FUNCTIONAL HYPOPARATHYROIDISM AMONG TYPE 2 DIABETIC PATIENTS ON HEMODIALYSIS: IMPACT OF GLYCEMIC CONTROL

Mohamed M. M. Hassaan 1 , Nearmeen M. Rashad 1 *, Ashraf A. Hammam 1 , Hoda G. Bakr 1 , Tarek M. H. Ibrahim 1 , Hazem M. Ghazal 1 and Samy H. Mohamed 2 . 1. Internal Medicine Department, Faculty of Medicine, Zagazig University, Egypt. 2. Medical Biochemistry Department, Faculty of Medicine, Zagazig University, Egypt. ...................................................................................................................... Manuscript Info Abstract ......................... ........................................................................ Manuscript History

There was great evidence that, the higher incidence of osteodystrophy among the diabetic patients on regular hemodialysis was attributed to high intact parathyroid hormone (iPTH) level (150-300 pg/ml),osteodystrophy due to high iPTH level is called High Turnover Bone Disease (HTBD) [6].
Interestingly, recent studies suggested that, there were another type of osteodystrophy in type 2 diabetic patients with ESRDon regular hemodialysis ,due to low iPTH level and called Low Turnover Bone Disease (LTBD) [6].
Thus, diabetic patients on maintenance hemodialysis (MHD) are affected withalteration of iPTH level in opposite direction. Consequently, renal osteodystrophy can be of two types. High Turnover Bone Disease (HTBD) due to high iPTH level and Low Turnover Bone Disease (LTBD) due to comparatively low iPTHlevel [7]. It has been revealed in some studies that, usually diabetic ESRD patients on MHD have lower iPTH level than non-diabetic ESRD patients on MHD [8][9][10].Increasing evidence suggests that,in both diabetic and non-diabetic haemodialyzed patients, impaired iPTH secretion appears to be the main determinant responsible for decreased bone turnover and 'adynamic bone disease [11].
There are controversies about the mechanisms of renal-related bone disease,and the actual role of iPTH serumlevels variation in thepathogenesis of renal osteodystrophy.Therefore, the purpose of current study was to estimate serum levels ofiPTHand to clarify the possible relationships betweeniPTH andHbA1c;which reflect glycemic controlas well as other clinical and biochemical parameters in ESRD patients on regular hemodialysis. iPTH level was decreased in poor glycemic control diabetic patients on hemodialysis, moreover it was negative correlated to measures of blood glucose, as well as biochemical parameters of end stage renal disease. Considering the controversy about the level of iPTH in diabetic patients on hemodialysis and its correlation with HbA1c and other biochemical parameters; our findings revealed the favorable effect of good control of blood glucose on iPTH. Furthermore, tight metabolic control of the diabetic patients is mandatory to avoid hypoparathyroidim. Ca and Vit D supplementations in ESRD may be fruitful in keeping iPTH level within target range.
Patients with poor glycemic control(PGC),67.8 % were male and 32.2% female, their mean age was 49.04 ± 11.28 year. In patients with good glycemic control(GGC),71.4% were male and 28.6% were female,their mean age was46.43 ± 12.79 year. Both diabetic groups were matched for age and gender.

Pearson correlations between serum iPTH (pg/ml),clinical and biochemical characters among both diabetic groups on hemodialysis( Table3):
In diabeticpatients with poor glycemic control,serum iPTH level was positively correlated with25-Hydroxyvitamin D, on the other hand, serum iPTHlevel was negatively correlated with alkaline phosphatase. Indiabetic patients with good glycemic control,serum iPTH level was positively correlated with 25-Hydroxyvitamin D, on the other hand there were significant negative correlations between serum iPTH level and creatinine, alkaline phosphatase, phosphorous and albumin, there were non-significant correlation between iPTH and other clinical and biochemical characters in both groups. Linear regression analyses in diabetic patients on hemodialysis (n=56) : stepwise linear regression analysis was done to assess the main independent parameters associated with serum iPTH.Our results showed that, serum iPTH levels were independently correlated with 25-Hydroxyvitamin D , diastolic blood pressure, serum phosphorus ,albumin,alkaline phosphatase,post prandial blood glucose, fasting blood glucose, hemoglobin A1c. (p< 0.001) ( Table 4).

Discussion:-
Worldwide, the incidence of individuals withend-stage renal disease (ESRD)has increased markedly over the past decades and imposes a major social and economic burden for healthcare systems [12].
Diabetes Mellitus (DM) is the main cause of chronic kidney disease (CKD). Given the prevalence of DM is estimated to increase from 366 million patients in 2011 to 552 million patients in the year 2030.Furthermore, it is well established that diabetic nephropathy particularly from type 2 diabetes and hypertensive nephrosclerosis are the leading causes of ESRD in developed and developing countries possibly because of increasing prevalence of obesity, diabetes and hypertension [13].
Numerous reports have described renal osteodystrophyas "the silent crippler"; affected patients may be completely asymptomatic. Nonetheless,if symptoms developed it observed in the late stages of the disease, these symptoms including bone and joint pain as well as bone deformity and fractures. Adynamic bone disease is a severe state of renal osteodystrophy characterized by low levels of PTH, lack of bone cell activity and a low bone turnover [14]. The excessive suppression of PTH can lead to adynamic bone disease (currently the most common osteodystrophy), mainly because of low bone turnover [15].

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Previous studies have shownadvanced glycation end products (AGEs) which produced in diabetic state play an important role in the pathogenesis of both impaired secretion of iPTH and decreased bone formation. Furthermore, (AGEs) inhibit hypersecretion of PTH in response to low serum calcium [16].Data on the association between T2DM and osteoporotic fractures is controversial. Martinez-Laguna D [17] reported 20% increased risk of hip fracture in the first years following T2DM diseaseonset compared to matched non-diabetic patients.
Nonetheless, numerous reports have linked the higher incidence of osteodystrophy among the diabetic patients on regular hemodialysis to high intact parathyroid hormone (iPTH) level, thus, the objective of the present studywas to estimate the serum levels of iPTH and to clarify the possible relationships between iPTH serum levels and HbA1c ;which reflect the glycemic control as well as other clinical and biochemical parameters in ESRD patients on regular hemodialysis.Our study revealed clear evidence that, diabetic patient on chronic hemodialysis had significantly higher values of PPBG, FBG,HbA1c, LDL , TG,TC, PO4, albumin and Alkaline phosphatase, compared to non diabeticpatients on hemodialysis .
This was in agreement with the findings detected by Paulo et al., [18],whoreported a statistical significant difference regarding fasting blood sugar, phosphorus and glycated hemoglobin in diabetic group compared to non diabetic group.Likewise ,Takeshi et al., [19], reported a high statistical significant difference between all groups regarding glycated hemoglobin. These results were in agreement with the study of Ahmed R. et al., [20], they reported a statistical significant difference between all diabetic and non-diabetic patients regarding HbA1c , fasting blood sugar ,serum albumin and phosphate .
Regarding the influence of hyperglycemia on clinical and biochemical parameters, our results revealed that in poor glycemic control group, systolic & diastolic blood pressure, FBG, PPBG,HbA1c ,urea, alkaline phosphatase, TG, and cholesterolwere significantly higher than in patients with good glycemic control.Similar results had been detected by other authorsAhmed R. et al., [20] they reported a statistical significant difference between controlled diabetic and uncontrolled diabetic patients regarding fasting blood sugar and glycated hemoglobin.
The main finding of our study, non diabetic patienton chronic hemodialysis had significantly higher values of serum iPTHmore than diabetic group,moreover, patients with good glycemic control had significantly higher levels of serum iPTH and 25 Hydroxyvitamin D compared to poor glycemic control group .
These findings are in a close agreement with results reported byAhmed R. et al., [20],who have also determined that serum iPTH levels in diabetic patients on hemodialysis were lower when compared with those in non-diabetic patients, also poor glycemic control further reduced levels of serum iPTH , also good glycemic control was associated with higher levels of serum iPTH, while no statistical difference of serum levels of iPTH between controlled diabetic patients and non-diabetic patients, suggesting that proper glycemic control could eliminate the effects of diabetic state on serum iPTH level.
Previous studies also have shown that, despite the fact that serum iPTH levels are considered important for the understanding of the mechanisms leading to renal related bone disease, changes in iPTH biological action play a significant role in the pathogenesis of renal osteodystrophy [21]. Both high and low circulating iPTH levels have been linked respectively to high and low bone turnover osteodystrophy or adynamic bone disease in patients on hemodialysis [14,22].PilzS et al;2011 [23] showed low 25(OH)D concentrations in patients with CKD . Molina P et al 2014 [24] have reported that cholecalciferol decreases albuminuria and improves iPTH levels Our study demonstrated that, in diabetic patients with poor glycemic control, serum iPTH level was positively correlated with 25-Hydroxyvitamin D,on the other hand, serum iPTHlevel was negatively correlated with Alkaline phosphatase. In good glycemic control,serum iPTH level was positively correlated with 25-Hydroxyvitamin D, but there were significant negative correlations between serum iPTH level and creatinine, alkaline phosphatase, phosphorous and albumin, there were non-significant correlation between iPTH and other clinical and biochemical characters in both groups.Regarding correlation between serum iPTHand parameters of glycemic control .In diabetic patients with poor glycemic control, serum iPTHlevel was negatively correlated with post prandial blood glucose, fasting blood glucose, as well as HbA1C.
These results were in agreement with the studies ofWasan et al., [25]andDan S et al., [26],they observed that in diabetic poor glycemic control group ,there was a significant inverse correlation between serum iPTH and serum 1563 alkaline phosphatase, cholesterol, triglycerides, fasting blood sugar, postprandial blood sugar and glycated hemoglobin.
Also our results revealed that diabetic patients with good glycemic control, serum iPTHlevel was negatively correlated with post prandial blood glucose, fasting blood glucose, as well as HbA1C. Similarly the study of Dan S et al., [26]observed that,in the diabetic good glycemic control group there was a significant positive correlation between serum iPTH and serum albumin and creatinine, while there is a significant inverse correlation between serum iPTH and serum phosphate, alkaline phosphatase, fasting blood sugar, postprandial blood sugar and glycated hemoglobin.
These results were supported previously by Murakami et al., [10], who reported that there was an inverse correlation betweenserum iPTH levels and glycemic control. Specifically, diabetic patients with poor glycemic control were characterized by low circulating iPTH, which is conversely found at higher levels in diabetic patients with good glycemic control. Atmaca et al [27] reported that, impaired blood glucose regulation in subjects with type II DM leads to functional hypoparathyroidism and advisedfurther investigation for the effect on bone loss and fragility. Also Polymeris et al [28] revealed reduction in parathyroid hormone which was inversely correlated with elevated blood glucose during oral glucose tolerance test in non diabetic postmenopausal women.
Our study explored that, In diabetic patients on hemodialysis, stepwise linear regression analysis showed that, serum iPTH levels were independently correlated with 25-Hydroxyvitamin D,diastolic blood pressure, serum phosphorus, albumin, alkaline phosphatase FBG, PPBG andHbA1c .
Also, Paula et al., [18],found that serum HbA1c levels were independent correlated with the serum iPTH levels in diabetic group .The inverse correlation noted between blood glucose and parathyroid hormone suggest that hyperglycemia may have an inhibitory action on the synthesis and secretion of parathyroid hormone and it is attractive to speculate that hyperglycemia together with an insulin deficit may lead to a hypoparathyriod state and a downregulation of PTH receptors [25].
Paula et al., [18]detected the inhibitory effects of insulin on both the secretion and the action of iPTH in both primary and secondary hyperparathyroidism. however, it is still unclear asProcopio M and Borretta G [29] studies suggest that poor metabolic control per se, could inhibit low calcium-mediated iPTH secretion.Guh et al., [30]detected the protective effect of diabetic process on the development of hyperparathyroidism and development of an adynamic bone lesion. In contrast,the uncontrolled hyperglycemia is parallel with increased risk of vascular calcification and increased cardiovascular mortality .
Also, Gnudi et al., [31] reported that low bone turnover osteodystrophy represents a risk factor for accelerated peripheral vascular disease in patients on hemodialysis. While low blood levels of intact PTH strongly suggest the presence of adynamic bone, a high PTH level does not exclude this possibility. Histological studies have found adynamic bone in patients on hemodialysis despite PTH values above 44.0 pmol/L. This may be related to limitations of the PTH assay due to accumulation of inhibitory PTH fragments [32].Despite the fact that K-DOQI [33] guidelines recommend keeping glycated hemoglobin below 7% in diabetic patients undergoing dialysis, this recommendation is not based on clinical trials for the population undergoing renal replacement therapy (RRT), and the target range might be challenged due to the lack of nationwide studies related to this issue, making way for an individualized approach for these patients [34].

Conclusion:-
Non diabetic patient on chronic hemodialysis had significantly higher values of serum 25-hydroxyvitamin D and intact parathyroid hormone (iPTH) more than diabetic group.Moreover,in diabetic patients with poor glycemic control, serum iPTH level and 25-hydroxyvitamin D were significantly lower than diabetic patients with good glycemic.Thus,tight metabolic control of the diabetic process is very important to avoid hypoparathyroidism and low bone turnover in these patients. Alongside, individual titration of CaandVit D supplementations in ESRD patients on hemodialysis may be fruitful in keeping iPTH level within target range. Further studies should be done to investigate whether targeting iPTH and other determinants involved in renal bone disease in dialysis patients may prevent or delay the development of vascular calcifications.