Altered Glucose Metabolism and Vitamin D in Severe Obesity
Altered Glucose Metabolism and Vitamin D in Severe Obesity
Context: The last decades have provided insights into vitamin D physiology linked to glucose homeostasis. Uncertainties remain in obesity due to its intrinsic effects on vitamin D and glucose tolerance.
Objectives: To assess the relationship between vitamin D and glucose abnormalities in severely obese individuals previously unknown to suffer from abnormal glucose metabolism.
Setting: Tertiary care centre.
Patients: 524 obese patients (50.3 ± 14.9 yrs; BMI, 47.7 ± 7.3 kg/m) screened by OGTT, HbA1c and the lipid profile. Vitamin D status was assessed by 25(OH)D3, PTH and electrolyte levels. 25(OH)D3 deficiency/insufficiency were set at 20 and 30 ng/ml, respectively. All comparative and regression analyses were controlled for age, BMI and gender.
Results: The prevalence of vitamin D deficiency/insufficiency and secondary hyperparathyroidism were 95% and 50.8%, respectively. Normal glucose tolerance (NGT), impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), and type 2 diabetes mellitus (T2DM) were found in 37.8%, 40.5% and 21.7% of cases, respectively. Large variations in metabolic parameters were seen across categories of vitamin D status, but the only significant differences were found for C-peptide, tryglicerides, LDL- and HDL-cholesterol levels (p < 0.05 for all). The prevalence of vitamin D deficiency was documented to be slightly but significantly more frequent in glucose-intolerant patients (IFG + IGT + T2DM) compared to the -normotolerant counterpart (87% vs. 80%, p < 0.05). In partial correlation analyses, there was no association between vitamin D levels and glucose-related markers but for HbA1c (r = −0.091, p < 0.05), and both basal and OGTT-stimulated insulin levels (r = 0.097 and r = 0.099; p < 0.05 for all). Vitamin D levels were also correlated to HDL-cholesterol (r = 0.13, p = 0.002). Multivariate regression analysis inclusive of vitamin D, age, BMI, gender and fat mass as independent variables, showed that vitamin D was capable of predicting HbA1c levels (β = −0.101, p < 0.05).
Conclusions: Given the inherent effect of obesity on vitamin D and glucose homeostasis, current data suggest a potential independent role for vitamin D in the regulation of glucose metabolism in a setting of obese patients previously unknown to harbour glucose metabolism abnormalities.
Vitamin D is a secosteroid hormone, with an established role in bone homeostasis. Its di-hydroxylated active metabolite, 1,25(OH)2D3, binds the vitamin D nuclear receptor (VDR) and translocates to the nucleus to regulate gene expression. Being the VDR located in several cells and tissues, a number of new hypothetical functions have been postulated to expand vitamin D role beyond its ability to regulate calcium homeostasis. As such, VDR has been found to affect 229 human genes, and in vivo and in vitro studies have increasingly linked vitamin D homeostasis to cardiovascular, autoimmune, tumoral, pulmonary and neurological diseases.
Assessment of vitamin D status relies on plasma measurement of its circulating metabolite, 25-hydroxyvitamin D (25(OH)D3), which is more stable, has a longer half-life and reflects vitamin D storage more accurately than the active form. Although no definitive consensus currently exists on the lowest 25(OH)D3 levels of normalcy, the 25(OH)D3 threshold of 30 ng/ml (75 nmol/l) is deemed as adequate for fracture prevention in the general older population, while the 20 ng/ml cutoff limit has been alternatively suggested to differentiate populations at true risk for the effects of vitamin D deficiency. Cohort studies showed that vitamin D inadequacy occurs in approximately 36% of otherwise healthy young adults and up to 57% of inpatients, with even higher rates applying to European populations.
Causal factors of vitamin D deficiency include aging, longer life expectancy, lifestyle habits, and metabolic disorders. An increased proportion of body fat as well as obesity have been documented to decrease bioavailability of cholecalciferol, due to its preferential accumulation in the adipose tissue. Especially, a deranged vitamin D status may reflect an increased risk of type 2 diabetes mellitus (T2DM) in the general population. While it is not completely clarified how vitamin D acts on glucose metabolism, postulated mechanisms include direct effects on insulin synthesis and release mediated by the VDR, and negative effects on insulin sensitivity elicited by secondary elevation of PTH levels. As vitamin D upregulates lipoprotein lipase (LPL), this latter has been suggested to act as a potential link between vitamin D and glucose metabolism. Nevertheless, the potential effects of vitamin D status on insulin sensitivity are debated, as the correlation between vitamin D and response to insulin has been found direct by some studies and modestly significant by others. Recently, Muscogiuri and colleagues found that the correlation between low vitamin D levels and insulin resistance could be influenced by obesity, which was demonstrated to be the only predictor of low vitamin D levels by multivariate analysis.
In this study, we aimed at exploring the relationship between vitamin D status and glucose homeostasis following screening for T2DM in a population of obese patients previously undiagnosed with abnormalities of glucose metabolism. To this purpose, our aims were: to subject obese patients to screening of glucose tolerance and insulin resistance by the OGTT and HbA1c levels, and evaluation of the lipid profile; to assess the prevalence of hypovitaminosis D and secondary hyperparathyroidism in severe obesity; to examine the relationship linking low vitamin D concentrations to glucose intolerance, T2DM and lipid markers after correction for key variables linked to these parameters; to identify a predictive role of vitamin D concentrations on glucose and lipid metabolism in this cohort.
Abstract and Introduction
Abstract
Context: The last decades have provided insights into vitamin D physiology linked to glucose homeostasis. Uncertainties remain in obesity due to its intrinsic effects on vitamin D and glucose tolerance.
Objectives: To assess the relationship between vitamin D and glucose abnormalities in severely obese individuals previously unknown to suffer from abnormal glucose metabolism.
Setting: Tertiary care centre.
Patients: 524 obese patients (50.3 ± 14.9 yrs; BMI, 47.7 ± 7.3 kg/m) screened by OGTT, HbA1c and the lipid profile. Vitamin D status was assessed by 25(OH)D3, PTH and electrolyte levels. 25(OH)D3 deficiency/insufficiency were set at 20 and 30 ng/ml, respectively. All comparative and regression analyses were controlled for age, BMI and gender.
Results: The prevalence of vitamin D deficiency/insufficiency and secondary hyperparathyroidism were 95% and 50.8%, respectively. Normal glucose tolerance (NGT), impaired fasting glucose (IFG) or impaired glucose tolerance (IGT), and type 2 diabetes mellitus (T2DM) were found in 37.8%, 40.5% and 21.7% of cases, respectively. Large variations in metabolic parameters were seen across categories of vitamin D status, but the only significant differences were found for C-peptide, tryglicerides, LDL- and HDL-cholesterol levels (p < 0.05 for all). The prevalence of vitamin D deficiency was documented to be slightly but significantly more frequent in glucose-intolerant patients (IFG + IGT + T2DM) compared to the -normotolerant counterpart (87% vs. 80%, p < 0.05). In partial correlation analyses, there was no association between vitamin D levels and glucose-related markers but for HbA1c (r = −0.091, p < 0.05), and both basal and OGTT-stimulated insulin levels (r = 0.097 and r = 0.099; p < 0.05 for all). Vitamin D levels were also correlated to HDL-cholesterol (r = 0.13, p = 0.002). Multivariate regression analysis inclusive of vitamin D, age, BMI, gender and fat mass as independent variables, showed that vitamin D was capable of predicting HbA1c levels (β = −0.101, p < 0.05).
Conclusions: Given the inherent effect of obesity on vitamin D and glucose homeostasis, current data suggest a potential independent role for vitamin D in the regulation of glucose metabolism in a setting of obese patients previously unknown to harbour glucose metabolism abnormalities.
Introduction
Vitamin D is a secosteroid hormone, with an established role in bone homeostasis. Its di-hydroxylated active metabolite, 1,25(OH)2D3, binds the vitamin D nuclear receptor (VDR) and translocates to the nucleus to regulate gene expression. Being the VDR located in several cells and tissues, a number of new hypothetical functions have been postulated to expand vitamin D role beyond its ability to regulate calcium homeostasis. As such, VDR has been found to affect 229 human genes, and in vivo and in vitro studies have increasingly linked vitamin D homeostasis to cardiovascular, autoimmune, tumoral, pulmonary and neurological diseases.
Assessment of vitamin D status relies on plasma measurement of its circulating metabolite, 25-hydroxyvitamin D (25(OH)D3), which is more stable, has a longer half-life and reflects vitamin D storage more accurately than the active form. Although no definitive consensus currently exists on the lowest 25(OH)D3 levels of normalcy, the 25(OH)D3 threshold of 30 ng/ml (75 nmol/l) is deemed as adequate for fracture prevention in the general older population, while the 20 ng/ml cutoff limit has been alternatively suggested to differentiate populations at true risk for the effects of vitamin D deficiency. Cohort studies showed that vitamin D inadequacy occurs in approximately 36% of otherwise healthy young adults and up to 57% of inpatients, with even higher rates applying to European populations.
Causal factors of vitamin D deficiency include aging, longer life expectancy, lifestyle habits, and metabolic disorders. An increased proportion of body fat as well as obesity have been documented to decrease bioavailability of cholecalciferol, due to its preferential accumulation in the adipose tissue. Especially, a deranged vitamin D status may reflect an increased risk of type 2 diabetes mellitus (T2DM) in the general population. While it is not completely clarified how vitamin D acts on glucose metabolism, postulated mechanisms include direct effects on insulin synthesis and release mediated by the VDR, and negative effects on insulin sensitivity elicited by secondary elevation of PTH levels. As vitamin D upregulates lipoprotein lipase (LPL), this latter has been suggested to act as a potential link between vitamin D and glucose metabolism. Nevertheless, the potential effects of vitamin D status on insulin sensitivity are debated, as the correlation between vitamin D and response to insulin has been found direct by some studies and modestly significant by others. Recently, Muscogiuri and colleagues found that the correlation between low vitamin D levels and insulin resistance could be influenced by obesity, which was demonstrated to be the only predictor of low vitamin D levels by multivariate analysis.
In this study, we aimed at exploring the relationship between vitamin D status and glucose homeostasis following screening for T2DM in a population of obese patients previously undiagnosed with abnormalities of glucose metabolism. To this purpose, our aims were: to subject obese patients to screening of glucose tolerance and insulin resistance by the OGTT and HbA1c levels, and evaluation of the lipid profile; to assess the prevalence of hypovitaminosis D and secondary hyperparathyroidism in severe obesity; to examine the relationship linking low vitamin D concentrations to glucose intolerance, T2DM and lipid markers after correction for key variables linked to these parameters; to identify a predictive role of vitamin D concentrations on glucose and lipid metabolism in this cohort.
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