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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2008  |  Volume : 19  |  Issue : 6  |  Page : 942-947
Impact of treatment with oral calcitriol on glucose intolerance and dyslipidemia(s) in hemodialysis patients


1 Endocrine Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
2 Department of Hematopathology, Mashhad University of Medical Sciences, Mashhad, Iran
3 Department of Internal Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
4 Department of Public Health Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

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   Abstract 

This study was conducted to assess the effect of oral calcitriol on glucose metabolism in patients on hemodialysis (HD). A total of 27 patients on HD at the Mashhad University of Medical Sciences, Iran, none of whom had received calcitriol or had history of diabetes, were selected. The patients were randomly divided into two groups; Group I: patients who received oral calcitriol for eight weeks and, Group II: patients who received placebo. In all cases, levels of fasting glucose, insulin, lipid profile, calcium, phosphorous, parathormone (PTH), HbA1C and blood sugar after administration of 75 grams of glucose, insulin resistance and beta cell function were measured, before and after the treatment period. The two sets of results were then compared with one another. In Group l patients, the levels of the parameters studied before and after the study period were as follows: blood sugar after 75 grams of glucose (88.67 ± 8.68 versus 99.83 ± 34.42 mg/dL, p = 0.045), HOMA-IR (2.05 ± 1.42 versus 2.42 ± 1.33, p = 0.035), HbA1C (5.99 ± 1.00 versus 6.14 ± 1.19, p = < 0.001), total cholesterol (153.3 ± 43.80 mg/dL versus 157.0 ± 52.62, p = 0.037) and triglycerides (175.30 ± 99.65 versus 214.9 ± 117.7 mg/dL, p = 0.036). Thus, there was a significant decrease after the study period. In Group II, fasting blood sugar (110.7 ± 26.12 versus 81.14 ± 13.31 mg/dL, p = 0.002), HbA1C (6.99 ± 1.44 versus 6.17 ± 1.66, p = 0.004) and HOMA-IR (5.85 ± 5.11 versus 3.20 ± 2.39, p = 0.036) significantly increased and beta cell function significantly decreased (149.5 ± 90.57 versus 355.7 ± 299.3, p = 0.032) after the study period. In conclusion, our results show that vitamin D has a significant influence on glucose metabolism. Similar studies on larger sample size are required to confirm this observation.

Keywords: Diabetes mellitus, Calcitriol, Uremia, HOMA -IR, Beta cell function

How to cite this article:
Bonakdaran S, Ayatollahi H, Mojahedi MJ, Sharifipoor F, Shakeri M. Impact of treatment with oral calcitriol on glucose intolerance and dyslipidemia(s) in hemodialysis patients. Saudi J Kidney Dis Transpl 2008;19:942-7

How to cite this URL:
Bonakdaran S, Ayatollahi H, Mojahedi MJ, Sharifipoor F, Shakeri M. Impact of treatment with oral calcitriol on glucose intolerance and dyslipidemia(s) in hemodialysis patients. Saudi J Kidney Dis Transpl [serial online] 2008 [cited 2019 Nov 21];19:942-7. Available from: http://www.sjkdt.org/text.asp?2008/19/6/942/43469

   Introduction Top


Impaired carbohydrate metabolism is a co­mmon finding in patients with chronic renal failure (CRF). [1] The site and mechanism of this seem to be both insulin resistance and im­paired insulin secretion. [2],[3],[4],[5] β cells of the pan­creas activate and enhance the secretion of insulin appropriately to insulin resistance. [6] If the B cells are unable to augment their secretion of insulin appropriately, an impaired glucose to­lerance would ensue. Although intermittent hemodialysis (HD) for a mean duration of 10 weeks results in a significant improvement of impaired glucose metabolism of uremia, com­plete normalization does not occur. [7] Elevated plasma insulin levels in the fasting state and in response to glucose have been reported in these patients. Increased levels of parathor­mone (PTH) in these patients augment hepatic glucose production through increased glyco­genolysis and gluconeogenesis. [8],[9] On the other hand, vitamin D 3 is linked with disturbance of glucose metabolism. A role of vitamin D in endocrine pancreatic function has been sug­gested earlier. [10],[11] Vitamin D deficiency may inhibit insulin secretion in uremia. [12] It seems that 1,25(OH) 2 D 3 , independent of PTH and calcium, has a role as an important modulator of insulin secretion and insulin sensitivity in uremic patients. [13] Several studies have shown that vitamin D deficiency results in diminished insulin stimulated glucose uptake and in­creased insulin resistance. [14],[15] The present stu­dy was designed for evaluation of the effect of treatment with 1,25(OH) 2 D 3 on glucose tole­rance, insulin sensitivity and B cell function in hemodialysis patients.


   Material and Methods Top


This study was a randomized clinical trial. Sixty-five patients (30 female, 35 male) with CRF on regular HD for more than one year in four dialysis centers attached to the Mashhad University of Medical Sciences (MUMS), Iran were selected. From this group, patients with history of diabetes, use of vitamin D or related drugs and any contraindication for calcitriol treatment were excluded. Finally, 32 patients (17 male, 15 female) were recruited into the study. Two patients did not complete the study and three others (2 male, 1 female) died during the study period. Thus, 27 patients (14 male, 13 female) completed this study.

The baseline laboratory data of the study pa­tients are given in [Table 1]. The patients were then randomized based on days of the week on which they received HD; Group I: patients on dialysis on Saturday, Monday, and Wednesday and, Group II: patients receiving dialysis on Sunday, Tuesday, Thursday. Group I consisted of 13 patients who received oral calcitriol (1,25-dihydroxy vitamin D 3 , the biologically active form of vitamin D) in dose of 0.5 mcg per day for eight weeks. Group II consisted of 14 patients who received placebo during the eight week study period. In all patients, the following tests were performed before and after eight weeks study period: fasting plasma glucose, insulin levels (immunoradiometric assay) with intra-assay co-efficient of variation (CV) 4.3% and inter-assay CV 3.4%, blood glucose after an oral load of 75 grams glucose, calcium (colorimetric assay) with intra-assay CV 3% and inter-assay CV 3.7%, phosphorus (colorimetric end point) with intra-assay CV 6% and inter-assay CV 7.5%, PTH (immuno­ radiometric assay) with intra-assay CV 2.1%and inter-assay CV 2.7%, total cholesterol (en­zymatic assay) with intra-assay CV 2.3% and inter-assay CV 2.5%, triglycerides (enzymatic assay) with intra-assay CV 2% and inter-assay 3.5% as well as LDL, HDL and Hb A1C. Insulin resistance (homeostasis model assess­ment-insulin resistance) was calculated as follows:



Beta cell function (Homeostasis model assess­ment-secretion) was obtained from:



Data are given as mean ± SD. Statistical ana­lysis was done by paired t test.

All patients gave informed voluntary consent to participate in the study according to the protocol approved by the local ethics committee of MUMS and in accordance with the ethical standards of the Helsiniki Declaration.


   Results Top


Group I consisted of 13 patients (6 female, 7 male) and Group 2 consisted of 14 patients (7 female, 7 male). The mean age of patients in the two groups was not significantly different, (48.00 ± 16.3 years in Group I versus 51.57 ± 19.88 years in Group II, p = 0.614)

In patients in Group I, following treatment with calcitriol, fasting blood sugar decreased although the reduction was not statistically significant (p = 0.067). The blood sugar levels significantly decreased after administration of 75 grams of glucose (p = 0.045). The HbA1C level and insulin resistance (HOMA-IR) both decreased after treatment and this change was significant (p< 0.001, p= 0.035 respectively). The serum calcium levels increased signifi­cantly (p = 0.014). The change in HOMA-IR was independent of alteration in PTH and calcium levels. Beta cell function (HOMA­SECR) increased after treatment but this change was not significant (p = 0.54). Calcitriol had a beneficial effect on lipids. Total choles­terol and triglyceride levels significantly de­creased after treatment (p = 0.037and 0.036 respectively). The changes in phosphorous, PTH, LDL, HDL were not significant [Table 2].

In Group II patients who were given placebo treatment, the fasting blood sugar levels significantly increased after eight weeks study period (p = 0.002). The HbA1C level increased significantly (p = 0.004), beta cell function dec­lined (p = 0.032) and insulin resistance was significantly increased (p= 0.036) after the stu­dy period. The change in other parameters was not significant [Table 3].

Based on the HOMA-IR, the patients were categorized into the following groups: < 2.24 : insulin sensitive, 2.24-3.59 : borderline and > 3.59 : insulin resistant). On comparison after the study period, the number and percentage of patients in the insulin resistant group dec­reased following treatment with calcitriol but, increased after placebo treatment [Table 4].


   Discussion Top


In our study, we found that treatment with calcitriol enhanced beta cell function although this increment was not significant. The effect on decrease of insulin resistance was signifi­cant. Several investigators have suggested the presence of a cytosolic receptor for 1,25 (OH) 2 D 3 in the pancreas and vitamin D has a potential role in the development and treatment of diabetes mellitus. [16],[17] These effects may be mediated by circulatory levels of 1,25(OH) 2 D 3 but local production of 1-alpha hydroxylase in pancreas is also likely to be important. [18]

Norman et al [19] showed that vitamin D defi­cient rats secreted less insulin than vitamin D repleted rats. Turk et al [20] showed that treat­ment with calcitriol significantly increased insulin secretion in both fasting and post-75 grams load of glucose state. In other studies, pharmacologic dose of calcitriol had therapeu­tic effect on hypertension and insulin resis­tance in dialysis patients. [21] Calcitriol affects insulin secretion both directly and indirectly. Serum calcium was reported to be an impor­tant regulator of insulin release. Thus, it is possible that calcitriol affects indirectly by altering serum calcium. [22] In our study, the rise of insulin and improvement of insulin resis­tance was independent of calcium.

Also, excess PTH may affect carbohydrate metabolism. [23] Elevated plasma insulin levels as well as insulin resistance in patients with CRF may be due to secondary hyperpara­thyroidism. Vitamin D deficiency results in hyperparathyroidism through which it may influence glucose metabolism. Akmal et al [24] showed that excess PTH in CRF patients interferes with the ability of the beta cell function to augment insulin secretion appro­priately in response to the insulin resistant state. Mak RH [14] reported that 1,25(OH) 2 D 3 , independent of PTH and calcium, was an important modulator of insulin secretion and insulin sensitivity in uremic patients. In their study, Scragg R et al [25] observed that associa­tion between vitamin D deficiency and insulin resistance differs between ethnic groups. Vita­min D receptor (VDR) polymorphism may be associated with disturbance in insulin secretion and insulin resistance. [26],[27] In our study, HOMA-IR decreased significantly after calcitriol treat­ment, but it was not related to change in PTH levels. It seems reasonable that factors other than hyperparathyroidism in patients with vita­min D deficiency, including VDR polymor­phism or sensitivity of muscle receptor of vitamin D, may affect insulin resistance. Chonchal et al [28] showed that serum 25 hydro­xy vitamin D levels and the amount of kidney function were inversely associated, indepen­dent of one another, with HOMA-IR.

Patients with high 25OH2D3 levels had lower HOMA-IR. [28] In our study; estimation of vita­min D levels was not available. Strazecki et al [29] investigated the influence of calcitriol on glucose metabolism in patients on HD and observed that this treatment significantly decreased HbA1C levels. The decrease in HbA1C in the present study was also signi­ficant.

Various studies have shown the beneficial effect of calcitriol on lipid profiles of HD pa­tients. Lin et al [30] reported that calcitriol treat­ment causes a significant decline in trigly­ceride levels and increment of apoprotein A1. We observed that calcitriol treatment signifi­cantly decreased total cholesterol and trigly­ceride levels.


   Conclusion Top


Our study indicates that calcitriol treatment influences glucose metabolism and the effect on insulin resistance was more than that on insulin secretion. The change in HbA1C as a marker of long-term glycemic control showed the desirable influence on glucose tolerance.However, the sample size of this study was small and measurement of levels of 25-hydro­xy vit D was not available. Similar studies with larger sample size and assessment of vita­min D level and VDR polymorphism are reco­mmended to clarify our observations.


   Acknowledgement Top


We would like to thank MUMS research council for their financial support.

 
   References Top

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2.De Fronzo RA, Tobin DJ, Rowe JW, Andres R. Glucose intolerance in uremia: Quantifi­cation of pancreatic B-cell sensitivity to glucose and tissue sensitivity to insulin. J Clin Invesig 1978;62(2):425-35.  Back to cited text no. 2    
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10.Boquist L, Hagstrom S, Strindlund L. Effect of 1,25 Dihydroxycholecalciferol administration on blood glucose and pancreatic islet morphology in mice. Acta Pathol Microbiol Scand 1977;85(4):485-91.  Back to cited text no. 10    
11.Kadowaki S, Norman AW. Pancreatic vitamin D - - dependent calcium binding protein: Bioc­hemical properties and responses to vita-min D. Arch Biochem Biophys 1984; 233(1):228­-33.  Back to cited text no. 11    
12.Tabata T,Suzuki R, Kikunami K. The effect of 1 alpha hydroxyvitamin D3 on cell mediated immunity in hemodialysis patients. J Clin Endocrinol Metab 1986;63(5):1218-21.  Back to cited text no. 12    
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17.Scragg R, Holdway I, Singh V, Metcalf P, Baker J, Dryson E. Serum 25 hydroxyvitamin D3 levels decreased in IGT and diabetes. Diabetes Res Clin Pract 1995;27(3):181-8.  Back to cited text no. 17    
18.Kanatsuka A, Makino H, Matsushima Y, Kasanuki J, Osegawa M, Kumagai A. Effect of calcium on the secretion of somatostatin and insulin from pancreatic islets. Endocrinology 1981;108(6):2254-7.  Back to cited text no. 18    
19.Norman AW, Frankel BJ, Heldt AM, Grodsky. GM. Vitamin D deficiency inhibits pancreatic secretion. Science 1980;209(4458): 823-5.  Back to cited text no. 19    
20.Turk S, Yaksan M, Gurbilek M, Erdogan Y, Erkul I. Effects of 1,25 (OH)2D3 treatment on glucose intolerance in uremia. Nephrol Dial Transplant 1992;7(12):1207-12.  Back to cited text no. 20    
21.Kautzky-Willer A, Pacini G, Barnas U, et al. Intravenous calcitriol normalizes insulin sensi­lipidemia in HD947tivity in uremic patients. Kidney Int 1995; 47(1):200-6.  Back to cited text no. 21    
22.Gerich J, Charles MA, Grodsky M. Regulation of pancreatic insulin and glucagons secretion. Annu Rev Physiol 1976;38:353-88.  Back to cited text no. 22    
23.Ginsberg H, Olefsky JM, Reaven M. Evalua­tion of insulin resistance in patients with primary hyperparathyroidism. Proc Exp Biol Med 1975;148(3):942-5.  Back to cited text no. 23    
24.Akmal M, Massry SH, Goldstein DA, Fanti P, Weisz A, Defronzo RA. Role of parathyroid hormone in glucose intolerance of chronic renal failure J Clin Investig 1985;75(3):1037­-44.  Back to cited text no. 24    
25.Scragg R, Sowers M, Bell C; Third National Health and Nutrition Examination Survey. Serum 25 hydroxy vitamin D, Diabetes, and ethnicity in the third national health and nutrition examination survey. Diabetes Care 2004;27(12):2813-8.  Back to cited text no. 25    
26.Ortlepp JR, Metrikat J, Albrecht M, Von Korff A, Hanrath P, Hoffmann R. The vitamin D receptor gene variant and physical activity predicts fasting glucose levels in healthy young men. Diabetes Med 2003;20(6):451-3.  Back to cited text no. 26    
27.Oh JY, Barret-Conner E. Association between vitamin D receptor polymorphism and type 2 diabetes or metabolic syndrome in community dwelling older adults. Metabolism 2002;51 (3):356-9.  Back to cited text no. 27    
28.Chonchol M, Scragg R. 25 Hydroxyvitamin D, insulin resistance, and kidney function in the third national health and nutrition examination survey. Kidney Int 2007;71(2):134-9.  Back to cited text no. 28    
29.Strrozecki P, Kretowicz M, Odrowas G, Manitius J. The influence of intravenous 1,25 (OH)2D3 therapy on glucose metabolism in hemodialyzed patients with secondary hyperparathyroidism. Ren Fail 2004;26(4):345-8.  Back to cited text no. 29    
30.Lin SH, Lin YF, Lu KC, et al. Effects of intravenous calcitriol on lipid profiles and glucose tolerance in uremic patients with secondary hyperparathyroidism. Clin Sci (Lond) 1994;87(5):533-8.  Back to cited text no. 30    

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Correspondence Address:
Hossein Ayatollahi
Department of Hematopathology, Mashhad University of Medical Sciences, Mashhad
Iran
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PMID: 18974581

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    Tables

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    Abstract
    Introduction
    Material and Methods
    Results
    Discussion
    Conclusion
    Acknowledgement
    References
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