25(OH)D Deficiency and Metabolic Control of Diabetes: A Problematic Balance

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1 Monari M,, 2017, 1:1 SciFed Nursing & Healthcare Journal Research Article Open Access 25(OH)D Deficiency and Metabolic Control of Diabetes: A Problematic Balance *1 Monari M, 1 Bianchi P, 1 Maura F, 1 Motta L, 2 Berra C, 2 Mirani M, 3 Montanelli A *1 Clinical investigation Laboratory, Humanitas Clinical and Research Center, Rozzano, Milan, Italy 2 Metabolic Section, Department of Internal Medicine Humanitas Clinical and Research Center, Rozzano, Milan, Italy 3 Clinical Investigation Laboratory, Diagnostics Department, Spedali Civili of Brescia, Brescia, Italy Abstract Increasing evidence suggests that vitamin D plays a role in the development of chronic diseases including type 2 diabetes (DM). Aim of the study was to explore the association of vitamin D levels with prevalent DM and we will focus our attention in a Northern Italy population. Methods This cross-sectional study involved 614 not compensed diabetic patients and 446 compensed subjects. Clinical characteristics were available including blood samples to determine vitamin D levels and diabetes status by fasting plasma glucose (FPG) and glycosylated haemoglobin (HbA1c). Vitamin D was grouped in four categories (<10 ng/ ml, ng/ml, ng/ml, 30 ng/ml). Bivariate associations between vitamin D categories and a composite indicator for DM (FPG 126 mg/dl or HbA1c 6.5% or self-reported diagnosis) were calculated; statistical models were used to test this association. Results (83.1% male, mean age 51.9±5.6 years). Severe vitamin D deficiency (<10 ng/ml) was associated with increasing FPG (β 3.13; 95% CI: 0.78, 5.47; p 0.01) and HbA1c (β 0.15; 95% CI: 0.08, 0.23; p 0.001) values in adjusted linear regression models Conclusions Vitamin D deficiency is associated with prevalent DM in adults. Keywords Diabetes; Evaluation; Chronic Disease; Comparative Effectiveness Introduction The prevalence of Vitamin D (25-hydroxyvitamin D, 25(OH)D) deficiency is an important public health problem because of its great impact on bone metabolism and its possible implication in cardiovascular outcome, diabetes, cancer and mortality [1]. Deficiency of 25(OH) D has been characterized by a concentration < 20 ng/ml (50nmol/L) and has been well recognized as a cause of rickets and adult osteomalacia. The suggested relationship between type 1 diabetes mellitus and 25(OH)D deficiency has been extensively reported [2]. These effects have been mainly attributed to the immune-modulatory actions of vitamin D [3]. Lack of knowledge still exists concerning association between 25(OH)D and type 2 diabetes mellitus. *Corresponding author: Monari M, Clinical investigation Laboratory, Humanitas Clinical and Research Center, Rozzano, Milan, Italy. marta_noemi.monari@humanitas.it Received June 26, 2017; Accepted July 15, 2017; Published August 04, 2017 Citation: Monari M (2017) 25(OH)D Deficiency and Metabolic Control of Diabetes: A Problematic Balance. 1:1. Copyright: 2017 Monari M. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. page 1 of 5

2 Citation: Monari M (2017) 25(OH)D Deficiency and Metabolic Control of Diabetes: A Problematic Balance. 1:1. Vitamin D causes reduced insulin secretion in humans and its replenishment improves β-cell function and glucose tolerance [4]. Allelic variations in the vitamin D receptor and vitamin D binding protein might influence glucose tolerance and insulin secretion thus contributing to the genetic risk for type 2 diabetes [5]. Observational studies have related vitamin D deficiency with the prevalence of diabetes but only few prospective studies had linked levels of 25-hydroxyvitamin D to the incidence of type 2 diabetes [6]. Glycosylated haemoglobin (HbA1c) is a form of haemoglobin that it was considered as a marker for average blood glucose levels over the previous 3 months, and in diabetes mellitus, higher amounts of glycosylated haemoglobin, indicating poorer control of blood glucose levels. Our study is aimed to examine the relationship between Vitamin D serum levels and plasma HbA1c levels in a cohort of people of North Italy during an observational study of one year. Patients and Methods Patients We matched 614 not compensed diabetic patients with 446 compensed subjects for vitamin D levels, for a total of 1060 subjects. This patients cohort enrolled only outpatients underwent insulin therapy and with a followup period higher than 10 years. Diagnosis of type 2 diabetes Following the criteria of the American Diabetes Association [7] and consensus statements issued by the World Health Organization (WHO), International Diabetes Federation, and European Association for the Study of Diabetes and for ADA revision guidelines and, diabetes mellitus was considered present if at least one of the following criteria was met: (1) two FPG 126 mg/ dl (7.0 mmol/l); (2) two HbA1c 6.5% (48 mmol/mol); [8] self-reported diabetes with confirmation of physician diagnosis. Classification of vitamin D levels We used widely accepted cut-off values for 25(OH)D to create four categories: Severe deficiency, <10 ng/ml (25 nmol/l); moderate deficiency, ng/ml ( nmol/l); insufficiency, ng/ml ( nmol/l); sufficiency, 30 ng/ml (75 nmol/l) [9, 10]. Methods 25(OH)D concentration on serum samples was measured by a competitive assay (25(OH) vitamin D TOTAL, Liaison, DiaSorin, USA) with the analytical performances of: sensitivity 1 ng/ml; linearity ng/ml, CV intra-serie 5% and inter-series 10%. The normal range proposed by Manufacturer s laboratory kit is ng/ml. HbA1c concentration was determined by a chromatographic separation on a ion exchange high performance (HPLC, Bio-Rad Laboratories GmbH, Munchen, Germany). The VARIANT II Clinical Data Manager (CDM) software is used for the analysis of the data. The different areas of the chromatogram are calculated using an exponentially modified Gaussian (EMG) algorithm and the results are expressed both in % of areas and mmol/molhb. The normal range proposed is 4-6 % end mmol/mol Hb. Data Analysis Demographic characteristics are showed as the mean value ± standard deviation (SD) and as frequencies and percentages for categorical variables. We tested linear trend for continuous variables and used the p for linear-bylinear test for categorical variables. Results Demographics The mean age in not compensed diabetic patients was 69.5+/ (range 55-98) with 65% women and 35% men, in the compensed group a mean age was of years+/- 12 years (range 51-99) with a 72% of women and 28% of men. 15% of patients were current smokers. The excluded subjects did not differ significantly from those included in the analysis with respect to age, gender, and smoking status. Data Analysis The mean 25(OH)D concentration were ng/ml in compensed group and ng/ml in non compensed patients with a median concentration of 5.9% ± 1.95 in the first (mmol/ ml) and 8.57% ± 3.9 ( mmol/ ml) in the second one. We focused our observation on the median levels of 25(OH)D between two groups of diabetic patients and we registered that in non compensed the levels of VIT D is lower than in compensed (Figure1). page 2 of 5

3 Citation: Monari M (2017) 25(OH)D Deficiency and Metabolic Control of Diabetes: A Problematic Balance. 1:1. Figure1. We compared the median levels of VitD and glycosilated haemoglobin: group 1 are not compensed patients and group 2 are compensed patients. The blue columns are median levels of vitamd D the red columns are median levels of glycosilated haemoglobin We have classified the 25(OH)D concentration data on the basis of : a) normal range proposed by Manufacturer; b) by the set point 20 ng/ml as proposed by Ioh; c) by the set point 32 ng/ml as Bischoff-Ferrari HA and Binkley N [9, 11]. The evaluation of results by three different classifications is summarized in Table n o 1 and 2. We also analyzed the 25(OH)D in relationship to the haemoglobin glycosylated in the 222 diabetic patients and we matched the data in accord to the level of 6.5% (32.5 mmol/mol) as a cut off of diabetic compensation status, where the international guideline proposed the gold standard for haemoglobin glycosylated is less than 7% for compensed patients with a low risk of comorbidity. We focused our attention to the two more restrictive set point of 20 ng/ml and 32 ng/ml of 25(OH)D (table n 2). We also followed three patients, for a pilot study, during six months and we analyzed the correlation between the 25(OH)D status in compensed of not compensed patients. In patients one and three the increases of glycosilated haemoglobin correlate with the decrease of 25(OH)D levels; in patients 2 we observed that both metabolites are stable (Figure n 2) Figure 2. variation of the two metabolite analyzed during time for trhee different patients Table1. Patients classification from different criteria of Vitamin D references divided for sex and different proposed cuts Scompensed Compensed ng/ml WOMEN 83 (57%) 155 (76%) MEN 44 (56%) 76 (73%) <20 ng/ml WOMEN 92 (63%) 112 (55%) MEN 50 (64%) 69 (66%) <32 ng/ml WOMEN 115 (79%) 164 (80%) MEN 69 (88%) 85 (81%) Table2. Summary of patient s classification based on the different set points proposed. Only 32%of patents are deficient for VitD if we adopt the normal range ng/ml, in contrast 88% are deficient for VitD if we adopt the normal range <32 ng/ml Scompensed Compensed ng/ml 127 (57%) 231 (75%) <20 ng/ml 142 (64%) 181 (59%) <32 ng/ml 184 (83%) 249 (81%) Discussion The relationship between HbA1c and 25(OH)D levels show an inverse correlation which demonstrated strong and mutual relations. Low levels of 25(OH)D has been already reported in patients with type 2 diabetes [8, 12-15]. With the data available, it is not possible to speculate about the intrinsic biochemical mechanism to establishing a negative synergism between the levels of two different molecules. However we can observe that the diabetic patients in good metabolic control have higher values of 25(OH)D [16, 17]. This observation also underlined by data collected in monitoring of three patients from which it appears that improvement of metabolic control are correlated an increase in vitamin D as already reported by Zoppini G et page 3 of 5

4 Citation: Monari M (2017) 25(OH)D Deficiency and Metabolic Control of Diabetes: A Problematic Balance. 1:1. al [18]. The definition of 25(OH)D status and serum levels could be very important in terms of therapeutic decisions. Defining normal/abnormal values is a critical step before the clinical use of a biomarker (2). At least three potential approaches exist for defining abnormal biomarker levels: (1) reference limits (2) discrimination limit (3) threshold defining risk or desirable level. The choice of a different approach for defining abnormal levels, can lead to inappropriate clinical evaluation of patients. Accordingly reference values should be defined for different pathology and subsets of. So for the assay used in the course of this study, the normal values are represented by the range ng / ml. Currently the literature is oriented towards a cut-off that defines an optimal level, but unfortunately there is no consensus about the proposals range (> 20 ng / ml,> 25 ng / ml,> 32 ng / ml) [9]. According to these criteria the clinical meaning of the data, clearly shifts significantly the supplementation accordingly with the cut off chosen. The latest indications from the literature [9] tend to outline that optimal levels can vary for different patients types and different clinical purposes, and this lack of consensus make necessary to find an agreement between clinical laboratory and physicians on the mode of reporting of the analytical data. On the basis of this consideration, remains to be determined what is the optimal levels to be achieved and validated, and it is the duty of the laboratory to give an help to the clinicians in defining them. As matured even from this limited experience, the value of 25 ng / ml could be considered applicable as the cut-off for the general population, while remains still debated, at scientific level, the question about how to define the optimal value for specific diseases, targeted to the aim of prevention and/or treatment. Conclusion The measurement of vitamin D levels in the blood is a punctual reference in the bioavailability of the vitamin to the organism. Current technologies allow rapid determination at low cost that might positively influencing the clinical making decision in many important diseases, by supplementation when the vitamin D low levels are well documented. In the clinical setting, should exists a close collaboration between the laboratory and the clinicians to better define the optimal levels according to the patient s course and on the basis of the disease. Therefore it is desirable that remarks should appear in the lab report.the findings highlight may be the start point for conducting large-scale health screening to identify those patients at risk of DM using vitamin D dosage. References 1. Holick MF (2010) Vitamin D: extraskeletal health. Endocrinology and metabolism clinics of North America 39: Afzal S, Brondum-Jacobsen P, Bojesen SE, et al. (2014) Vitamin D concentration, obesity, and risk of diabetes: a mendelian randomisation study. The lancet Diabetes & endocrinology 2: Baeke F, van Etten E, Gysemans C, et al. (2008) Vitamin D signaling in immune-mediated disorders: Evolving insights and therapeutic opportunities. Molecular aspects of medicine 29: Kayaniyil S, Retnakaran R, Harris SB, et al. (2011) Prospective associations of vitamin D with beta-cell function and glycemia: the PROspective Metabolism and ISlet cell Evaluation (PROMISE) cohort study. Diabetes 60: Alvarez JA, Ashraf A (2010) Role of vitamin d in insulin secretion and insulin sensitivity for glucose homeostasis. International journal of endocrinology. 6. Hurskainen AR, Virtanen JK, Tuomainen TP, et al. (2012) Association of serum 25-hydroxyvitamin D with type 2 diabetes and markers of insulin resistance in a general older population in Finland. Diabetes/metabolism research and reviews 28: Puavilai G, Chanprasertyotin S, Sriphrapradaeng A (1999) Diagnostic criteria for diabetes mellitus and other categories of glucose intolerance: 1997 criteria by the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (ADA), 1998 WHO consultation criteria, and 1985 WHO criteria. World Health Organization. Diabetes research and clinical practice 44: Mathieu C, Gysemans C, Giulietti A, et al. (2005) Vitamin D and diabetes. Diabetologia 48: Bischoff-Ferrari HA, Giovannucci E, Willett WC, et al. (2006) Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. The American journal of clinical nutrition 84: Boucher BJ, Mannan N, Noonan K, et al. (1995) Glucose intolerance and impairment of insulin secretion in relation to vitamin D deficiency in east London Asians. Diabetologia. 38: page 4 of 5

5 Citation: Monari M (2017) 25(OH)D Deficiency and Metabolic Control of Diabetes: A Problematic Balance. 1: Binkley N, Krueger D, Gemar D, et al. (2008) Correlation among 25-hydroxy-vitamin D assays. The Journal of clinical endocrinology and metabolism 93: Cigolini M, Iagulli MP, Miconi V, et al. (2006) Serum 25-hydroxyvitamin D3 concentrations and prevalence of cardiovascular disease among type 2 diabetic patients. Diabetes care. 29: Hutchinson MS, Figenschau Y, Njolstad I, et al. (2011) Serum 25-hydroxyvitamin D levels are inversely associated with glycated haemoglobin (HbA(1c)). The Tromso Study. Scandinavian journal of clinical and laboratory investigation 71: Kositsawat J, Freeman VL, Gerber BS, et al. (2010) Association of A1C levels with vitamin D status in U.S. adults: data from the National Health and Nutrition Examination Survey. Diabetes care 33: Maxwell CS, Wood RJ (2011) Update on vitamin D and type 2 diabetes. Nutrition reviews 69: Ozfirat Z, Chowdhury TA (2010) Vitamin D deficiency and type 2 diabetes. Postgraduate medical journal 86: Tahrani AA, Ball A, Shepherd L, et al. (2010) The prevalence of vitamin D abnormalities in South Asians with type 2 diabetes mellitus in the UK. International journal of clinical practice 64: Zoppini G, Galletti A, Targher G, et al. (2013) Glycated haemoglobin is inversely related to serum vitamin D levels in type 2 diabetic patients. PloS one 8: e Citation: Monari M (2017) 25(OH)D Deficiency and Metabolic Control of Diabetes: A Problematic Balance. 1:1. page 5 of 5