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ORIGINAL ARTICLE
Year : 2022  |  Volume : 10  |  Issue : 2  |  Page : 35-39

Correlation of glycemic control with calcium, inorganic phosphate, and alkaline phosphatase in type 1 diabetes mellitus


Department of Chemical Pathology, University of Benin, Benin City, Edo State, Nigeria

Date of Submission21-May-2022
Date of Decision03-Jun-2022
Date of Acceptance13-Jun-2022
Date of Web Publication27-Oct-2022

Correspondence Address:
Dr. Ekiye Ayinbuomwan
Department of Chemical Pathology, University of Benin, Benin City, Edo State
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njecp.njecp_3_22

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  Abstract 


Context: Type 1 diabetes mellitus (T1DM) accounts for over 90% of diabetic cases with a prevalence of 0.33/1000 children in the African subregion. Hyperglycemia which is the major characteristic of T1DM may have a direct toxicity on osteoblasts and could lead to increased bone fragility and fractures in patients with T1DM. However, long-term glucose control can be monitored effectively with the measurement of glycated hemoglobin (HbA1c), while alkaline phosphatase (ALP), serum calcium, and inorganic phosphate are simple ways of assessing bone mineral density. Aim: This study aimed to evaluate the association between HbA1c and serum calcium, inorganic phosphate, and ALP. Subjects and Methods: This was a prospective cross-sectional study with a total of 26 T1DM patients and 20 apparently well children within the age range of 1–18 years. Blood samples were collected from the patients for measurement of HbAIc, serum ALP, serum calcium, and inorganic phosphate at the beginning of the study and after 3 months of insulin therapy. Results: The baseline mean HbA1c was significantly higher in the T1DM patients than in the controls (P = 0.00) and there was no significant decrease in HbA1c after 3 months of insulin therapy (P = 0.13) although HbA1c tended to be lower (12.57 ± 0.86% [baseline], 10.12 ± 0.74% [3 months postinsulin therapy]). There was a statistically significant reduction in ALP (P = 0.00). There was also a statistically significant correlation between ALP and mean HbA1c (r = 0.79, P = 0.00). Conclusion: Patients with T1DM often exhibit disorders related to calcium, inorganic phosphate, and ALP homeostasis with associated poor bone metabolism which may improve with adequate glycemic control and the addition of calcium supplements to their therapy.

Keywords: Alkaline phosphatase, calcium, glycated hemoglobin, inorganic phosphate, Type 1 diabetes mellitus


How to cite this article:
Ayinbuomwan E, Onovughakpo-Sakpa EO. Correlation of glycemic control with calcium, inorganic phosphate, and alkaline phosphatase in type 1 diabetes mellitus. Niger J Exp Clin Biosci 2022;10:35-9

How to cite this URL:
Ayinbuomwan E, Onovughakpo-Sakpa EO. Correlation of glycemic control with calcium, inorganic phosphate, and alkaline phosphatase in type 1 diabetes mellitus. Niger J Exp Clin Biosci [serial online] 2022 [cited 2022 Dec 7];10:35-9. Available from: https://www.njecbonline.org/text.asp?2022/10/2/35/359777




  Introduction Top


Diabetes mellitus is one of the most common chronic diseases in children and Type 1 diabetes mellitus (T1DM) accounts for over 90% of cases.[1] T1DM results from cell-mediated autoimmune destruction of the insulin-secreting cells of pancreatic β-cells.[2] The prevalence of T1DM varies from country to country and in the African subregion, the prevalence of T1DM in Nigeria is 0.33/1000 children.[3] Measurement of glycated hemoglobin (HbA1c) is effective in monitoring long-term glycemic control in persons with diabetes mellitus.[1] It provides in retrospect, glucose values for about 3 months and is not subject to the wide fluctuations observed with blood glucose assays. Hence, it is a valuable and widely used adjunct to blood glucose determinations for monitoring long-term glycemic control.

Hyperglycemia and hypoinsulinemia are well-known characteristics of T1DM. Hyperglycemia may have a direct toxicity on osteoblasts, affecting the osteoblast signaling pathway, thus leading to an increase in reactive oxygen species and increased nonenzymatic glycosylation of proteins and DNA, leading to the formation and deposition of advanced glycation end products in different tissues, including bone.[4] This is thought to be the main mechanism of increased bone fragility and fractures in T1DM.[5] Insulin has a stimulatory effect on the bone matrix through its action on the differentiating function of osteoblasts and thus, insulin is necessary for bone mineralization. Osteoblasts contain alkaline phosphatase (ALP) which is used to generate phosphate ions from inorganic phosphates. Osteoblasts also control bone mineralization by regulating the passage of calcium and phosphate ions across their cell membranes.[6]

The World Health Organization has established criteria for assessing bone mineral density which includes bone formation markers (ALP, osteocalcin, and procollagen extension peptides) and bone resorption markers (serum calcium, 24 h urinary calcium, and urinary hydroxyproline).[7],[8] The aim of this study was to compare HbA1c levels with serum calcium, inorganic phosphate, and ALP in children with T1DM.


  Subjects and Methods Top


This was a cross-sectional study conducted at the Pediatric outpatients' clinic and the Department of Chemical Pathology, University of Benin Teaching Hospital, between May 2019 and December 2020. Approval of the ethical committee of the hospital was obtained (ADM/E22/A/VOL. VII/14798) in accordance with the Helsinki Declaration of 1975, as revised in the year 2000, and written informed consent was obtained from the parents before examination and sample collection. A total of 46 participants were involved in the study, consisting of 26 patients in the test group and 20 participants in the control group (the Cochran formula was used to calculate sample size).[9] The test group was made up of known T1DM patients attending the pediatric outpatient clinic, who were on insulin therapy and were recruited by simple random sampling in the clinic. The control group consisted of apparently healthy children recruited from the Ugbowo community where the hospital is situated. The age range was 1–18 years. Patients with a history of rickets, malabsorption, parathyroid, renal or liver disease and those on diuretics, glucocorticoids, and calcium/phosphate supplements were excluded from the study.

An interviewer-administered questionnaire was used to obtain information from patients and patients were physically examined. Body mass index (BMI) was calculated using the Quetelet's formula (weight in kg/[height in meters]2).[10] Six milliliters of blood was collected from each subject, of which 4 ml was dispensed into a plain bottle and 2 ml in an ethylenediaminetetraacetic acid (EDTA) bottle. Blood samples were collected on the first clinic visit and after 90 days of insulin therapy. Samples in the plain bottle were allowed to clot, centrifuged at 2500 rpm and serum was separated and stored at −20°C and analyzed within 1 month for calcium, phosphate, and ALP. The samples in the EDTA bottle were analyzed immediately for HbA1c. HbA1c was estimated using the High-performance liquid chromatography method while serum calcium, phosphate, and ALP were estimated using the colorimetric method.[11],[12],[13],[14]

Data were collected and entered into a pro forma and analyzed using the Statistical Package for the Social Sciences (SPSS) version 16 software (SPSS Inc., Chicago, IL, U.S.A). Mean and standard errors of the mean of age, BMI, and HbA1c were calculated. Comparisons of means between the groups were made using the Student's t-test. Pearson's correlation was used in calculating correlations between any two variables. The level of statistical significance was set at a P < 0.05 for all tests.


  Results Top


A total of 26 patients and 20 participants were studied and majority of them were females (19 [73%]) and the mean age of the patients was 14.19 ± 0.62 years. Mean BMI was 18.43 ± 0.7 kg/m2 for the patients and 21.48 ± 0.51 kg/m2 for the controls. The BMI of the controls was significantly higher than that of the patients (P = 0.02) [Table 1].
Table 1: Anthropometric findings in subjects and controls

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The baseline HbA1c for the T1DM patients (12.57% ± 0.86%) was significantly higher than that of the controls (4.88% ± 0.91%) (P = 0.00). Baseline serum calcium (7.57 ± 0.16 mg/dl) and phosphate (3.41 ± 0.15 mg/dl) levels were significantly lower in the diabetics than the controls (8.70 ± 0.16 mg/dl and 4.05 ± 0.12 mg/dl, respectively) (P = 0.00 and P = 0.02, respectively). Baseline serum ALP (108.35 ± 6.41 IU/L) was significantly higher in the diabetics than the controls (80.45 ± 2.49 IU/L) (P = 0.01) [Table 2].
Table 2: Comparison of blood glycated hemoglobin, calcium, inorganic phosphate, and alkaline phosphatase in controls and type 1 diabetes mellitus patients

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There was no significant decrease in HbA1c in the T1DM patients after 3 months of insulin therapy though the baseline HbA1c (12.57% ± 0.86%) was higher than the 3 months postinsulin HbA1c (10.12% ± 0.74%) (P = 0.13). There was no appreciable change in serum calcium (P = 0.89) and phosphate (P = 0.80) after 3 months of insulin therapy, while the mean concentration of ALP was significantly lower in the T1DM patients after 3 months of insulin therapy (P = 0.00) [Table 3].
Table 3: Biochemical parameters of type 1 diabetes mellitus patients

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There was a significant negative correlation between HbA1c and inorganic phosphate (r = −0.66, P = 0.00) and a nonsignificant negative correlation with serum calcium (r = −0.32, P = 0.13) in the T1DM patients. However, there was a significant positive correlation between baseline HbA1c and serum ALP in these patients (r = 0.74, P = 0.00) [Table 4].
Table 4: Correlation between glycated hemoglobin and calcium, inorganic phosphate and alkaline phosphatase (baseline values)

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There was a nonsignificant positive correlation between serum calcium and HbA1c in the T1DM patients 3 months postinsulin therapy (r = 0.41, P = 0.05). No correlation was found between inorganic phosphate and HbA1c (r = −0.07, P = 0.73) 3 months postinsulin therapy. However, there was a significant positive correlation between serum ALP and HbA1c after 3 months postinsulin therapy (r = 0.79, P = 0.00) [Table 5].
Table 5: Correlation between glycated hemoglobin and calcium, inorganic phosphate and alkaline phosphatase (3 months postinsulin therapy)

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  Discussion Top


Poor bone health is a complication of T1DM which is often ignored. It is normally characterized by slow bone turnover which leads to reduced mineralization and reduced bone quality and strength with consequent fracture event as the most important clinical manifestation.[15] Easy-to-perform methods which can be used in predicting the risk of fractures in T1DM patients are serum ALP, calcium, and inorganic phosphate.[8]

BMI has a very strong relationship with diabetes and insulin resistance though patients with TIDM are generally not obese and Driver et al., in their study reported low BMI to be associated with low bone mineral density.[16],[17] We found in this study, that the mean BMI of the T1DM patients was within the healthy range of the 5th percentile to <85th percentile.

Uncontrolled diabetes is usually associated with high levels of HbA1c and with adequate control of blood glucose in T1DM (insulin therapy) there is a reduction in the level of HbA1c. The reference interval of HbA1c in Nigerian children is 4%–5.1% and the goal of therapy as stated by the American Diabetes Association is <7%.[18],[19] In our study, the baseline mean HbA1c in the patients was quite high and indicative of poor glycemic control. However, after 3 months of insulin therapy, there was a reduction in mean HbA1c.

Calcium is necessary for both glucose-induced insulin secretion by the pancreatic β-cells and insulin-mediated glucose uptake by skeletal muscle and the function of many tissues is compromised by calcium insufficiency including those that regulate the metabolism and absorption of glucose.[20],[21],[22] Hyppönen et al. found a link between calcium status and the risk of T1DM. Their study showed that the probability of developing T1DM amongst children with suspected rickets in their 1st year of life was three times higher, compared with healthy infants.[23] In another study, Yang et al. found an association between hormonal regulation of calcium homeostasis and the development of diabetes mellitus.[24] Diabetes mellitus also results in impaired calcium absorption, bone deterioration, decelerated bone elongation, and renal calcium wasting due to the effect of the disease on the function of calcium-regulating organs.[25] We found a significantly lower level of serum calcium in patients with T1DM when compared with nondiabetic children and no increase was found in serum calcium levels after 3 months on insulin therapy.

Changes in blood glucose can be easily recognized by clinical symptoms, but hypophosphatemia or hyperphosphatemia may present with vague and nonspecific symptoms. Studies have shown that disturbances in the metabolism of inorganic phosphate in diabetes lead to early functional microvascular changes in the retina and kidneys.[26] Furthermore, the homeostatic function of the kidney is suboptimal in diabetics, because elevated blood glucose concentrations depolarize the brush border membrane for phosphate reabsorption, leading to a lack of intracellular phosphate and hyperphosphaturia with consequent hypophosphatemia.[27] We found in this study that patients with T1DM had hypophosphatemia when compared with healthy children, but there was no change in the concentration of inorganic phosphate after 3 months of glycemic control.

Our observations showed an elevation in total serum ALP concentration in patients with T1DM which decreased with improved glycemic control. Our findings are consistent with former studies by Maxwell et al. and Moshtaghie et al., who proposed an association between the severity of diabetes and diabetic bone disease. They noticed in their studies that mean fasting glucose was significantly higher in T1DM patients with elevated total ALP.[28],[29] Our study was limited to total serum ALP and T1DM patients. However, in another study, Cheung and Cheung found that insulin resistance-related traits were found to be strongly and independently associated with serum-bone-specific ALP levels, but not total ALP levels.[30] Moreover, others found no significant relationship between ALP and diabetes mellitus.[31]


  Conclusion Top


Patients with T1DM often exhibit electrolyte disorders related to calcium, inorganic phosphate, and ALP homeostasis with associated poor bone mineralization. Hence, supplementation with calcium may be useful in these patients. However, intensive insulin therapy which is the standard treatment of T1DM would improve glycemic control and thus exert a beneficial effect on bone mineralization. Further studies focused on the relationship between bone mineralization and insulin therapy in patients with T1DM are necessary to detect osteopenia and prevent the development of osteoporosis later in life.

Acknowledgment

We acknowledge the contributions of the staff of the Pediatric outpatient clinic and Chemical Pathology Department, University of Benin Teaching Hospital for the success of this work.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Tietz NW. Fundamentals of Clinical Chemistry. Philadelphia: WB Saunders; 1976. p. 917.  Back to cited text no. 13
    
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Driver JP, Foreman O, Mathieu C, van Etten E, Serreze DV. Comparative therapeutic effects of orally administered 1,25-dihydroxyvitamin D(3) and 1alpha-hydroxyvitamin D(3) on type-1 diabetes in non-obese diabetic mice fed a normal-calcaemic diet. Clin Exp Immunol 2008;151:76-85.  Back to cited text no. 17
    
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Allison FI, Oule A. Reference interval of fasting plasma glucose and glycated hemoglobin in children in Port Harcourt, Rivers State, Nigeria. Int J Biomed Adv Res 2019;10:5294.  Back to cited text no. 18
    
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Hyppönen E, Läärä E, Reunanen A, Järvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: A birth-cohort study. Lancet 2001;358:1500-3.  Back to cited text no. 23
    
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Yang Y, Zhang X, Bao M, Liu L, Xian Y, Wu J, et al. Effect of serum 25-hydroxyvitamin D3 on insulin resistance and β-cell function in newly diagnosed type 2 diabetes patients. J Diabetes Investig 2016;7:226-32.  Back to cited text no. 24
    
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Wongdee K, Krishnamra N, Charoenphandhu N. Derangement of calcium metabolism in diabetes mellitus: Negative outcome from the synergy between impaired bone turnover and intestinal calcium absorption. J Physiol Sci 2017;67:71-81.  Back to cited text no. 25
    
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Girindra Kr.B, Rashmi R, Sanjeeb K, Sushma Y. Serum inorganic phosphate concentration and glycated hemoglobin percent in type 2 diabetes mellitus – A hospital based study. Int J Health Sci Res 2016;6:96-104.  Back to cited text no. 27
    
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Maxwell DB, Fisher EA, Ross-Clunis HA 3rd, Estep HL. Serum alkaline phosphatase in diabetes mellitus. J Am Coll Nutr 1986;5:55-9.  Back to cited text no. 28
    
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Moshtaghie AA, Taher M, Urogi H, Emami A, Amini M, Pourmoghadas H, et al. Interrelation between blood glucose level and incidence of bone disease in diabetes. Med J Islamic Acad Sci 2000;13:119-24.  Back to cited text no. 29
    
30.
Cheung CL, Cheung BM. Bone-specific alkaline phosphatase is elevated in insulin resistance: Implications for vascular calcification in diabetes. Eur Heart J 2013;34:5473.  Back to cited text no. 30
    
31.
Léger J, Marinovic D, Alberti C, Dorgeret S, Chevenne D, Marchal CL, et al. Lower bone mineral content in children with type 1 diabetes mellitus is linked to female sex, low insulin-like growth factor type I levels, and high insulin requirement. J Clin Endocrinol Metab 2006;91:3947-53.  Back to cited text no. 31
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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