Year : 2008 | Volume
: 19 | Issue : 6 | Page : 942--947
Impact of treatment with oral calcitriol on glucose intolerance and dyslipidemia(s) in hemodialysis patients
Shokoufeh Bonakdaran1, Hossein Ayatollahi2, Mohammad Javad Mojahedi3, Farzaneh Sharifipoor3, Mohammad Shakeri4,
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
Department of Hematopathology, Mashhad University of Medical Sciences, Mashhad
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.
|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;19:942-947
|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 2021 Jan 22 ];19:942-947
Available from: https://www.sjkdt.org/text.asp?2008/19/6/942/43469
Impaired carbohydrate metabolism is a common finding in patients with chronic renal failure (CRF).  The site and mechanism of this seem to be both insulin resistance and impaired insulin secretion. ,,, β cells of the pancreas activate and enhance the secretion of insulin appropriately to insulin resistance.  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.  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. , 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. , Vitamin D deficiency may inhibit insulin secretion in uremia.  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.  Several studies have shown that vitamin D deficiency results in diminished insulin stimulated glucose uptake and increased insulin resistance. , 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
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.
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: 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].
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. , 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. 
Norman et al  showed that vitamin D deficient rats secreted less insulin than vitamin D repleted rats. Turk et al  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.  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.  In our study, the rise of insulin and improvement of insulin resistance was independent of calcium.
Also, excess PTH may affect carbohydrate metabolism.  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  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  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  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. , 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  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.  In our study; estimation of vitamin D levels was not available. Strazecki et al  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  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.
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.
We would like to thank MUMS research council for their financial support.
|1||Stefanovic V, Nesic V, Stojimirovic B. Treatment of insulin resistance in uremia. Int J Artif Organs 2003;26(2):100-4.|
|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.|
|3||De Fronzo RA, Alvestrand A. Glucose intolerance in uremia site and mechanism. Am J Clin Nutr 1980;33(7):1438-45.|
|4||De Fronzo RA, Alvestrand A, Smith D, et al. Insulin resistance in uremia. J Clin lnvestig 1973;67:563-8.|
|5||De Fronzo RA. Andres R, Edgar P, Walker WG. Carbohydrate metabolism in uremia: a review. Medicine (Baltimore) 1973;52(5):469-81.|
|6||Lowrie EG, Seldner JS, Hampers CL, Merrill JP. Glucose metabolisrn and insulin secretion in uremic, prediabetic and normal subjects. J Lab Clin Med 1970;76(4):603-15.|
|7||Hutchings RH, Hegstrom RM, Scribner BH. Glucose intolerance in patients on long term intermittent dialysis. Ann Intern Med 1966; 65:275-85.|
|8||Moxely MA, Bell NH, Wagle R, Allan O, Ashmore J. Parathyroid hormone stimulation in isolated liver cells. Am J Physiol 1974; 227(5):1058-61.|
|9||Hems DA, Harmon CS, Whitton PD. Inhibition by parathyroid hormone of glycogen synthesis in the perfused liver. FEBS Lett 1975;58(1):167-9.|
|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.|
|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.|
|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.|
|13||Mak RH. 1,25 - - dihydroxyvitamin D3 corrects insulin and lipid abnormalities in uremia. Kidney Int 1998;53(5):1353-7.|
|14||Mak RH. Amelorattion of hypertension and insulin resistance by 1,25 dihydroxycholecalciferol in hemodialysis patients. Pediatr Nephrol 1992;6(4):345-8.|
|15||Chiu KC, Chu A, Go VL, Saad MF. Hypovitaminose D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr 2004;79(5):820-5.|
|16||Zitterman A. Vitamin D in preventive medicine: Are we ignoring the evidence? Br J Nut 2003;89(5);552-7.|
|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.|
|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.|
|19||Norman AW, Frankel BJ, Heldt AM, Grodsky. GM. Vitamin D deficiency inhibits pancreatic secretion. Science 1980;209(4458): 823-5.|
|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.|
|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.|
|22||Gerich J, Charles MA, Grodsky M. Regulation of pancreatic insulin and glucagons secretion. Annu Rev Physiol 1976;38:353-88.|
|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.|
|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.|
|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.|
|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.|
|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.|
|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.|
|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.|
|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.|