Vitamin D is a hormone derived from cholesterol in the skin with the effect of ultraviolet rays (1). Vitamin D deficiency is a common condition today, due to life indoors and use of sunscreens (2,3,4,5). While the effects of low levels of vitamin D on osteomalacia, rachitis and osteoporosis are known, many recent studies have demonstrated the association of low vitamin D levels with malignancies, fracture risk, inflammation, cardiovascular disorders and diabetes (6). The relationship between vitamin D deficiency and diabetes mellitus, both type 1 and 2, has been shown by several studies (7,8,9). Measurement of hydroxy vitamin D [25(OH)D] is acknowledged to provide an indicator of vitamin D status of an individual patient (10). In addition, low serum calcium and phosphorus levels, increased serum alkaline phosphatase and parathormone levels and reduced urinary calcium elimination may also suggest vitamin D deficiency. Diabetic patients, particularly poorly controlled ones, may have further alterations in their calcium metabolism in addition to vitamin D deficiency. Osmotic diuresis secondary to glycosuria in patients with type 1 and type 2 diabetes mellitus has been shown to increase urinary calcium and phosphorus elimination (11,12). Vitamin D deficiency leads to secondary hyperparathyroidism by increasing parathormone release. In type 1 diabetic patients with vitamin D deficiency, however, it was shown that parathormone levels did not elevate adequately, resulting in functional hypoparathyroidism. The mechanism held responsible for this is hypomagnesemia resulting from osmotic diuresis (13,14). The association of poorly-controlled type 2 diabetes mellitus with functional hypoparathyroidism has not been established (11). The present study aims to investigate the extent of vitamin deficiency and its effect on calcium metabolism in patients with type 2 diabetes mellitus.
The study was conducted in the endocrinology outpatient clinic at Van Yüzüncü Yıl University Medical Faculty. Patients with type 2 diabetes mellitus who presented to the endocrinology outpatient clinic for regular check-up between August 2013 and October 2013 were included in the study.
Fasting blood glucose, HbA1c, calcium, phosphorus, magnesium, albumin, creatinine, parathormone, 25(OH)D, spot urine calcium and creatinine levels were studied for each patient. Biochemical assays were performed with Cobus Integra® 800, parathormone levels were measured by Architec® i4000 and 25(OH)D levels were evaluated by HPLC with HP Agilent® 1200 using commercial kits.
Patients with chronic renal failure, chronic hepatic disease, primary hyperparathyroidism and those with conditions that may impair calcium and Vitamin D metabolism including conditions requiring diuretic use and patients with type 2 diabetes mellitus receiving calcium and/or vitamin D for osteoporosis were excluded.
A total of 132 patients meeting the inclusion criteria were grouped according to 25(OH)D levels as <30 ng/mL and <20 ng/mL, according to parathormone levels as below and above 65 ng/mL, and according to HbA1c levels as below and above 10%.
The results were analyzed using the SPSS 16 statistics software. Two groups comparisons were performed with the Unpaired t-test. Chi-square test was used to determine the relationships between categorical variables. Pearson’s test was used for correlation analysis. The results were expressed as mean ± standard deviation and statistical significance was set at p<0.05.
The study included 132 patients with type 2 diabetes mellitus. Of these, 53% were females and 47% were males, and their average age was 54.7 years. Vitamin D levels below 30 ng/mL were detected in 96.9% (n=128) and vitamin D levels below 20 ng/mL in 78.7% (n=102). Descriptive statistics of the patients included in the study are provided in Table 1.
Of the 128 patients with 25(OH)D levels below 30 ng/mL, the percentages of those with HbA1c levels above and below 10% were 42% and 58%, respectively. The patients with impaired blood sugar regulation (HbA1c >10%) had lower levels of PTH, albumin and 25 (OH) vitamin D and higher levels of phosphorus compared to those with HbA1c levels below 10% (p=0.018, p=0.043, p=0.002, p=0.01, respectively) (Table 2).
HbA1c levels in 74 patients were below 10%. Of these, 56.75% (n=42) were female, 43.25% (n=32) were male. HbA1c levels in 54 patients were above 10%. Of these, 57.4% (n=31) were female, 42,60% (n=23) were male. Only 25(OH)D levels were significantly lower in females compared to that in males in subgroup analysis according to gender (p<0.001 for both groups).
The frequencies of functional hypoparathyroidism (parathormone <65 ng/mL) in patients with vitamin D level <30 ng/mL and <20 ng/mL were 63.2% and 59.6%, respectively. The distribution of patients with functional hypoparathyroidism among those with HbA1c levels above and below 10% is shown in Figure 1. The number of patients with functional hypoparathyroidism in the subset of patients with HbA1c >10% was markedly higher (p=0.035 and p=0.031 for patients with vitamin D levels below 30 ng/mL and below 20 ng/mL, respectively).
Comparison of cases with parathormone levels below and above 65 ng/mL in diabetic patients with vitamin D levels <30 ng/mL is shown in Table 3. The number of patients with parathormone levels below and above 65 ng/mL was 81 and 47, respectively. Phosphorus and urine calcium/creatinine levels were higher and magnesium levels were significantly lower in those with functional hypoparathyroidism (parathormone <65 ng/mL) compared to those with secondary hyperparathyroidism (p=0.009, p=0.001, p=0.015, respectively).
Parathormone levels in 81 patients were below 65 ng/mL. Of these, 50.6% (n=41) were female, 49.4% (n=40) were male. Parathormone levels in 47 patients were above 65 ng/mL. Of these, 68.08% (n=32) were female, 31.02% (n=15) were male. Only 25(OH)D levels were significantly lower in females compared with males in subgroup analysis according to gender (p<0.001 and p=0.012 for patients with parathormone levels below 65 ng/mL and above 65 ng/mL, respectively).
With Pearson’s correlation analysis of patients with vitamin D deficiency, PTH was positively correlated with alkaline phosphatase and negatively correlated with urine calcium creatinine (r=0.462, p<0.001; r=-0.346, p<0.001, respectively). Calcium was negatively correlated with HbA1c and positively correlated with vitamin D (r=-0.215, p=0.016; r=0.206, p=0.021, respectively). Phosphorus was negatively correlated with vitamin D (r=-0,194, p=0.033). Vitamin D was negatively correlated with ALP and HbA1c (r=-0,235, p=0.019; r=-0,295, p=0.001, respectively).
In our study, 96.9% of the patients with type 2 diabetes mellitus had vitamin D levels below 30 ng/mL and 78.7% below 20 ng/mL. In poorly-controlled diabetic patients (HbA1c >10), vitamin D levels were lower than in those with HbA1c <10% (p=0.002). There was a corresponding negative correlation between vitamin D and HbA1c levels (p=0.001). This correlation was probably associated with the effect of vitamin D on insulin secretion. Presence of vitamin D receptors in pancreatic beta cells was demonstrated previously, and vitamin D supplementation given to type 2 diabetic patients with vitamin D deficiency has been shown to improve insulin release and diminish insulin resistance by several studies (15,16,17,18).
In our poorly-controlled diabetic patients (HbA1c >10), parathormone levels as well as vitamin D levels were lower compared to those with HbA1c levels <10% (p=0.018). This was probably associated with the effect of hyperglycemia and/or glycosuria on calcium metabolism. Sugimoto et al. demonstrated that glucose at high concentrations inhibited parathormone secretion in bovine parathyroid cell culture (19). This in vitro evidence was later supported by several clinical studies. For example, Polymeris et al. reported parathormone reduction, which was negatively correlated with increases in blood glucose levels, during oral glucose tolerance test in non-diabetic postmenopausal women (20). There are also similar studies with comparable results in patients with type 1 diabetes mellitus. In one of these, Thalasinos et al. demonstrated elevated parathormone levels following blood sugar regulation in patients with poorly-controlled type 1 diabetes mellitus (11). McNair et al. also reported that low serum immunoreactive parathroid hormone levels were correlated with high glycosuria and long duration of diabetes mellitus in patients with type 1 diabetes mellitus (21). Besides impaired blood sugar regulation, magnesium loss developing during osmotic diuresis secondary to glycosuria is another mechanism held responsible for impaired parathormone secretion in patients with type 1 diabetes mellitus. As such, chronic magnesium deficiency impairs parathormone release, resulting in functional hypoparathyroidism (22). In a study by Sagesse et al. in patients with type 1 diabetes mellitus, magnesium replacement resulted in increased parathormone levels, which is supportive of the above evidence (14). Similarly, Paula et al. demonstrated blunted parathormone responses to hypocalcemia induced by EDTA infusion in most type 1 diabetes mellitus patients with poor metabolic control. This study also determined low serum magnesium levels in poorly-controlled diabetic patients compared to controls (23). However, there is a very limited number of studies in the literature investigating the effect of poorly-controlled type 2 diabetes mellitus on parathormone secretion and the results conflict with those obtained with subjects with type 1 diabetes mellitus. In their study comparing subjects with type 1 and type 2 diabetes mellitus, Thalassinoss et al. reported that parathormone secretion was maintained in subjects with type 2 diabetes mellitus (11). The study was limited due to the limited number of type 2 diabetic subjects enrolled (37) and the lack of analysis on vitamin D levels. Similarly, there are published data demonstrating reduced parathormone levels following blood sugar regulation and lack of a relationship between blood glucose levels and parathormone in poorly-controlled type 2 diabetes mellitus patients as opposed to the findings obtained with type 1 diabetes mellitus patients (12,24). Likewise, vitamin D levels were not investigated in these studies. Vitamin D deficiency is associated with an increase in parathormone levels. Absence of elevated parathormone levels in vitamin D deficiency is defined as functional hypoparathyroidism (24). In our study, the frequency of functional hypoparathyroidism was higher in patients with impaired blood sugar regulation (HbA1c >10). Magnesium levels were also lower in these patients with functional hypoparathyroidism. This finding was consistent with functional hypoparathyroidism resulting from osmotic diuresis due to glycosuria in patients with type 1 diabetes.
In conclusion, our study is important in that it is the first to demonstrate the increased frequency of functional hypoparathyroidism in patients with type 2 diabetes mellitus with impaired blood sugar regulation, which was described previously for patients with type 1 diabetes mellitus. This should be evaluated by further studies to investigate the effects on bone loss and fragility in patients with type 2 diabetes mellitus.
Conflicts of Interest
There are no conflicts of interest.
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