcomes | Adjustments | Main study results |
|---|---|---|---|---|
| Ding et al., 2014(11) (China) | M/F (n = 897) | Lg (HOMA-IR) | age, gender, BMI | 25(OH)D inversely associated with Lg (HOMA-IR) (p<0.001) |
| Tao et al., 2013(14) (China) | F (n = 1,382) | HOMA-IR, HOMA-B | age, PTH, Ca2+, BMI | 25(OH)D inversely associated with HOMA-IR (p<0.001) and HOMA-B (p = 0.001) |
| Del Gobbo et al., 2011(19) (Canada) | M/F (n = 510) | HOMA-IR, HOMA-B | age, gender, physical activity, smoking, alcohol, education, BMI, WC, body fat percentage | 25(OH)D not associated with HOMA-IR (p = 0.572) and HOMA-B (p = 0.498) |
| Zhao et al., 2010(25) (USA) | M/F (n = 3,206) | HOMA-IR | age, gender, race/ethnicity, education, smoking, heavy alcohol, drinking, physical activity, abdominal obesity, BMI | 25(OH)D inversely associated with HOMA-IR (ptrend<0.001) |
| Liu et al., 2009(26) (USA) | M/F (n = 2,803) | HOMA-IR, ISI0,120 | age, gender, current smoking status, BMI, WC | 25(OH)D inversely associated with HOMA-IR (p<0.001), but not associated with ISI0,120 (p = 0.310) |
| Hao et al., 2014(27) (China) | M (n = 567) | HOMA-IR | age, BMI | 25(OH)D not associated with HOMA-IR (p = 0.558) |
In studies on the association between vitamin D and beta cell function, previous results were not consistent according to ethnicity and country, healthy subjects and subjects with disease.(16–20,30–32) Kayaniyil and his colleagues(16) evaluated the association between 25(OH)D and beta cell dysfunction in type 2 diabetes and suggested that the serum 25(OH)D level was positively associated with beta cell function (p<0.001). On the other hand, some studies reported that the association of serum 25(OH)D level and HOMA-B is not relevant.(19,20) In the study of Del Gobbo and his colleagues,(19) the serum 25(OH)D level was not associated with HOMA-B in non-diabetic Canadian Cree (p = 0.498). Cai and his colleagues(20) evaluated the associations between vitamin D and beta cell function in type 2 diabetes in a Chinese population. After adjusting for multiple variables, the serum 25(OH)D level was not associated with either beta cell function (p = 0.206) or insulin resistance (p = 0.150).
Vitamin D is essential for insulin secretion and peripheral action through binding to the vitamin D receptor in the pancreatic beta cell.(15) Therefore, vitamin D is necessary for beta cell function in the synthesis of insulin in the subjects with insulin resistance. In our results, although an inverse association between vitamin D and HOMA-B may seem contradictory, the subjects of our study included a non-diabetic population. In healthy subjects, beta cells sense changes in plasma glucose concentration and are activated to secrete insulin by corresponding elevated levels of plasma glucose.(33) Tao and his colleagues(14) evaluated the association between 25(OH)D level and beta cell function in non-diabetic female Chinese adults. The serum 25(OH)D level (51.75 ± 16.75 nM) and HOMA-B (means: 134.6 [89.7–186.0]) were similar to those of the Korean adults of our study (serum 25(OH)D levels, 44.95 ± 16.73 nM; HOMA-B, 133.09 ± 70.39), and serum 25(OH)D level was inversely associated with HOMA-B (p<0.001). In addition, Rhee and his colleagues(12) evaluated the association between 25(OH)D and diabetes in Korean adults, and suggested that the serum 25(OH)D level was inversely associated with HOMA-B (p<0.001). Several studies reported that vitamin D was inversely associated with blood glucose.(34–36) Research findings on the association between vitamin D and beta cell function were not consistent according to ethnicity, country, or study. These inconsistencies may be attributed to differences of measurements of beta cell function (e.g., clamps, IVGTT, ISSI, ISOGTT, HOMA indices). Although HOMA indices were not the “gold-standard” method (e.g., hyperinsulinemic-euglycemic clamp and the hyperglycemic clamp test), HOMA may be more appropriate for use in large epidemiological studies.(37) In addition, one of the difficulties in conducting the extensive research required to determine the clinical utility of measures of insulin resistance, sensitivity, and secretion is the lack of standardized insulin assays. Results reported from one study to the next are not comparable, which makes only qualitative comparisons between studies possible.(38) Therefore, the introduction of a sustainable insulin assay standardization program is necessary.
The association between beta cell function and vitamin D in non-diabetic subjects continues to be debated. In the present study results, it is unclear whether the increased beta cell function decreases the vitamin D levels, or the reduction of vitamin D increases beta cell function. In either case, the serum 25(OH)D level was inversely associated with beta cell function in non-diabetic Korean adults. In conclusion, the serum 25(OH)D level was inversely associated with beta cell function in non-diabetic Korean adults, but was not associated with insulin resistance.
The present study has a few limitations. First, the OGTTs are more sensitive than the FPG test in the diagnosis of diabetes. However, the OGGTs were not employed in the KNHANES V-1 study (2010). Second, season is the most important determinant of serum 25(OH)D levels, but the data of the KNHANES V-1 study did not specify serum 25(OH)D levels according to season. Therefore, season could not be used as adjustment variable. Third, serum calcium concentration and daily intake volume of vitamin D are important determinant of serum 25(OH)D levels, but the KNHANES V-1 did not measure serum calcium concentration and daily intake volume of vitamin D. Therefore, serum calcium concentration and daily intake volume of vitamin D could not be used as adjustment variable. Fourth, parathyroid hormone (PTH) is an important determinant of serum vitamin D levels. Increased PTH promotes calcium influx into adipocytes, where intracellular calcium enhances lipogenesis.(39) Therefore, the serum vitamin D levels could change depending on serum PTH. However, the data of the KNHANES V-1 study also failed to measure the PTH of these participants (adults ≥20 years of age). The serum 25(OH)D levels for each season, along with calcium and PTH levels, should be included as variables of vitamin D status in future studies. Although the present study has these limitations, this is the first reported study to determine the relationship between vitamin D and insulin resistance and beta cell function in non-diabetic Korean adults. Therefore, more accurate results might be obtained by performing a cohort study by adding these variables.
References
- 1.Guo J, Xiao Z, Xue X, et al. 25-Hydroxyvitamin D is closely related with the function of the pancreatic islet β cells. Pak J Med Sci. 2013;29:809–813. doi: 10.12669/pjms.293.2982. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Fradin D, Bougneres P. T2DM: why epigenetics? J Nutr Metab. 2011;2011:647514. doi: 10.1155/2011/647514. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Nagpal J, Pande JN, Bhartia A. A double-blind, randomized, placebo-controlled trial of the short-term effect of vitamin D3 supplementation on insulin sensitivity in apparently healthy, middle-aged, centrally obese men. Diabet Med. 2009;26:19–27. doi: 10.1111/j.1464-5491.2008.02636.x. [DOI] [PubMed] [Google Scholar]
- 4.Choi HS, Kim KA, Lim CY, et al. Low serum vitamin D is associated with high risk of diabetes in Korean adults. J Nutr. 2011;141:1524–1528. doi: 10.3945/jn.111.139121. [DOI] [PubMed] [Google Scholar]
- 5.Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266–281. doi: 10.1056/NEJMra070553. [DOI] [PubMed] [Google Scholar]
- 6.Pittas AG, Chung M, Trikalinos T, et al. Systematic review: vitamin D and cardiometabolic outcomes. Ann Intern Med. 2010;152:307–314. doi: 10.1059/0003-4819-152-5-201003020-00009. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Mitri J, Muraru MD, Pittas AG. Vitamin D and type 2 diabetes: a systematic review. Eur J Clin Nutr. 2011;65:1005–1015. doi: 10.1038/ejcn.2011.118. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Pittas AG, Lau J, Hu FB, Dawson-Hughes B. The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis. J Clin Endocrinol Metab. 2007;92:2017–2029. doi: 10.1210/jc.2007-0298. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Dutta. D, Maisnam I, Shrivastava A, et al. Serum vitamin-D predicts insulin resistance in individuals with prediabetes. Indian J Med Res. 2013;138:853–860. [PMC free article] [PubMed] [Google Scholar]
- 10.Chiu KC, Chu A, Go VL, Saad MF. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr. 2004;79:820–825. doi: 10.1093/ajcn/79.5.820. [DOI] [PubMed] [Google Scholar]
- 11.Ding L, Wang C, Ma H, Tian Y, Lu Y, Pang S. The study of serum vitamin D and insulin resistance in Chinese populations with normal glucose tolerance. Int J Endocrinol. 2014;2014:870235. doi: 10.1155/2014/870235. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Rhee SY, Hwang YC, Chung HY, Woo JT. Vitamin D and diabetes in Koreans: analyses based on the Fourth Korea National Health and Nutrition Examination Survey (KNHANES), 2008–2009. Diabet Med. 2012;29:1003–1010. doi: 10.1111/j.1464-5491.2012.03575.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Rajakumar K, de las Heras J, Lee SJ, Holick MF, Arslanian SA. 25-Hydroxyvitamin D concentrations and in vivo insulin sensitivity and β-cell function relative to insulin sensitivity in black and white youth. Diabetes Care. 2012;35:627–633. doi: 10.2337/dc11-1825. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Tao MF, Zhang Z, Ke YH, et al. Association of serum 25-hydroxyvitamin D with insulin resistance and β-cell function in a healthy Chinese female population. Acta Pharmacol Sin. 2013;34:1070–1074. doi: 10.1038/aps.2013.13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Kamycheva E, Jorde R, Figenschau Y, Haug E. Insulin sensitivity in subjects with secondary hyperparathyroidism and the effect of a low serum 25-hydroxyvitamin D level on insulin sensitivity. J Endocrinol Invest. 2007;30:126–132. doi: 10.1007/BF03347410. [DOI] [PubMed] [Google Scholar]
- 16.Kayaniyil S, Vieth R, Retnakaran R, et al. Association of vitamin D with insulin resistance and beta-cell dysfunction in subjects at risk for type 2 diabetes. Diabetes Care. 2010;33:1379–1381. doi: 10.2337/dc09-2321. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Song BM, Kim HC, Choi DP, Oh SM, Suh I. Association between serum 25-hydroxyvitamin D level and insulin resistance in a rural population. Yonsei Med J. 2014;55:1036–1041. doi: 10.3349/ymj.2014.55.4.1036. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Scragg R, Sowers M, Bell C; Third National Health and Nutrition Examination Survey. Serum 25-hydroxyvitamin D, diabetes, and ethnicity in the Third National Health and Nutrition Examination Survey. Diabetes Care. 2004;27:2813–2818. doi: 10.2337/diacare.27.12.2813. [DOI] [PubMed] [Google Scholar]
- 19.Del Gobbo LC, Song Y, Dannenbaum DA, Dewailly E, Egeland GM. Serum 25-hydroxyvitamin D is not associated with insulin resistance or beta cell function in Canadian Cree. J Nutr. 2011;141:290–295. doi: 10.3945/jn.110.129619. [DOI] [PubMed] [Google Scholar]
- 20.Cai X, Hu Z, Chen L, Han X, Ji L. Analysis of the associations between vitamin D and albuminuria or β-cell function in Chinese type 2 diabetes. Biomed Res Int. 2014;2014:640909. doi: 10.1155/2014/640909. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Jung IK. Prevalence of vitamin D deficiency in Korea: Results from KNHANES 2010 to 2011. J Nutr Health. 2013;46:540–551. [Google Scholar]
- 22.Ministry of Health and Welfare, Korea Centers for Disease Control and Prevention. Korea Health Statistics 2010: Korea National Health and Nutrition Examination Survey (KNHANES V-1). https://knhanes.cdc.go.kr/knhanes/index.do [Google Scholar]
- 23.Thacher TD, Clarke BL. Vitamin D insufficiency. Mayo Clin Proc. 2011;86:50–60. doi: 10.4065/mcp.2010.0567. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28:412–419. doi: 10.1007/BF00280883. [DOI] [PubMed] [Google Scholar]
- 25.Zhao G, Ford ES, Li C. Associations of serum concentrations of 25-hydroxyvitamin D and parathyroid hormone with surrogate markers of insulin resistance among U.S. adults without physician-diagnosed diabetes: NHANES, 2003–2006. Diabetes Care. 2010;33:334–347. doi: 10.2337/dc09-0924. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Liu E, Meigs JB, Pittas AG, et al. Plasma 25-hydroxyvitamin D is associated with markers of the insulin resistant phenotype in nondiabetic adults. J Nutr. 2009;139:329–334. doi: 10.3945/jn.108.093831. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Hao Y, Ma X, Shen Y, et al. Associations of serum 25-hydroxyvitamin D3 levels with visceral adipose tissue in Chinese men with normal glucose tolerance. PLoS One. 2014;9:e86773. doi: 10.1371/journal.pone.0086773. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Choi DP, Oh SM, Lee JM, et al. Serum 25-hydroxyvitamin D and insulin resistance in apparently healthy adolescents. PLoS One. 2014;9:e103108. doi: 10.1371/journal.pone.0103108. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Gulseth HL, Gjelstad IM, Tierney AC, et al. Serum vitamin D concentration does not predict insulin action or secretion in European subjects with the metabolic syndrome. Diabetes Care. 2010;33:923–925. doi: 10.2337/dc09-1692. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Mitri J, Dawson-Hughes B, Hu FB, Pittas AG. Effects of vitamin D and calcium supplementation on pancreatic β cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial. Am J Clin Nutr. 2011;94:486–494. doi: 10.3945/ajcn.111.011684. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Gagnon C, Daly RM, Carpentier A, et al. Effects of combined calcium and vitamin D supplementation on insulin secretion, insulin sensitivity and β-cell function in multi-ethnic vitamin D-deficient adults at risk for type 2 diabetes: a pilot randomized, placebo-controlled trial. PLoS One. 2014;9:e109607. doi: 10.1371/journal.pone.0109607. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Gao Y, Wu X, Fu Q, Li Y, Yang T, Tang W. The relationship between serum 25-hydroxy vitamin D and insulin sensitivity and β-cell function in newly diagnosed type 2 diabetes. J Diabetes Res. 2015;2015:636891. doi: 10.1155/2015/636891. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Schmitz O, Rungby J, Edge L, Juhl CB. On high-frequency insulin oscillations. Ageing Res Rev. 2008;7:301–305. doi: 10.1016/j.arr.2008.04.002. [DOI] [PubMed] [Google Scholar]
- 34.Liu S, Song Y, Ford ES, Manson JE, Buring JE, Ridker PM. Dietary calcium, vitamin D, and the prevalence of metabolic syndrome in middle-aged and older U.S. women. Diabetes Care. 2005;28:2926–2932. doi: 10.2337/diacare.28.12.2926. [DOI] [PubMed] [Google Scholar]
- 35.Knekt P, Laaksonen M, Mattila C, et al. Serum vitamin D and subsequent occurrence of type 2 diabetes. Epidemiology. 2008;19:666–671. doi: 10.1097/EDE.0b013e318176b8ad. [DOI] [PubMed] [Google Scholar]
- 36.Ashraf AP, Alvarez JA, Gower BA, Saenz KH, McCormick KL. Associations of serum 25-hydroxyvitamin D and components of the metabolic syndrome in obese adolescent females. Obesity (Silver Spring) 2011;19:2214–2221. doi: 10.1038/oby.2011.110. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care. 2004;27:1487–1495. doi: 10.2337/diacare.27.6.1487. [DOI] [PubMed] [Google Scholar]
- 38.Statan MA, Stern MP, Miller WG, Steffes MW, Campbell SE. Insulin assay standardization. Diabetes Care. 2010;33:205–206. doi: 10.2337/dc09-1206. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Snijder MB, van Dam RM, Visser M, et al. Adiposity in relation to vitamin D status and parathyroid hormone levels: a population-based study in older men and women. J Clin Endocrinol Metab. 2005;90:4119–4123. doi: 10.1210/jc.2005-0216. [DOI] [PubMed] [Google Scholar]