1 Department of Nephrology, Shonan Kamakura General Hospital, Yamazaki Kamakura, 2 Division of Nephrology, Department of Medicine, NTT Kanto Teishin Hospital, Gotanda, Shinagawa and 3 First Department of Medicine, Teikyo University School of Medicine, Itabashiku, Tokyo, Japan
Correspondence and offprint requests to: Shuzo Kobayashi, MD, PhD., Department of Medicine, Shonan Kamakura General Hospital, 12021 Yamazaki Kamakura 247-8533, Japan.
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Abstract |
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Methods. Insulin resistance was examined in 19 non-diabetic patients with end-stage renal disease (ESRD) before and after dialysis therapy (HD, n=10; CAPD, n=9), as well as in 10 healthy controls using the hyperinsulinaemic euglycaemic glucose clamp technique. The glucose disposal rate (GDR mg/kg/min) was used as an index of insulin sensitivity during the clamp technique. We also determined which of various biochemical parameters might be associated with change in insulin resistance by carrying out multiple logistic regression analysis.
Results. GDR was significantly lower (6.44±1.76) in ESRD subjects than in normal subjects (9.90±2.01). HD and CAPD therapies significantly normalized GDR from 6.53±1.84 to 9.74±2.88 and from 6.35±1.65 to 8.18±1.76 respectively. Multiple logistic regression analysis showed that changes in BUN, haematocrit and plasma bicarbonate were significant predictive factors for the change in insulin resistance.
Conclusion. CAPD therapy, in spite of its possible adverse effects in patients with atherosclerotic disease, has been shown to improve insulin resistance in adult uraemic patients, similarly to HD therapy.
Keywords: atherosclerosis; continuous ambulatory peritoneal dialysis; glucose metabolism; haemodialysis; insulin resistance; uraemia
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Introduction |
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DeFronzo et al. [8,9,11,12] investigated glucose intolerance in uraemic patients using a glucose clamp technique and showed that thrice weekly haemodialysis (HD) for 10 weeks improved insulin resistance in ESRD [11]. Mak et al. [13,14] and others [15,16] demonstrated that the correction of anaemia or treatment with 1,25 dihydroxycholecalciferol reversed insulin resistance, although their results were not confirmed by others [17,18]. Despite numerous clinical studies regarding insulin sensitivity of patients undergoing HD therapy, there is little data available concerning the effect of continuous ambulatory peritonal dialysis (CAPD) therapy, particularly in adult uraemic patients. This is a critical issue concerning the choice of dialysis therapy for patients at risk for atherosclerotic disorders.
Using the euglycaemic hyperinsulinaemic glucose clamp technique, we compared the effects of HD and CAPD on insulin resistance in adult uraemic patients. In addition, we determined which of various biochemical parameters are most closely associated with a change in insulin resistance by carrying out multiple logistic regression analysis.
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Methods |
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After fasting serum samples for glucose and insulin were obtained, a continuous infusion of insulin (Humarin R, Shionogi, Japan) was administered initially at 3.56 mU/kg/min for 1 min and gradually decreased every 1 min to a constant rate of 1.12 mU/kg/min to achieve a steady-state hyperinsulinaemia. At 5 min intervals, serum glucose concentration was measured in blood samples that were continuously withdrawn at 2 ml/h through the catheter. The glucose clamp level was 100 mg/dl during the 2-h clamp study and was maintained by infusion of 20% glucose. These procedures were performed using automation according to insulin and glucose algorithms controlled by a computer system installed in the artificial endocrine pancreas based on the instructions of the manufacture. Under steady-state conditions of euglycaemia and hyperinsulinaemia, the rate of glucose infusion during euglycaemic clamp studies provides an index of insulin-stimulated glucose metabolism and is used as an index of insulin sensitivity (GDR, mg/kg/min). For the last 30 min, GDR values (six measurements from 90 to 120 min) were averaged to obtain the insulin sensitivity of the subject. The glucose clamp technique was again performed at the time of discharge (4.9±0.8 weeks and 5.4±1.3 weeks after initiation of HD and CAPD therapy respectively; P=0.32), as mentioned above. The patients undergoing HD therapy were subjected to the clamp procedure between two HD sessions scheduled three times a week and patients on CAPD therapy were subjected to the study without dialysate to avoid glucose load. HD patients were examined after an overnight fast and CAPD patients were examined 3 h after the dialysate was drained from the abdomen.
Biochemical measurements
The serum glucose concentration was measured using the glucose oxidase method. The insulin level was measured by means of a competitive enzyme immunoassay with a double antibody procedure using EIA Test Insulin II kit (BMY, Boehringer). Cholesterol and triglyceride levels were measured by means of an enzymatic technique using an automatic analyser. High-density lipoprotein cholesterol (HDL) was measured after precipitation of low-density lipoprotein, very-low-density lipoprotein, and chylomicrons with dextran sulfate, magnesium chloride, and polyethylene glycol, respectively. The atherogenic index (AI) was defined as (total cholesterolHDL)/HDL. Other variables were measured by standard methods on a multichannel autoanalyser. As parameters of a change in body fluid, the cardiothoracic rate (CTR) was examined by thoracic radiography and the left ventricular mass index (LVMI) was estimated by echocardiography. The LVMI [21] was determined by means of Penn conversion using the following formula: LVM (left ventricular mass)=1.04[(IVS+LVID+PWT)3LVID3]13.6, where IVS is the width of the interventricular septum at the end of the mitral leaflet in diastole, PWT is the posterior wall thickness of the left ventricule in diastole and LVID is the diameter of the ventricle at the end of diastole. The LVMI was expressed as the LVM divided by the height of the subject (g/m).
Statistical analyses
All values were expressed as means±SD. Statistical differences were analysed by the paired Student's t-test or ANOVA followed by Student-NewmanKeuls test. Multiple logistic regression analysis was performed using a stepwise forwardbackward procedure to determine the respective relationships between various factors and altered insulin resistance after HD/CAPD therapy of uraemic patients. The F value for a candidate's inclusion in or exclusion from the discriminant function test was set at 4.0. A P value of <0.05 was considered significant.
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Results |
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The steady-state plasma glucose concentration during the last 30 min of the glucose clamp study was 98.9±1.8 mg/dl for patients before dialysis therapy and 98.3±1.6 for the control, a difference which was not statistically significant. The coefficient of variation of the plasma glucose level during the study was <3%. The mean values of plasma insulin determined at 120 min during the glucose clamp study were 64.8±10.8 µU/ml in normal subjects, 75.5±9.8µU/ml and 66.8±9.1µU/ml in pre- and post-HD patients, and 77.9±8.6 µU/ml and 70.6±10.2 µU/ml in pre- and post-CAPD patients respectively. There was no statistically significant difference between these groups. As shown in Figure 1, insulin sensitivity (GDR mg/kg/min) as measured by the glucose infusion rate during the last 30 min of the glucose clamp, was 9.93±1.33 in healthy control subjects. In contrast, the GDR of uraemic individuals was 6.44±1.76 significantly lower than that of control subjects, which suggested insulin resistance in ESRD patients (Figure 1
). After HD therapy (n=10), insulin sensitivity increased by 49.0% (P<0.01) from 6.53±1.84 to 9.74±2.88 so that the value was no longer different from control values (Figure 1
). The GDR of patients on CAPD (n=9) was also significantly improved after dialysis (from 6.35±1.65 to 8.18±1.76, P<0.05) (Figure 1
). Thus, both HD and CAPD therapy improved insulin resistance found in the patients with ESRD. The changes in GDR, plasma levels of metabolites and hormones, CTR and LVMI from before the start of therapy and at the end of follow-up are shown in Table 1
. Body weight did not change significantly with therapy, nor was there a change in CTR and LVMI, suggesting that there was no change in levels of body fluid. In contrast, blood urea nitrogen, Ht, HCO3 and phosphate were all normalized significantly by both HD and CAPD therapy. Serum creatinine decreased significantly in patients with HD, whereas no significant reduction was found in patients with CAPD. There was no change in the serum potassium or calcium concentration. Plasma insulin and glucose levels were unchanged by both dialysis therapies. Serum total protein, albumin, and lipid profile were not significantly changed. However, in the patients with CAPD, there was a trend for total cholesterol and triglyceride to be increased, but it did not reach statistically significant levels.
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Discussion |
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The present study clearly confirmed that before the initiation of dialysis therapy, insulin-mediated glucose disposal rate (insulin sensitivity as measured by the clamp technique) was markedly reduced in ESRD patients compared with control subjects. The mean duration of 4.9 weeks of HD therapy completely normalized insulin sensitivity. This result is compatible with the finding by DeFronzo and Mak et al. who demonstrated that 10 weeks of HD therapy resulted in a marked improvement in glucose metabolism, but did not completely normalize glucose utilization [11].
There is little data available regarding the effect of CAPD therapy on insulin sensitivity. This is important because of the possibility that glucose loading may worsen insulin sensitivity. In the present study we showed that CAPD therapy for 5.4 weeks normalized insulin resistance similar to HD therapy. Recently, Mak reported similar favourable results regarding the effect of peritoneal dialysis therapy on insulin resistance in uraemia. He compared the effect of continuous cycling peritoneal dialysis (CCPD) to that of HD on insulin resistance in younger adolescent uraemic patients, and showed that the percentage increase, as well as the final insulin sensitivity, was significantly higher in the CCPD group than the HD group [24]. In the present study, this trend is reversed. Although we do not have an explanation, the difference may be due to the different modalities of peritoneal dialysis, namely CAPD and CCPD. There is another report showing that CAPD tended to improve insulin resistance [25]. In contrast, there is a report, albeit with a less sophisticated technique, that CAPD patients display an insulin-resistance [26].
Numerous factors have been implicated in the pathogenesis of carbohydrate intolerance of uraemia [8,10,27]. It seems unlikely that excess body fluid is involved in insulin resistance in peripheral tissues since body weight, CTR and LVMI measured by echocardiography were unchanged after dialysis therapy. It has been recently reported that the correction of anaemia by erythropoietin reversed insulin resistance in uraemic patients [13,15,16]. However, the subjects studied by those investigators were already being maintained on regular HD so that values of other biochemical parameters such as BUN were not changed after correction of the anaemia. Therefore, the role of factors other than anaemia could not be ascertained even if insulin resistance is caused, at least in part, by the anaemia. All patients were receiving epoetin so that Ht increased up to 30%. We carried out a statistical investigation of various biochemical parameters using multiple logistic regression analysis although the value of this statistical analysis may be limited because of a large number of factors in small groups of patients. The results indicated that BUN, HCO3 and Ht were independent predictive factors for a change in insulin resistance. However, when only the Ht value was altered, there was no correlation between Ht and insulin resistance (data not shown). In contrast, a close correlation was found between changes in BUN or HCO3, and insulin resistance. This suggests that a change in Ht, which contributes to insulin resistance, must accompany a change in BUN or HCO3. On the other hand, it has been reported that urea is probably not the crucial toxin [28] and the duration of azotaemia may be important [29]. We believe that, in addition to BUN, unknown uraemic toxin(s) can contribute to insulin resistance. These may be guanidino substances, hippurate or pseudouridine or other toxins including advanced glycation end products [3032]. Indeed, there is a report that specific uraemic toxins such as creatinine, creatine and glycocyamine may play an important role in the mechanisms of altered insulin binding to erythrocyte receptors during HD [23]. Taking another approach, Mak et al. [33] studied the effect of protein restriction on the insulin sensitivity of uraemic patients. Six months after the initiation of protein restriction with amino acid and keto acid supplementation, significant reductions in blood urea concentrations were observed and these were accompanied by normalization of insulin resistance.
Metabolic acidosis has also been known to contribute to insulin resistance [34]. In our study, blood HCO3 levels correlated well with GDR values. Malnutrition [35], an excess of PTH [36] or a deficiency in 1,25(OH)2D3 [14] has been implicated in the pathogenesis of insulin abnormalities in uraemia. However, since in the present study, serum albumin and PTH levels were unchanged after dialysis, it is unlikely that either nutrition or PTH level is an important factor. We unfortunately did not measure 1,25(OH)2D3 which may be an important contributing factor [14]. Among other important factors, dyslipidaemia might have a contributory role in insulin resistance [3739]. Serum LDL level was significantly lowered in patients who received HD therapy, while there was no change in LDL level in patients with CAPD. Moreover, no change in the level of any lipid could be significantly correlated with a change in GDR, nor did multiple regression analysis result in selection of these variables. Therefore, a role for dyslipidaemia in insulin resistance is less likely. It is also unlikely that the change in physical activity [40] contribute to the altered insulin sensitivity since patients were still in hospital.
In conclusion, we showed that the patients with ESRD before the initiation of dialysis therapy had insulin resistance, which was completely reversed by either HD or CAPD therapy. Stepwise forward multiple regression analysis revealed that changes in BUN, Ht and HCO3 were significant predictive factors for an improvement in insulin resistance. Since there is evidence suggesting that insulin resistance may be involved in the pathogenesis of hypertension and atherosclerosis often seen in uraemia and since cardiovascular complications are the most significant causes of mortality and morbidity in patients with ESRD, delayed initiation of dialysis therapy or insufficient dialysis may worsen atherosclerosis through long-standing insulin resistance. Of particular importance in the present study is the finding that CAPD therapy also improved insulin resistance found in ESRD patients.
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References |
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