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Calcium Regulating in Children with Dependent Mellitus (IDDM) Hanan G. Azouz, 1 Mohamed Kamal Ghitany,2 and Zakaria A. Olyan 3 From the department of Pediatrics,1 Internal Medicine, 2 Faculty of Medicine, Alexandria University and Clinical Pathology, 3 National Cancer Institute, Cairo University, Egypt

Abstract: Recent studies have revealed that altered mineral is observed in diabetic patients with the of osteopenia. In order to elucidate the role of calcium regulating hormones on calcium and whether they are linked to glycemic control, we have designed this study. The study included 20 children with insulin dependent diabetes mellitus (IDDM) aged from 5.8 - 13 years and 20 age and sex matched normal children who served as control. level of parathyroid , 1,25 dihydroxy vitamin D, calcitonin, serum total and ionized calcium, phosphorus and magnesium were measured. The study included also measurement of biochemical remodeling markers (serum alkaline phophatase and osteocalcin). Glycemic control was assessed in diabetic children by measurement of level and glycosylated . The levels of serum calcium, and magnesium were significantly lower in diabetic patients than control and they were significantly correlated with the fasting . In parallel, significant lower levels of 1,25 dihydroxy vitamin D were observed in diabetic patients than control group and were significantly correlated to glycosylated hemoglobin This may indicate that poor control of diabetes significantly affects the level of this active metabolite of Vitamin D. Serum level of calcitonin was slightly higher in diabetic children than control but this was not statistically significant. The levels of serum osteocalcin were significantly lower in diabetic patients than control and they were significantly correlated with the level of glycosylated hemoglobin This may indicate that the degree of metabolic control and duration of disease affected it. It was concluded that, in IDDM, an osteoblastic deficit appears to exist with decreased bone turnover and increased bone resorption. This deficit is aggravated by lower level of 1,25 dihydroxy vitamin D, increased levels of calcitonin and failure of activation of parathyroid hormone. Glucosuric induced osmotic diuresis may also be responsible for the negative calcium balance observed in these patients.

Introduction: Twenty children with insulin-dependent diabetes mellitus were studied. They were admitted to Decreased bone mineral content is now a well- Pediatric Department in Al Hayat Hospital, Jeddah. recognized feature of insulin dependent diabetes None of these patients experienced any known mellitus ( IDDM ). Several studies have shown that episodes of diabetic for the 6 months 20% to 50% of children with IDDM have significant that immediately preceded the study. They did not bone loss.(1-4) Although the clinical significance of receive any vitamin supplement and the only drug this bone loss is still ill-defined, its presence they received was human insulin. suggests that alteration in skeletal metabolism and / Twenty age and sex matched healthy children, or remodeling do occur in the growing diabetic child. chosen from those undergoing minor outpatient (5,6) The pathogenesis of this diabetes associated surgical procedures, were studied as a control. osteopenia is still not fully understood. Clinical Individuals with known endocrine, hepatic, renal or studies of mineral homeostasis in diabetic patients gastrointestinal disease were excluded from the have yielded conflicting data as to the type, extent study. and severity of this disorder.(7-10) This study was Peripheral venous blood samples were obtained in carried out in order to elucidate the role of calcium the fasting state between 8 and 9 AM. Serum was regulating hormones on calcium homeostasis in separated by centrifugation and stored immediately IDDM children, and whether they are influenced by at –70o C until assayed in batch. glycemic control and /or the duration of clinical Serum levels of calcium, phosphorus, magnesium, illness. albumin, and were measured by standard laboratory methods. Ionized ++ Subjects and Methods : Calcium (Ca ) was detected by an ion selective

Alexandria Journal of Pediatrics, Volume 13, Number 2, July 1999 477 electrode, at 37oC and the results were normalized parathyroid hormone were slightly lower in diabetic for a pH of 7.4. children but were not significantly different from Osteocalcin was measured by solid-phase control children. Calcitonin level was slightly higher (sandwich) immuno radiometric assay (ELSA- in diabetic patients (43,58 ± 6.7 vs 41.6 ± 5.24 ) but OSTEO, cis bio international) using two monoclonal the difference was not statistically significant. There antibodies.(11) was no significant difference between the results Concentrations of immunoreactive parathyroid obtained from boys and girls in the two groups. hormone (PTH) were determined by use of DPC's Serum calcium, phosphorus, magnesium and double antibody PTH.M. It is an I 125 radio immuno parathyroid hormone concentration were negatively assay that recognizes the intact, mid regain and c- correlated with fasting blood level (table III). terminal portion of the parathyroid hormone Serum osteocalcin and 1,25 (OH)2D were molecule.(12) negatively correlated with HbA1c (r : -0.586, r:-0.812 1,25 dihydroxy vitamin D [1,25 (OH)2D] was respectively, P <0.01). Correlation within the determined by competitive protein binding assay studied diabetic children between duration of clinical after a high-performance liquid chromatography illness and measures of calcium homeostasis purification of serum lipid extracts.(13) showed significant negative correlation with serum Serum calcitonin (CT) was determined by radio phosphorus and parathyroid hormone concentration immuno assay (DSL, diagnostic system ( r : -0.481, r : -0.496 respectively, P <0.05 ). laboratories).(14) Each sample was assayed in duplicate. Serum osteocalcin mean concentration was Diabetic control was assessed by measurement of significantly lower in studied IDDM children with fasting blood glucose level. Glycosylated clinical illness more than 2 years compared with hemoglobin (Hb A1c) was done by the colorimetric mean concentration in patients with illness less than thiobarbituric acid reaction.(15) 2 years (11.18 ± 1.3 vs 12.1 ± 2.2, P <0.05) Statistical Analysis : (figure 1). Results were expressed as means and standard Discussion: deviation (SD). The t-test for unrelated samples was applied to compare data between diabetic and Hormonal control of skeletal growth, modeling and control subjects. It was also applied to compare remodeling is characterized by a complex data between diabetic children for less than 2 years interaction between the calciotropic hormones. This and diabetic children for more than 2 years. study demonstrated low level of circulating 1,25 Pearson and regression analysis formulas were dihydroxy vitamin D. Levels of immuno reactive used to calculate correlation among the parathyroid hormone and calcitonin were not measurement. We used the SPSS version 7.5 statistically different compared with levels in normal program for analysis of the data. P value control group in spite of the hypocalcemia observed considered significant if less than 0.05 and highly in diabetic children. significant if less than 0.01. Our findings of decreased circulating 1,2(OH)2D in young growing diabetic individuals are similar to Results: those of Frazer et al.,(1) Saito, (17) and Gertner et al. Age, sex, and biochemical data in the studied (18) The observations made by Tabeshita et al.,(19) in diabetic children and control group are listed in the growing rats with experimental insulin deficiency tables I and II. The mean concentration of serum were analogous to our results. In contrast, Heath calcium, magnesium, osteocalcin and 1,25 (OH)2D et al.,(7) found no abnormality of vitamin D were significantly lower in the diabetic children than metabolites, total and ionized calcium, phosphorus in control group. Serum alkaline phophatase was or PTH among 82 persons with diabetes aged 18 to significantly higher in diabetic patient than control 75 years. however, it must be noted that this was a (P<0.01). Serum inorganic phosphorus and population of adults.

Table I. Clinical data, fasting blood glucose level, glycosylated hemoglobin, serum albumin and serum creatinine in diabetic children and control group.

Diabetic Children Control P value

Alex J Pediatr, 13(2), July 1999 478 Number 20 20 Gender Ratio ( M/F ) 9 : 11 10 : 11 Non Significant Age ( Year ) Range ( 5.8 - 13 ) ( 6 - 13 ) Non Significant Mean ± SD 9.1 ± 2.3 9.04 ± 2.07 Duration of IDDM ( months ) Range ( 10 - 48 ) Mean ± SD 22.25 ± 9.89 Fasting Blood Glucose (mg/dL) Range ( 150 - 240 ) ( 69 - 110 ) < 0.01 ** Mean ± SD 190 ± 25.4 82.6 ± 8.9 Glycosylated hemoglobin ( % ) Range ( 6.5 - 10.6 ) ( 3.8 - 4.6 ) < 0.01 ** Mean ± SD 8.17 ± 1.07 4.27 ± 0.23 Serum Albumin ( mg/dL ) Range ( 3.5 - 4.8 ) 3.8 - 4.6 Non Significant Mean ± SD 4.2 ± 0.33 4.27 ± 0.23 Serum Creatinine ( mg/dL ) Range 0.4 - 1 ( 0.5 - 1 ) Non Significant Mean ± SD 0.7 ± 0.16 0.69 ± 0.14 ** Significant.

Table II. Calcium homeostasis parameters in IDDM group and in control group.

Variables Diabetic Children Control P Value Range Mean SD Range Mean S D Serum Calcium ( mg/dL ) 7.5-9.8 8.41 0.62 8-10.6 9.42 0.79 < 0.05 * Ionized Calcium ( mg/dL ) 3.3-4.8 3.8 0.41 3.6-5.1 4.21 0.32 < 0.05 * Serum Phosphorus ( mg/dL ) 3.5-5.5 4.19 0.49 3.7-5.3 4.44 0.53 0.132 Serum Magnesium ( mg/dL ) 1.2-1.8 1.49 0.17 1.6-2.2 1.88 0.19 < 0.01 ** Serum Alkaline Phosphatase (unit/Litre) 200-360 269 48.8 120-265 199.15 39.5 < 0.01 ** Osteocalcin ( ng/ml ) 8.8-14.5 11.64 1.89 13.5-23.1 16.4 2.94 < 0.01 ** Parathyroid Hormone (ng/dL) 10.8-24.1 17.11 4.17 10.9-26 18.76 5.87 0.315 1,25-dihydroxy Vitamin D (pg/ml) 20.2-34.1 27.2 4.18 26.4-38.2 31.57 3.74 < 0.05 * Calcitonin ( pg/ml ) 36.1-56.1 43.58 6.7 35-1-53 41.60 5.24 0.281 * Significant

Table III. Correlation between calcium homeostasis parameters with glycemic control parameters and duration of illness in diabetic children.

Variables Fasting blood glucose Glycosylated hemoglobin Duration of IDDM ( r ) value ( r ) value ( r ) value Serum calcium ( mg/dL ) - 0.800 ** - 0.253 0.200 Ionized calcium ( mg/dL ) - 0.564 * - 0.281 0.271 Serum Phosphorus ( mg/dL ) - 0.522 * 0.203 - 0.481 * Serum Magnesium ( mg/dL ) - 0.601 ** 0.059 0.157 Alkaline Phosphatase ( unit /liter ) 0.329 - 0.086 0.274 Osteocalcin ( ng/ml ) - 0.086 - 0.586 ** - 0.176 Parathyroid Hormone ( ng/dL ) 0.450 * - 0.083 - 0.496 * 1,25-dihydroxy Vitamin D ( pg/ml ) 0.005 - 0.812 ** 0.139 Calcitonin ( pg/ml ) - 0.323 0.370 0.048 * Correlation is significant at the 0.05 level, ** Correlation is significant at the 0.01 level.

479 Alex J Pediatr, 13(2), July 1999

13 12 SERUM 11 OSTEOCALCIN (ng/ml) 10 9 8 < 2 YEARS > 2 YEARS DURATION OF IDDM

Figure 1. Comparison between mean concentration of osteocalcin in studied diabetic children with clinical illness less than 2 years and diabetic children with clinical illness more than 2 years.

Potential explanations for a reduction in the in our patients than control which may explain low circulating concentration of 1,25 (OH)2D include a concentration of circulating 1,25 (OH)2D. decrease in 1,25(OH)2D synthesis and /or an Parathyroid hormone deficiency results in reduced increase in 1,25 (OH)2D . The diabetic activity of renal 25 hydroxy vitamin D-1-alpha- state could impair 1 alpha hydroxylation of 25 hydroxylase and consequently, in decreased serum hydroxy vitamin D, as insulin deficiency suppresses level of 1,25 dihydroxy vitamin D.(22) The levels of 1 alpha hydroxylase . (20) In our study, serum parathyroid hormone in our patients were concentration of circulating 1,25 (OH)2D was comparable to those of normal control however they negatively correlated with glycosylated hemoglobin, were inappropriately low in response to decreased so poorly controlled diabetes and insulinopenia ionized calcium and could account for the low serum could adversely effect the level of vitamin D active concentrations of 1,25 (OH)2D. metabolite. Moreover, normomagnesemia is necessary to Important physiological regulators of 1,25 (OH)2D maintain adequate parathyroid function. synthesis and secretion are serum phosphorus Magnesium is needed for the action of membrane level, parathyroid hormone and the serum bound adenylate cyclase in generating c-AMP magnesium level.(21) Hypophosphatemia results in required for release of parathyroid hormone from an increase in the serum 1,25 (OH)2D glandular stores.(25) The apparent inability to secrete concentrations. The mean serum phosphorus PTH maximally in response to the diminished concentration in our patients was slightly below extracellular calcium concentration observed in our normal and therefore, an increase rather than a patients may be in part the consequence of decrease in the serum concentration would be decreased magnesium levels. (26) expected. Furthermore we found no correlation Rosenbloom (27) suggested a diabetes-related defect between serum 1,25 ( OH )2D and serum in parathyroid function. In our study, the level of phosphorus concentration. PTH was correlated to the levels of fasting blood Magnesium may be an important factor in vitamin D glucose level and inversely correlated to the metabolism and action since magnesium supports duration of clinical illness. This association could be 25OHD-1 alpha hydroxylase activity.(23) An explained by this hypothesis. impairment of vitamin D mediated intestinal calcium Another mechanism was suggested by Ishida et absorption in magnesium deficient rats has been al.,(28) They observed high levels of serum found.(24) Serum magnesium was significantly lower parathyroid-related peptide instead of low levels of parathyroid hormone, so they suggested that serum

Alex J Pediatr, 13(2), July 1999 480 parathyroid related peptide might have a calcium losses. (33) Serum alkaline phophatase level physiologically compensatory role on the calcium was significantly elevated in our studied diabetic regulating system in diabetes. However, this finding children. The tissue of origin of the elevated needs to be further investigated and to be applied alkaline phosphatase in our cases was not for pediatric population. characterized as we did not determine isoenzymes. Calcitonin participates in the homeostasis of calcium However, Shieh et al.,(34) measured bone isoenzyme and is an important regulator of insulin secretion. of alkaline phosphatase and they found increased Calcitonin has been shown to affect calcium level of this bone specific indicating handling within cells thus impairing insulin secretion increased bone resorption and demineralization. and glucose tolerance.(29) Kokot et al.,(30) measured Total and ionized calcium has been reported as calcitonin concentration in 52 children with IDDM, diminished by McNair et al.,(2) Wisk et al.,(4) and divided into freshly diagnosed, well-controlled Soggese et al.(35) Others reported normal level of diabetics and poorly controlled diabetic groups. serum calcium in diabetic control. (1, 31) They found significantly elevated level of calcitonin Diabetes mellitus is the most frequent chronic in first and third group. Well-controlled group had disease associated with hypomagnesemia. Patients concentration close to normal. In our study mean with diabetes mellitus have a 25% to 38% concentration of calcitonin was slightly higher that prevalence of hypomagnesemia and many of these control but not statistically significant, however level cases are clinically undetected in the asymptomatic of glycosylated hemoglobin observed in our patients stage.(36) The cause of hypomagnesemia in was moderately increased in comparison to levels diabetes was attributed to [1]. Osmatic renal loss recorded by Kokot in uncontrolled group. However from glucosuria, [2]. Decreased intestinal we failed to find any correlation between level of absorption, and [3]. Redistribution of magnesium serum calcitonin and fasting blood glucose level or from plasma into red blood cells by insulin effect. glycosylated hemoglobin in our diabetic children. Recently, a specific tubular magnesium defect in Similar to our results, Heath et al.,(7) and Saito(17) diabetes has been postulated.(37) These multiple reported insignificant increased level of calcitonin in mechanisms could explain our finding of more their patients. significant lowering of serum magnesium than Significant lower levels of serum calcium and calcium and phosphorus in our diabetic children magnesium were observed in our study. Serum compared to control group. phosphorus level was not sufficiently low to become The non-significant decrease of phosphorus levels statistically significant compared to control level. that we found in the study are not against an altered This can be explained by a decrease in tubular parathyroid function in our patients, because a reabsorption of calcium, phosphorus and broad spectrum of serum phosphorus values magnesium in the presence of as a ranging from normal values to overt result of competitive effect of glucose for hypophosphatemia, may be present in reabsorption of these minerals in the proximal hypoparathyroid states.(38) tubules.(25) This explanation is more likely to be the Relatively little information is currently available cause of our reported data as there was a significant regarding the effect of diabetes mellitus on the negative correlation between levels of these integrity of bone. The appearance of bone mineral minerals in blood and level of fasting blood glucose deficiency early in diabetes in childhood has level. However, we did not measure urinary suggested that diabetes is characterized by excretion of these minerals to confirm this glucosuric defective bone formation in this age group. (4,7) - induced osmatic diuresis. Non enzymatic collagen cross-linking occurs in a McNair et al.,(8) found a strong correlation between variety of connective tissues as a results of fasting blood sugar concentration, glucosuria and formation of advanced glycosylation end products in urinary excretion of calcium and phosphorus. diabetic patients. (39) An experimental study done by Similar results were reported by Malone et al.(31) Tomasek et al., (40) showed increased levels of non- Alternatively, other investigators have failed to find enzymatic collagen cross-linking in bone. These any correlation with measures of diabetic control. (1, changes may contribute to alterations observed in 4, 32) bone with diabetes by influencing bone cell function Changes in the metabolism, induced by lack of and the ability of the matrix to be responsive to bone insulin may act directly upon bone causing bone cells. Verhaeghe et al., (41) reported decreased mineral loss with a secondary rise in the urinary number of osteoblats by histomorphometry of excretion of calcium and phosphorus. Insulin proximal tibial metaphyses in spontaneously treatment has been shown to correct diabetic renal diabetic rats.

481 Alex J Pediatr, 13(2), July 1999 Osteocalcin, a specific marker for osteoblastic aggravated by diminished levels of 1,25 dihydroxy activity, was significantly lower in our studied vitamin D, and failure of activation of parathyroid patients than that of normal control group, indicating hormone. that bone turn over was reduced. In agreement with Other factors, such as hypercalciuria, our finding, Kruse et al.,(41) Olmos et al., (6) and hyperphophaturia and insulin deficiency may Pedrazzoni et al.,(42) reported similar results. There contribute to impaired bone and calcium was significant negative correlations between the homeostasis in IDDM. Thus further studies are level of osteocalcin and glycosylated hemoglobin in needed to obtain more information on the exact role our patients, similar to that observed by Olmos et played by each of these factor in impairing mineral al.(6) Mean osteocalcin level in diabetic children with homeostasis in IDDM. clinical illness more than 2 years was significantly We recommend better control and regular follow up lower than those with clinical illness less than 2 of diabetic children and regular assessment of their years, so degree of metabolic control and duration mineral level in circulation. Whether administration of the disease may affect osteoblastic activity in of alpha-hydroxy vitamin D could attenuate the diabetic patients. osteopenia observed in the growing diabetic child, Our study confirms the presence, in diabetic more detailed longitudinal study on vitamin D are children, of an osteoblastic deficit leading to needed before this can be placed in proper decreased bone turnover, bone demineralization perspective. and increased bone resorption. This deficit is

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483 Alex J Pediatr, 13(2), July 1999