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
Abstract
OBJECTIVE To examine whether concentrations of serum 25-hydroxyvitamin D (25[OH]D) and parathyroid hormone (PTH) are associated with surrogate markers of insulin resistance (IR) in U.S. adults without physician-diagnosed diabetes.
RESEARCH DESIGN AND METHODS Cross-sectional data (n = 3,206) from the National Health and Nutrition Examination Survey (NHANES) 2003–2006 were analyzed.
RESULTS The age-adjusted prevalence of hyperinsulinemia, high homeostasis model assessment-IR, high GHb, and fasting and 2-h hyperglycemia decreased linearly across quintiles of 25(OH)D but increased linearly across quintiles of PTH (except for a quadratic trend for fasting hyperglycemia). After extensive adjustment for potential confounders, the relationships between 25(OH)D and the markers of IR and 2-h hyperglycemia persisted. Only hyperinsulinemia was positively associated with PTH (P < 0.05).
CONCLUSIONS Among U.S. adults without physician-diagnosed diabetes, low concentrations of serum 25(OH)D were associated with markers of IR. The role of PTH in IR deserves further investigation.
The role of vitamin D and parathyroid hormone (PTH) in metabolic syndrome and diabetes is receiving increased attention. Insulin resistance (IR) may represent a potential mechanism linking vitamin D and PTH to these conditions. The inverse associations between vitamin D and fasting insulin concentrations or the homeostasis model assessment of IR (HOMA-IR) index have been reported in some (1–5) but not all studies (6). Moreover, evidence linking PTH to markers of IR is limited and inconsistent (7–9). This study examined whether serum 25-hydroxyvitamin D (25[OH]D) and PTH are associated with surrogate markers of IR in U.S. adults without physician-diagnosed diabetes.
RESEARCH DESIGN AND METHODS
We used data from the National Health and Nutrition Examination Survey (NHANES) 2003–2006. Participants who were aged ≥20 years, attended the morning examination after fasting ≥8 h, and had not been diagnosed with diabetes were included as were participants with undiagnosed diabetes (fasting glucose ≥126 mg/dl or GHb ≥6.5%) (10). Serum 25(OH)D concentrations were measured using a radioimmunoassay procedure. Serum PTH concentrations were measured on the Elecsys 1010 analyzer using an electrochemiluminescent procedure. The quintiles of 25(OH)D and PTH were created after taking into account the sampling weights.
Plasma concentrations of fasting and 2-h glucose, fasting insulin, and GHb were adjusted for differences in laboratory methodology between NHANES 2003–2004 and 2005–2006. Oral glucose tolerance test data were available only for NHANES 2005–2006. We defined fasting hyperglycemia as a fasting glucose ≥100 mg/dl, 2-h hyperglycemia as a 2-h glucose ≥140 mg/dl, and high GHb as a value of ≥6.0%. HOMA-IR index was calculated as (fasting plasma insulin [mU/l] × fasting plasma glucose [mmol/l])/22.5. Hyperinsulinemia and high HOMA-IR were defined using the weighted 75th percentiles.
Covariates in our analyses included age, sex, race/ethnicity, education, smoking, physical activity, alcohol drinking, BMI, abdominal obesity, and serum calcium concentrations. From 3,551 participants without physician-diagnosed diabetes, 3,206 (1,582 male subjects and 1,624 female subjects) remained in our analyses after excluding those who had missing values for study variables. The prevalence of surrogate markers of IR was age-standardized to the 2000 U.S. population. Linear trends across quintiles of 25(OH)D and PTH were tested using orthogonal contrasts in SUDAAN software. Multiple logistic regression analyses were conducted to test associations of 25(OH)D or PTH with markers of IR.
RESULTS
Among 3,206 participants, 118 had undiagnosed diabetes. The age-adjusted prevalence was 5.7% (95% CI 4.8–6.7%) for high GHb, 30.6 (27.8–33.6) for fasting hyperglycemia, and 20.4 (17.7–23.4) for 2-h hyperglycemia. The prevalence of all outcome measures and the multivariate-adjusted odds ratios (ORs) for hyperinsulinemia, high HOMA-IR, high GHb, and 2-h hyperglycemia decreased linearly across quintiles of 25(OH)D (P < 0.05 for all) (Table 1). After excluding participants without physician-diagnosed diabetes but who had diabetes based on fasting glucose or GHb values, similar results were observed except the significant association between high GHb and 25(OH)D disappeared.
Age-adjusted prevalence and adjusted ORs (95% CIs) of the surrogate markers of IR by quintiles of serum 25(OH)D and PTH concentrations among U.S. adults aged ≥20 years without physician-diagnosed diabetes, NHANES 2003–2006 (n = 3,206)*
Interactions between race/ethnicity and 25(OH)D for outcome measures were not significant in the full models.
The prevalence of hyperinsulinemia, high HOMA-IR, high GHb, and 2-h hyperglycemia increased linearly, and the prevalence of fasting hyperglycemia increased nonlinearly across quintiles of PTH. After adjusting for demographic and lifestyle factors, the ORs for hyperinsulinemia, high HOMA-IR, and high GHb were significantly higher in the highest than in the lowest quintile of PTH, and significantly increasing trends existed for all measures except for 2-h hyperglycemia. After further adjusting for all potential confounders, most of the associations lost statistical significance; only an increasing trend for hyperinsulinemia across quintiles of PTH persisted (P < 0.05). These results did not change much after excluding participants without physician-diagnosed diabetes but who had diabetes based on fasting glucose or GHb values.
CONCLUSIONS
Our findings of an inverse association between 25(OH)D and IR among adults without physician-diagnosed diabetes are consistent with previous findings from cross-sectional (1–4) and prospective (5) studies. These results offer further support that lower concentrations of 25(OH)D may be a predictor of increased likelihood of diabetes in the population (11–14).
Compared with previous studies that examined the associations of 25(OH)D with IR (1–4), an advantage of our study was that we were able to simultaneously examine the associations between serum 25(OH)D and PTH—both of which play an essential role in regulating calcium homeostasis—and IR. In addition, we were able to adjust for overall obesity (i.e., BMI) and abdominal obesity, which were strong confounders for the analyses. The expression of vitamin D receptors in both pancreatic β-cells and skeletal muscle cells, which, upon activation by vitamin D supplementation, result in increased insulin release and responsiveness to insulin for glucose transport (14), may serve as an underlying mechanism.
Our results regarding possible racial/ethnic disparities in the associations of 25(OH)D with IR conflict with those from Scragg et al. (3). Given the high proportion of African Americans with vitamin D deficiency or insufficiency, the issue of possible racial/ethnic disparities deserves further investigation (15).
Primary hyperparathyroidism was associated with impaired glucose tolerance, insulin insensitivity, and diabetes (7). However, a significant correlation between PTH and HOMA-IR was observed in adults aged 70 years with an average BMI of 27 kg/m2 (8), but not in middle-aged, morbidly obese adults (average BMI 44.7 kg/m2) (9). These studies were conducted in selected populations, and the data analyses did not adequately control for potential confounders. Our study, based on a nationally representative sample, showed a significant association between PTH and hyperinsulinemia after adjusting for potential confounders. However, analyses limited to participants with concentrations of 25(OH)D <30 ng/ml (n = 2,518), a point at which PTH concentrations begin to increase, revealed no associations between PTH and hyperinsulinemia or HOMA-IR.
Our study was limited by the inability to establish the causality between 25(OH)D and IR based on our cross-sectional study and by the inability to account for sunlight exposure due to lack of data.
In conclusion, low concentrations of 25(OH)D were associated with markers of IR among U.S. adults without physician-diagnosed diabetes. Future prospective studies and intervention trials are needed to confirm the associations of 25(OH)D with IR and to further investigate the role of PTH in IR.
Acknowledgments
No potential conflicts of interests relevant to this article were reported.
Footnotes
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The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
- Received May 20, 2009.
- Accepted October 13, 2009.
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Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.
- © 2010 by the American Diabetes Association.
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