Associations Between Serum 25-Hydroxyvitamin D,Insulin Sensitivity,Insulin Secretion,and β-Cell Function According to Glucose Tolerance Status

Abstract

Background:

The objective of this study was to determine whether glucose tolerance status influences the associations between serum 25-hydroxyvitamin D [25(OH)D], insulin sensitivity, insulin secretion, and β-cell function.

Methods:

This cross-sectional study included 112 French Canadian postmenopausal women with normal glucose tolerance (NGT; n=65) or abnormal glucose tolerance (AGT; n=47). Estimates of insulin sensitivity [homeostasis model assessment of insulin sensitivity (HOMA%S) and glucose disposal rate (GDR)], insulin secretion [area under the curve of C-peptide (AUC C-peptide)], and β-cell function (GDR×AUC C-peptide) were derived from a 2-hr euglycemic–hyperinsulinemic clamp and a 75-gram 3-hr oral glucose tolerance test (OGTT). Measures of adiposity were taken (waist circumference, body mass index, fat mass by the hydrostatic weighting technique, and computed tomography (CT)-derived total and visceral adiposity), questionnaires on physical activity, dietary calcium, and vitamin D intake were administered, and blood was sampled for measurement of parathyroid hormone, interleukin-6, and adiponectin.

Results:

AGT status was significantly associated with lower insulin sensitivity and β-cell function (P≤0.01 for all) but not with insulin secretion. Lower serum 25(OH)D concentrations were significantly associated with lower insulin sensitivity and secretion (P≤0.01 for all) but not with β-cell function. The interaction between glucose tolerance status and serum 25(OH)D concentration was not significant for either insulin sensitivity, insulin secretion, or β-cell function, even after adjustment for potential confounders.

Conclusion:

Vitamin D and glucose tolerance status are both independently associated with measures of insulin sensitivity, insulin secretion, and β-cell function. However, the association between serum 25(OH)D and these surrogate markers of type 2 diabetes mellitus risk is not influenced by glucose tolerance status.

Introduction

A recent review of several observational studies showed that the risk of developing type 2 diabetes mellitus (T2DM) was increased with lower serum 25-hydroxyvitamin D [25(OH)D] concentrations.¹ Low vitamin D status has also been associated with impaired insulin sensitivity, insulin secretion, and β-cell function in several studies, although others have failed to demonstrate this association.^2

–5 Being a strong correlate of T2DM risk, insulin sensitivity, insulin secretion, and β-cell function,⁶ glucose tolerance status may explain, at least in part, the discrepant results among studies. Heterogeneity of results could also be explained by the accuracy of the methods used to assess insulin sensitivity and insulin secretion. Indeed, the gold standard method to assess insulin sensitivity, the euglycemic–hyperinsulinemic clamp (EHC), has been used by very few studies.⁷

Therefore, we aimed to determine whether glucose tolerance status influences the associations between serum 25(OH)D and insulin sensitivity, insulin secretion, and β-cell function in a well-characterized sample of French Canadian postmenopausal women.

Subjects and Methods

Subjects

This cross-sectional study was conducted in 112 French Canadian postmenopausal women aged between 46 and 68 years and living in Quebec City, Canada (latitude of 46°N). They were recruited through newspapers between 1999 and 2003. Postmenopausal status was determined by the absence of menses for ≥1 year and confirmed with a follicle-stimulating hormone measurement >40 IU/L. All women on hormone replacement therapy were excluded. Participants were also excluded if they were treated for coronary heart disease, diabetes, dyslipidemia, or other endocrine disorders, with the exception of stable thyroid disease. Moreover, four women with positive anti-insulin antibodies were excluded. The research was conducted according to the Declaration of Helsinki. A written informed consent, approved by the Laval University and the Centre Hospitalier de l'Université Laval Research Ethics Committees, was obtained from all participants upon study entrance.

Anthropometry and adiposity measures by computed tomography

Body weight, height, and waist circumference (WC) were determined with standardized methods. Body weight was measured in light clothing to the nearest 0.1 kg on a calibrated balance and height to the nearest millimeter with a stadiometer. WC was recorded to the nearest millimeter as the average of two measurements taken midway between the iliac crest and last rib. Body density was estimated by the hydrostatic weighing technique.⁸ The mean of six valid measurements was used to calculate the percentage of body fat with the equation of Siri.⁹ Fat mass was estimated from the derived percent body fat and total body weight.

Measures of abdominal adipose tissue areas (total and visceral) were performed by computed tomography (CT) with a GE High-Speed Advantage scanner (General Electric Medical Systems, Milwaukee, WI), using the procedures of Sjöström et al.¹⁰ A single slice was obtained at the abdominal level between the L4 and L5 vertebrae and positioned to the nearest millimeter using a skeletal radiograph. Total abdominal adipose tissue areas were calculated by delineating the abdominal scans with a graph pen and then by computing the adipose tissue surfaces using attenuation range of −190 to −30 Hounsfield units.¹⁰ Abdominal visceral adipose tissue area was measured by drawing a line within the muscle wall surrounding the abdominal cavity.

Dietary data, physical activity questionnaire, and seasonality

A validated 3-day physical activity diary, including 2 weekdays and 1 weekend day, was completed by participants.¹¹ For each 15-min period over 24 hr, the activities were recorded and categorized according to mean energy expenditure (EE) on a 1–9 intensity scale. This scale ranged from very low EE (category 1, sleeping) to very high EE (category 9, running). Only mean EE values for moderate-to-intense activities were considered (i.e., categories 6– 9) and averaged over 3 days. A 3-day food record, which was reviewed by the study nutritionist, was also completed during 2 weekdays and 1 weekend day. A scale to weigh the food was provided. Specific nutrient intakes, such as calcium and vitamin D, were assessed using Food Processor Nutrition Analysis software, version 7.2 (ESHA Research, Salem, OR). On the basis of the month of blood testing, women were divided into two groups—spring/summer (from April to September) and fall/winter (from October to March).

Measures of insulin sensitivity, insulin secretion, and β-cell function

Oral glucose tolerance test

A 75-gram 3-hr oral glucose tolerance test (OGTT) was performed in the morning after an overnight fast. Blood was collected in EDTA-containing tubes through a venous catheter at times −15, 0, 15, 30, 45, 60, 90, 120, 150, and 180 min for the determination of plasma glucose, insulin and C-peptide. Homeostasis model assessment of insulin sensitivity (HOMA%S) index was calculated as previously shown.^12
–14 Glucose tolerance status was defined according to the 2003 Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Normal glucose tolerance (NGT) was defined as a 2-hr plasma glucose (2-hr PG) <7.8 mmol/L, impaired glucose tolerance (IGT) as a 2-hr PG between 7.8 and 11.0 mmol/L, and T2DM as a 2-hr PG ≥11.1 mmol/L.¹⁵ Insulin secretion was estimated using the area under the curve (AUC) of C-peptide.

Euglycemic–hyperinsulinemic clamp

The clamp was performed after a 12-hr overnight fast, as previously described by DeFronzo et al.¹⁶ A first intravenous catheter was placed in an antecubital vein for the infusion of insulin and glucose (20% dextrose). A second catheter was placed in the other arm for sampling of blood glucose and insulin. A continuous infusion of insulin was started at a rate of 40 mU·m² · min⁻¹. The glucose infusion rate was adjusted to reach a glucose target of 5.5 mmol/L. Once a steady state was reached, the insulin infusion was continued for a total of 2 hr. Blood was collected in EDTA-containing tubes from time −15 min and then every 5 min to measure glucose using an Elite Bayer glucometer (3903-E) and every 10 min to measure insulin. The glucose disposal rate (GDR, or M value) was calculated as the mean glucose infusion rate during the last 30 min of the clamp divided by body weight (kg), measured on a calibrated balance.¹⁶ Another insulin sensitivity measure, M/I, was defined as the M value divided by the mean plasma insulin concentration during the last 30 min of the clamp (I).¹⁷ β-Cell function was evaluated using the disposition index (GDR×AUC C-peptide).

Assay methods

Plasma was stored at −80°C until measurements were done in batch at the end of the study. Plasma glucose was measured enzymatically, whereas plasma insulin was measured by radioimmunoassay with polyethylene glycol separation.^18,19 Parathyroid hormone (PTH) was measured with a chemiluminescence immunoassay (Beckman Coulter, Mississauga, Canada) and 25(OH)D by electrochemiluminescence (Cobas System, Roche, Laval, Canada). Plasma interleukin-6 (IL-6) and adiponectin concentrations were measured by high-sensitivity enzyme-linked immunosorbent assays (ELISA; R&D Systems, Minneapolis, MN), according to the manufacturer's procedures.

Statistical analyses

Statistical analyses were performed using the JMP statistical software version 10.0 (SAS Institute, Cary, NC). Baseline characteristics were compared between women with serum 25(OH)D concentrations below or above the median of 65 nmol/L using a chi-squared or a Student t-test for categorical and continuous variables, respectively. Logarithmic transformations were applied to nonnormally distributed variables (HOMA%S, M/I, and AUC C-peptide).

Univariate linear regression analyses were conducted to identify variables that were significantly associated with insulin sensitivity, insulin secretion, and β-cell function, including serum 25(OH)D concentrations and glucose tolerance status as well as age, visceral adipose tissue area, season, physical activity, serum PTH concentrations, IL-6 and adiponectin concentrations, dietary calcium, and vitamin D intake. Associations between glucose tolerance status, serum 25(OH)D concentrations, and measures of insulin sensitivity, insulin secretion, and β-cell function were further assessed using multivariate regression analyses. Serum 25(OH)D concentrations and glucose tolerance status were both entered simultaneously in a multivariate linear regression model along with the interaction term (25(OH)D * glucose tolerance status) to assess whether glucose tolerance status influences the association between serum 25(OH)D and each one of the outcome measures (insulin sensitivity, insulin secretion, and β-cell function). Finally, the variables that were associated with each one of these outcomes with a P value<0.1 in univariate linear regression analyses (potential confounders) were entered all together in the model to evaluate whether the results were affected.

Results

Characteristics of women with serum 25(OH)D concentrations below or above the median of 65 nmol/L are presented in Table 1. Women were on average 57 years old and were overweight with a mean body mass index (BMI) of 28.6 kg/m². Neither insulin sensitivity nor β-cell function was statistically different between groups. However, insulin secretion was significantly higher in women with serum 25(OH)D concentrations below the median compared with those with serum 25(OH)D concentrations above the median. No difference was observed for age, BMI, WC, total body fat mass, and total or visceral adipose tissue area between groups. Moreover, serum adiponectin and IL-6 concentrations, dietary variables, energy expenditure, season of blood sampling, and serum PTH concentrations were similar between groups.

Table 1.

Characteristics of the 112 Postmenopausal Women Based on Serum 25-Hydroxyvitamin D Concentrations

	25(OH)D≤65 nmol/L (n=56)	25(OH)D>65 nmol/L (n=56)	P value ^*
Age (years)	56.5±4.5	57.2±4.2	0.34
BMI (kg/m²)	28.4±4.8	29.0±6.9	0.95
Waist circumference (cm)^a	90.7±12.1	94.2±14.4	0.82
Total body fat mass (kg)^b	29.2±9.1	30.1±13.6	0.91
Total adipose tissue area (cm²)^c	499.6±155.8	516.7±179.8	0.60
Visceral adipose tissue area (cm²)^c	143.0±58.4	135.7±55.2	0.51
Sampling (fall/winter) (%)	55	45	0.19
25-Hydroxyvitamin D (nmol/L)	48.8±10.2	75.8±9.1	<0.0001
Parathyroid hormone (ng/L)^a	44.7±14.5	40.0±13.9	0.08
Fasting glucose (mmol/L)	5.6±0.6	5.6±1.0	0.70
Fasting insulin (pmol/L)	78.6±36.7	70.2±30.2	0.18
2-hr post-OGTT glucose (mmol/L)	7.8±2.7	7.9±3.1	0.99
HOMA%S index^a	46.3±30.7	52.0±34.2	0.24
Glucose disposal rate (mL · min⁻¹ · kg⁻¹)^d	6.5±2.9	7.4±3.0	0.12
I (pmol/L)	687±23	697±22	0.71
M/I (mL·min⁻¹·kg⁻¹/pmol/L)	0.010±0.005	0.011±0.005	0.28
AUC C-peptide^a	460,335±168,824	399,010±121,448	0.03
Disposition index^e,**	2,844,821±1,220,383	2,775,536±1,063,196	0.75
Adiponectin (ng/L)	12.1±4.8	13.5±4.8	0.11
IL-6 (ng/L)^a	1.63±0.87	1.48±0.91	0.27
Total energy intake (kcal/day)^b	1,983±479	1,921±420	0.48
Dietary vitamin D intake (IU/day)^f	172±108	157±82	0.59
Dietary calcium intake (mg/day)^b	904±317	943±333	0.54
Energy expenditure (kcal/kg per day)^d,***	3.0±4.6	2.8±3.0	0.86

Data are presented as mean±standard deviation (SD) or %.

n=111, ^b n=107, ^c n=105, ^d n=109, ^e n=108, ^f n=103.

Using an unpaired t-test or a chi-squared test.

Disposition index was calculated by multiplying AUC C-peptide by the glucose disposal rate.

***

Energy expenditure comprises only moderate to intense activity assessed by a physical activity questionnaire.

25(OH)D, 25-hydroxyvitamin D; BMI, body mass index; OGTT, oral glucose tolerance test; HOMA%S, homeostasis model assessment of insulin sensitivity; I, mean plasma insulin concentration during the last 30 min of the clamp; M/I, glucose disposal rate divided by the mean plasma insulin concentration during the last 30 min of the clamp; AUC, area under the curve; IL-6, interleukin-6.

Table 2 displays the variables associated with each one of the outcome measures in univariate regression analyses. Abnormal glucose tolerance status was significantly associated with lower insulin sensitivity, assessed by HOMA%S, GDR, or M/I, and with a decrease in β-cell function, but not with insulin secretion. On the other hand, lower serum 25(OH)D concentrations were significantly associated with lower insulin sensitivity, assessed by HOMA%S and GDR, and with lower insulin secretion, but not with β-cell function. Furthermore, visceral adipose tissue area as well as serum adiponectin and IL-6 concentrations were also significantly associated with all measures of insulin sensitivity, insulin secretion, and β-cell function. Age, physical activity, serum PTH concentrations, and dietary vitamin D and calcium intake were significantly associated with only some of the surrogate markers of T2DM risk.

Table 2.

Variables Associated with Measures of Insulin Sensitivity, Insulin Secretion, and β-Cell Function in Univariate Analyses

	HOMA%S index ^a		Glucose disposal rate		M/I ^a		AUC C-peptide ^a		Disposition index
Variables	β	P value	β	P value	β	P value	β	P value	β	P value
Glucose tolerance status (AGT vs. NGT)	−15.85	0.0008	−3.26	<0.0001	−0.005	0.0008	54,966	0.11	−1,041,514	<0.0001
Serum 25(OH)D concentrations	0.26	0.06	0.03	0.05	0.00003	0.20	−1853	0.02	1,293	0.84
Visceral adipose tissue area	−0.12	0.004	−0.03	<0.0001	−4.84e⁻⁵	<0.0001	791	0.006	−7,540	0.0002
Age	−0.72	0.12	−0.18	0.005	−0.0003	0.006	2,994	0.32	−63,029	0.01
Physical activity	2.83	0.0003	0.28	<0.0001	0.0004	0.0015	−8,683	0.01	430,001	0.13
Serum PTH concentrations	−0.64	0.001	−0.05	0.02	−0.00008	0.02	541	0.28	−10,827	0.16
Season of blood sampling (fall/winter vs. spring/summer)	0.87	0.76	0.25	0.67	0.0007	0.72	20,870	0.29	229,268	0.30
Serum adiponectin concentrations	2.02	<0.0001	0.31	<0.0001	0.0004	<0.0001	−9,077	0.001	73,241	0.001
Serum IL-6 concentrations	−6.84	0.003	−1.66	<0.0001	−0.0021	<0.0001	17,668	0.08	−509,980	<0.0001
Dietary vitamin D intake	−0.03	0.88	0.07	0.60	6.23e⁻⁶	0.22	−243	0.08	−22,540	0.64
Dietary calcium intake	−0.00	0.73	0.00	0.09	2.14e⁻⁶	0.06	−64	0.15	368	0.29

Log-transformed variable.

HOMA%S, homeostasis model assessment of insulin sensitivity; M/I, glucose disposal rate divided by mean plasma insulin concentration during the last 30 min of the clamp; AUC, area under the curve; AGT, abnormal glucose tolerance; β, beta coefficient; NGT, normal glucose tolerance; serum 25(OH)D, serum 25-hydroxyvitamin D; PTH, parathyroid hormone; IL-6, interleukin-6.

In multivariate regression analyses (Table 3), both abnormal glucose tolerance status and lower serum 25(OH)D concentrations were independently and significantly associated with lower insulin sensitivity, assessed by HOMA%S or GDR. Lower serum 25(OH)D concentrations were independently and significantly associated with higher insulin secretion, whereas abnormal glucose tolerance status was significantly and independently associated with a decrease in β-cell function. However, the interaction between glucose tolerance status and serum 25(OH)D concentration was not significant in the multivariate analyses evaluating either insulin sensitivity, insulin secretion, or β-cell function, even after adjustment for potential confounders (data not shown). These results indicate that glucose tolerance status does not influence the association between serum 25(OH)D and insulin sensitivity, insulin secretion, and β-cell function.

Table 3.

Associations Between Glucose Tolerance Status, Serum 25-Hydroxyvitamin D Concentrations, and Measures of Insulin Sensitivity, Insulin Secretion, and β-Cell Function in Multivariate Analyses

Outcomes	Variables	β	P value
HOMA%S index^a	Glucose tolerance status (NGT vs. AGT)	8.06	0.0008
	Serum 25(OH)D concentrations	0.27	0.04
	Glucose tolerance status ^* 25(OH)D^b	−0.10	0.35
Glucose disposal rate	Glucose tolerance status (NGT vs. AGT)	1.65	<0.0001
	Serum 25(OH)D concentrations	0.04	0.01
	Glucose tolerance status ^* 25(OH)D^b	−0.00	0.94
M/I^a	Glucose tolerance status (NGT vs. AGT)	0.0027	<0.0001
	Serum 25(OH)D concentrations	3.4e^–5	0.15
	Glucose tolerance status ^* 25(OH)D^b	−6.3e⁻⁶	0.79
AUC C-peptide^a	Glucose tolerance status (NGT vs. AGT)	−1,831	0.09
	Serum 25(OH)D concentrations	−28,734	0.02
	Glucose tolerance status ^* 25(OH)D^b	1,021	0.38
Disposition index	Glucose tolerance status (NGT vs. AGT)	522,205	<0.0001
	Serum 25(OH)D concentrations	2,631	0.68
	Glucose tolerance status ^* 25(OH)D^b	2,149	0.72

Log-transformed variable.

Interaction between glucose tolerance status and serum 25-hydroxyvitamin D concentration.

β, beta coefficient; HOMA%S, homeostasis model assessment of insulin sensitivity; NGT, normal glucose tolerance; AGT, abnormal glucose tolerance; serum 25(OH)D, serum 25-hydroxyvitamin D; M/I, glucose disposal rate divided by mean plasma insulin concentration during the last 30 min of the clamp; AUC, area under the curve.

Discussion

Our main objective was to determine whether glucose tolerance status affected the associations between serum 25(OH)D concentrations and insulin sensitivity, insulin secretion, and β-cell function in a sample of French Canadian postmenopausal women. We found that both abnormal glucose tolerance status and lower serum 25(OH)D concentrations were significantly associated with lower insulin sensitivity, assessed by HOMA%S or GDR. While lower serum 25(OH)D concentrations were significantly associated with higher insulin secretion, abnormal glucose tolerance status was significantly associated with a decrease in β-cell function. However, the interaction between glucose tolerance status and serum 25(OH)D concentration was not associated with any of the markers of T2DM risk, even after adjustment for several potential confounders. It thus suggests that the association between serum 25(OH)D concentrations and insulin sensitivity, insulin secretion, and β-cell function is not influenced by glucose tolerance status.

In line with our findings, most studies have shown a significant association between serum 25(OH)D concentrations and insulin sensitivity, insulin secretion, and β-cell function in healthy individuals^20
–22 as well as in people with abnormal glucose tolerance.²³ Chiu et al. investigated the relationship between 25(OH)D concentrations and insulin sensitivity in a population of 126 young (mean age 26 years) and healthy glucose-tolerant men and women living in California.²⁰ Insulin sensitivity index (ISI) and first- and second-phase insulin responses were assessed using a hyperglycemic clamp. The data showed a positive correlation between serum 25(OH)D concentration and insulin sensitivity, and a negative correlation between serum 25(OH)D and first and second insulin responses.²⁰ Another cross-sectional study by Kayaniyil et al. demonstrated independent and positive associations between serum 25(OH)D and both insulin sensitivity (Matsuda) and β-cell function [insulinogenic index/HOMA-insulin resistance (IR) and the insulin secretion sensitivity index-2] in a group of 712 men and women aged 30 years and over at high risk of T2DM and/or metabolic syndrome, after adjusting for sociodemographics, physical activity, supplement use, PTH, and BMI.²² The studies by Chiu and Kayaniyil demonstrated that the association between serum 25(OH)D, insulin sensitivity, and β-cell function is seen in healthy individuals as well as in people at high risk of T2DM. However, other studies have failed to demonstrate an association between vitamin D status and markers of T2DM risk across the spectrum of glucose tolerance status. For instance, the study by Al-Daghri et al. reported that the associations between serum 25(OH)D and metabolic disturbances were only seen in patients with T2DM.²³ In their sample of 266 men and women aged between 26 and 80 years from Saudi Arabia, negative correlations were observed between serum 25(OH)D and insulin resistance assessed by HOMA-IR in the 153 individuals with T2DM, but not in the healthy controls.²³ Overall, it appears that the association between serum 25(OH)D concentrations and insulin sensitivity, insulin secretion, and β-cell function according to the glucose tolerance status is variable among studies.

Several factors other than glucose tolerance status may explain the heterogeneity of results observed between studies evaluating the association between serum 25(OH)D and markers of T2DM risk. These include the variable precision of methods used to assess insulin sensitivity and insulin secretion. Moreover, important confounding factors such as adiposity are not always taken into account. Finally, it is also possible that differences in population characteristics, such as sex, age, ethnic background, and menopausal status may contribute to the variability of results. These factors would need to be evaluated specifically in larger and more diverse populations.

Our study has several limitations. First, our sample consisted entirely of French Canadian postmenopausal women. Thus, the external validity of our study is limited and results cannot be applied to premenopausal women, to men, or to other ethnic groups. Second, because of the inherent limitations of its cross-sectional design, our study cannot establish a causal relationship between serum 25(OH)D and insulin sensitivity, insulin secretion, and β-cell function in individuals with NGT and AGT. On the other hand, our study has strengths worthy of mention. First, we used the EHC, the gold standard method to assess insulin sensitivity. Furthermore, we accounted for multiple potential confounding factors in our analyses, including age, physical activity, serum PTH concentrations, seasonality, adiponectin and cytokine concentrations, and, most importantly, visceral adiposity.

In conclusion, we have demonstrated that serum 25(OH)D concentrations and glucose tolerance status are independently associated with hepatic and peripheral measures of insulin sensitivity, insulin secretion, and β-cell function. However, the association between serum 25(OH)D and insulin sensitivity, insulin secretion, and β-cell function is not influenced by glucose tolerance status. Thus, it is unlikely that this factor contributes to the heterogeneity of the results among studies evaluating the association between vitamin D status and markers of T2DM risk.

Footnotes

Acknowledgments

This study was supported by funds from Laval University and the CHU de Québec Research Centre to measure serum 25(OH)D. The Heart and Stroke Foundation of Canada and the Canadian Institutes of Health Research financed the conduct of the original study.

Author Disclosure Statement

No competing financial interests exist.

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