腹膜透析患者胰岛素抵抗、代谢紊乱的预后及干预的前瞻性研究
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摘要
腹膜透析患者胰岛素抵抗、代谢紊乱的预后及干预的前瞻性研究
第一部分
胰岛素抵抗指数是预测腹透患者心脑血管疾病发生和全因死亡的危险因素——前瞻性队列研究
背景
胰岛素抵抗(Insulin Resistance, IR)与代谢紊乱密切相关。对非尿毒症的普通人群研究认为,IR是引起动脉硬化的重要危险因素。对于腹膜透析(Peritoneal Dialysis, PD)患者,虽然透析治疗能在一定程度上改善IR,但传统腹透液高糖负荷在一定程度上加重了PD患者工R、糖/脂代谢紊乱、肥胖的发生发展。然而,PD患者胰岛素抵抗、糖/脂代谢紊乱、肥胖和心血管事件发生、长期生存率的关系并不明确,甚至出现一些“逆流行病学”的结论。所以,本研究的目的是通过前瞻性队列研究,观察比较不同IR水平的PD患者全因死亡危险性、心脑血管疾病发生和死亡危险性的差异。
方法
前瞻性队列研究：入选原发病为非糖尿病肾病、透析龄大于3个月的PD患者69人,在相同条件下测定其体重指数(BMI)、血压、空腹血糖、空腹胰岛素及血脂、C反应蛋白(C Reactive Protein, CRP)、铁蛋白等生化指标。用ELISA法测定脂联素、瘦素、抵抗素等脂肪因子。用公式(空腹血糖×空腹胰岛素)／22.5)计算稳态胰岛素抵抗指数(HOMA-IR)。根据该人群HOMA-IR中位数水平将人群分为两组,比较①入选时两组患者脂代谢、炎症、脂肪因子代谢等各方面情况的差异；②两组患者透析后新发糖尿病、心脑血管事件发生危险性的差异；③通过对两组患者行生存分析比较两组心脑血管疾病死亡、全因死亡危险性的差异。
结果
PD患者69人(男/女：32/37),平均年龄61.95±16.06岁,中位数透析龄15.17月,平均随访时间22.82±11.07月。根据HOMA-IR中位数2.86分组：IR-H组,HOMA-IR≥2.86(n=35); IR-L组,HOMA-IR<2.86 (n=34)。两组相比：年龄、透析龄、24小时腹透液葡萄糖吸收量、肾脏原发病构成比例、残肾功能均无明显统计学差异。IR-H组平均BMI、平均空腹血糖、平均铁蛋白、中位数甘油三酯水平、中位数CRP水平、中位数血瘦素水平均高于IR-L组,差异均有统计学意义。而IR-H组的HDL水平、脂联素水平低于IR-L组,差异有统计学意义。HOMA-IR水平与CRP、瘦素、甘油三酯、BMI呈正相关；与高密度脂蛋白、脂联素水平呈负相关。
在进入PD治疗后,IR-H组10例出现新发糖尿病,而IR-L组无新发糖尿病,两组差异有统计学意义(P=0.001)。IR-H组发生心脑血管事件11例次(脑梗塞4例次、脑出血2例次、急性心肌梗塞1例次、急性左心衰2例次、下肢动脉栓塞1例、肺梗塞1例),IR-L组1例次发生心脑血管事件(典型心绞痛伴异常心肌核素显像1例),经校正年龄、性别后,IR-H组透后心脑血管事件发生的风险仍高于IR-L组(RR=16.35;95%CI:4.75-56.29;P=0.011)。IR-H组9例死亡(心脑血管事件5例,肿瘤1例,腹透感染不能控制1例,原因不详2例),IR-L组2例死亡(肠穿孔1例,重症肺炎1例)。经Kaplan-Meier分析和log rank检验,IR-H组生存率低于IR-L组(x2=4.76,P=0.0291)。经校王年龄、性别、残肾功能、血白蛋白等因素后,R-H组的全因死亡危险性仍高于IR-L组(RR=3.28;95%CI:1.32-8.16;P=0.011).IR-H组因心脑血管死记患者的比例显著高于IR-L组(IR-H组：5/35例,IR-L组：0/34例；P=0.029)。
结论
胰岛素抵抗指数较高的维持性PD患者肥胖、透析后新发糖尿病、脂质代谢紊乱、炎症的发生率明显高于胰岛素抵抗指数较低的患者。腆岛素抵抗水平高是原发病为非糖尿病肾病的PD患者心脑血管事件发生、全因死亡的危险因素。提示纠正胰岛素抵抗是改善PD患者长期生存率的重：要环节。
第二部分
吡格列酮对维持性腹膜透析患者代谢紊乱及炎症反应的治疗作用——随机交叉设计研究
背景
本文的第一部分研究表明胰岛素抵抗、脂代谢紊乱在维持性PD患者中常见而严重,并与心脑血管事件发生密切相关,是PD患者死亡的危险因素。但是,对PD患者代谢紊乱的治疗,尤其是对高甘油三酯血症的治疗一直是个棘手的问题。研究发现被广泛用于治疗2型糖尿病的吡格列酮不仅能恢复胰岛素敏感性,降低血糖并且对于2型糖尿病患者的血脂和炎症反应也有积极的治疗作用。所以,可以设想吡格列酮在代谢紊乱严重的腹膜透析人群中有良好的应有前景。本研究的目的是研究口服吡格列酮对腹膜透析患者脂代谢紊乱、IR、炎症反应以及脂肪因子代谢紊乱的治疗作用。
方法
随机交叉设计研究：入选36例血清甘油三酯水平>1.8mmol/L的维持性PD患者,随机分成两组。第一阶段(12周)A组先用口服吡格列酮15mg/天治疗,B组作为空白对照；第二阶段(12周)A组作为空白对照,B组用口服吡格列酮15mg/天治疗；两个阶段之间的洗脱期为4周。每6周随访一次,进行人体测量和检测空腹血清甘油三酯、其它血脂水平、空腹血糖、胰岛素(计算HOMA-IR用)、C反应蛋白、肝功能、脂肪因子等水平。
结果
所有36例受试对象(10例有糖尿病,26例非糖尿病)完成本研究。虽然12周的吡格列酮治疗并没有显著改善血甘油三酯水平和低密度脂蛋白水平,但治疗后高密度脂蛋白水平有所上升,差异有统计学意义(治疗前：0.94±0.20mmol/L,治疗后1.00±0.21mm0l/L,P=0.0038)。治疗后,胰岛素抵抗指数HOMA-IR(治疗前6.23(1.39-29.03),治疗后5.28(0.97-14.95),P=0.0060)和空腹血糖(治疗前7±2.35mm0l/L,治疗后6.6±2.45mmol/L,P=0.0106)水平下降,差异有统计学意义；糖化血红蛋白水平变化不明显。毗格列酮治疗后血C反应蛋白水平明显下降,差异有统计学意义(治疗前：11.30(0.18-53)mg/L,治疗后：3.36(0.17-26.30)mg/L(P=0.0049))；血总脂联素水平上升而血抵抗素水平下降,差异均有统计学意义(脂联素：治疗前13.38±8.86ug/ml,治疗后49.87±33.34ug/ml,P<0.0001；抵抗素：治疗前33.09±16.81ng/ml,治疗后28.89±10.76ng/ml,P=0.0219).治疗前后体重指数无明显变化。整个试验期间除了1例有残肾功能的患者出现下肢水肿外,无心血管事件、低血糖、肝功能受损、骨折等不良反应发生。
结论
尽管12周的毗格列酮治疗(15mg/天)并没有降低维持性PD患者血甘油三酯水平,但却降低了该人群的胰岛素抵抗水平和炎症反应、改善了脂肪因子代谢紊乱。提示吡格列酮在该人群代谢紊乱治疗方面有很好的应用前景。
Insulin Resistance and Lipid Metabolic Disorder in Peritoneal Dialysis Patients:Prognosis and Therapy
Part I
Insulin Resistance as a Predictor of Cardiocerebrovascular Morbidity and All Cause Mortality in Peritoneal Dialysis Patients: A Prospective Cohort Study
Background
Insulin resistance (IR) contributes to metabolic disorder. The overload of glucose aggravates IR in PD patients. Whereas IR, metabolic disorder, obesity are the established risk factors for increased morbidity and mortality in the general population, epidemiological studies and clinical trials in end stage renal disease patients have created uncertainties with regards to the impact of metabolic disorder on mortality. Prospective study about the relationship between IR, metabolic disorder and cardiocerebrovascular morbidity and mortality in nondiabetic PD patients is limited. We hypothesized that high level of insulin resistance is associated with dysmetabolism development and cardiocerebrovascular morbidity and mortality in nondiabetic PD patients.
Methods
A cohort of 69 nondiabetic uremic patients was prospectively enrolled. They had been treated by regular peritoneal dialysis for more than 3 months. At baseline, the HOMA-IR (fasting serum insulinμU/mL×fasting serum glucose mmol/L/22.5) formula was used to determine the insul in resistance. The cut-off point for IR was established by the median. According to it, the patients were divided into two groups:High IR group (IR-H group) if HOMA-IR was greater than or equal to the median and low IR group(IR-L group) if less than this level. The differences of dysmetabolism parameters (BMI, serum cholesterol, triglyceride, HDL, LDL, CRP, total adiponectin, leptin, resistin) and development of new onset diabetes mellitus, cardiocerebrovascular morbidity and all-cause mortality were investigated between the two groups.
Results
At the beginning of the study, average age was 61.95±16.06years, 37 were female, and the median time on PD was 15.17months. The average follow-up period was 22.82±11.07 months. The cut-off point of IR was 2.86: IR-H group, HOMA-IR(?)2.86(n=35);IR-L group, HOMA-IR<2.86 (n=34). Average age, PD duration,24 hour peritoneal dialysate glucose absorption, average blood pressure, the distribution of primary renal disease and residue renal function did not differ between the two groups. The level of BMI, average fasting serum glucose, average ferritin, median triglyceride, median CRP, median leptin were statistically significantly higher in IR-H group than those in IR-L group. However, median HDL, median adiponectin levels were statistically significantly lower in IR-H group than those in IR-L group. There were positive correlations between HOMA-IR and CRP, leptin, triglycerides. Inverse associations were observed between HOMA-IR and HDL, HOMA-IR and adiponectin.
There were 10 patients in IR-H group but no patient in IR-L group developed diabetes mellitus (P=0.001). During the follow-up period,11 Cardiocerebrovascular events (including cerebral infarction 4, cerebral hemorrhage 2, myocardial infarction 1, left heart failure 2, pulmonary infarction 1, and phlebothrombosis in lower limb 1) were occurred in IR-H group but only 1 event (angina pectoris) occurred in IR-L group. HOMA-IR were found to be significant predictors of cardiocerebrovascular events even after adjusted for age and gender (RR=16.35; 95%CI:4.75-56.29; P=0.O11). There were 9 patients died (cardiocerebrovascular events 5, cancer 1, serious peritonitisl, unknown reason 2) in IR-H group but only 2 patients died (serious pneumonia 1, intestinal perforationl) in IR-L group. The survival curves estimated by the Kaplan-Meier method and log rank test showed that patients in IR-H group had a significantly lower survival rate compared with those in IR-L group (x2=4.76, P=0.0291) HOMA-IR remained to be significant predictors of all cause mortality even after adjusted for age, gender, residue renal function, serum albumin (RR=3.28;95%CI:1.32-8.16;P=0.O11). The percentage of patients who died because of cardiocerebrovascular disease in IR-H group were higher than that in IR-L group (IR-H group:5/35, IR-L:0/34; P=0.029)
Conclusions
Insulin resistance is particularly prevalent in PD patients. PD patients who had higher IR level had more serious metabolic disorders, higher rates of diabetes development, cardiocerebrovascular morbidity and all cause mortality. It was accepted that being able to correct the insulin resistance could be a novel therapeutic approach to reduce mortality in this cohort.
PartⅡ
Twelve weeks of pioglitazone therapy significantly attenuates dysmetabolism and reduces inflammation in prevalent peritoneal dialysis patients:A randomized, cross-over trial
Backgrounds
In the first part, we have demonstrated that cardiocerebrovascular disease is the major cause of mortality in PD patients, which is attributable to a higher prevalence of insulin resistance and metabolic disturbance. However, treatment for metabolic disorder, esp. hypertriglyceride is difficult in PD patients in China where the icodextrin dialysate has still been unavailable. The aim of this study is to investigate the effect of oral pioglitazone on lipid metabolism, insulin resistance, inflammation and adipokine metabolism in PD patients.
Methods
We randomly assigned 36 prevalent PD patients with serum triglyceride levels> 1.8mmol/L to receive either oral pioglitazone (15mg once daily) or no medication for 12 weeks. After a four weeks wash out, patients then continued with the alternative therapy. Anthropometrics and fasting serum triglycerides, low density lipoprotein(LDL), high density lipoprotein(HDL), glucose, insulin (for calculation of HOMA-IR), C-reactive protein(CRP), liver function tests, leptin, total adiponectin and resistin were measured every six weeks.
Results
All 36 patients (10 diabetes,26 non-diabetes) completed the study. Although no significant differences of 12 weeks therapy of pioglitazone on serum TG and LDL were recorded, pioglitazone significantly increased HDL level (0.94±0.20 to.1.00±0.21mmol/L, p=0.0038). HOMA-IR level (6.23(1.39-29.03) to 5.28(0.97-14.95), p=0.0060) and fasting serum glucose level (7±2.35 to 6.6±2.45mmol/L, p=0.0106) were decreased significantly, whereas no significant change was occurred in HbAlc level. Pioglitazone significantly reduced median CRP level from 11.30(0.18-53) to 3.36 (0.17-26.30) mg/L (p=0.0049). Total adiponectin level (13.38±8.86 to.49.87±33.34, p<0.0001) increased and resistin level decreased (33.09±16.81 to.28.89±10.76, p=0.0219) significantly. There were also no significant changes in BMI after treatment. Pioglitazone was well tolerated that no adverse effects as hypoglycemia, hepatic impairment and heart failure were observed during the study period except that 1 patient with significant residue renal function developed lowered-extremity edema.
Conclusion
12 weeks of pioglitazone (15mg once daily) did not alter serum triglycerides in prevalent PD patients, but decreased insulin resistance, inflammation and attenuated adipokine imbalance. Pioglitazone may be a beneficial therapy for this patient group.
第一部分
胰岛素抵抗指数是预测腹透患者心脑血管疾病发生和全因死亡的危险因素——前瞻性队列研究
背景
胰岛素抵抗(Insulin Resistance, IR)与代谢紊乱密切相关。对非尿毒症的普通人群研究认为,IR是引起动脉硬化的重要危险因素。对于腹膜透析(Peritoneal Dialysis, PD)患者,虽然透析治疗能在一定程度上改善IR,但传统腹透液高糖负荷在一定程度上加重了PD患者工R、糖/脂代谢紊乱、肥胖的发生发展。然而,PD患者胰岛素抵抗、糖/脂代谢紊乱、肥胖和心血管事件发生、长期生存率的关系并不明确,甚至出现一些“逆流行病学”的结论。所以,本研究的目的是通过前瞻性队列研究,观察比较不同IR水平的PD患者全因死亡危险性、心脑血管疾病发生和死亡危险性的差异。
方法
前瞻性队列研究：入选原发病为非糖尿病肾病、透析龄大于3个月的PD患者69人,在相同条件下测定其体重指数(BMI)、血压、空腹血糖、空腹胰岛素及血脂、C反应蛋白(C Reactive Protein, CRP)、铁蛋白等生化指标。用ELISA法测定脂联素、瘦素、抵抗素等脂肪因子。用公式(空腹血糖×空腹胰岛素)／22.5)计算稳态胰岛素抵抗指数(HOMA-IR)。根据该人群HOMA-IR中位数水平将人群分为两组,比较①入选时两组患者脂代谢、炎症、脂肪因子代谢等各方面情况的差异；②两组患者透析后新发糖尿病、心脑血管事件发生危险性的差异；③通过对两组患者行生存分析比较两组心脑血管疾病死亡、全因死亡危险性的差异。
结果
PD患者69人(男/女：32/37),平均年龄61.95±16.06岁,中位数透析龄15.17月,平均随访时间22.82±11.07月。根据HOMA-IR中位数2.86分组：IR-H组,HOMA-IR≥2.86(n=35); IR-L组,HOMA-IR<2.86 (n=34)。两组相比：年龄、透析龄、24小时腹透液葡萄糖吸收量、肾脏原发病构成比例、残肾功能均无明显统计学差异。IR-H组平均BMI、平均空腹血糖、平均铁蛋白、中位数甘油三酯水平、中位数CRP水平、中位数血瘦素水平均高于IR-L组,差异均有统计学意义。而IR-H组的HDL水平、脂联素水平低于IR-L组,差异有统计学意义。HOMA-IR水平与CRP、瘦素、甘油三酯、BMI呈正相关；与高密度脂蛋白、脂联素水平呈负相关。
在进入PD治疗后,IR-H组10例出现新发糖尿病,而IR-L组无新发糖尿病,两组差异有统计学意义(P=0.001)。IR-H组发生心脑血管事件11例次(脑梗塞4例次、脑出血2例次、急性心肌梗塞1例次、急性左心衰2例次、下肢动脉栓塞1例、肺梗塞1例),IR-L组1例次发生心脑血管事件(典型心绞痛伴异常心肌核素显像1例),经校正年龄、性别后,IR-H组透后心脑血管事件发生的风险仍高于IR-L组(RR=16.35;95%CI:4.75-56.29;P=0.011)。IR-H组9例死亡(心脑血管事件5例,肿瘤1例,腹透感染不能控制1例,原因不详2例),IR-L组2例死亡(肠穿孔1例,重症肺炎1例)。经Kaplan-Meier分析和log rank检验,IR-H组生存率低于IR-L组(x2=4.76,P=0.0291)。经校王年龄、性别、残肾功能、血白蛋白等因素后,R-H组的全因死亡危险性仍高于IR-L组(RR=3.28;95%CI:1.32-8.16;P=0.011).IR-H组因心脑血管死记患者的比例显著高于IR-L组(IR-H组：5/35例,IR-L组：0/34例；P=0.029)。
结论
胰岛素抵抗指数较高的维持性PD患者肥胖、透析后新发糖尿病、脂质代谢紊乱、炎症的发生率明显高于胰岛素抵抗指数较低的患者。腆岛素抵抗水平高是原发病为非糖尿病肾病的PD患者心脑血管事件发生、全因死亡的危险因素。提示纠正胰岛素抵抗是改善PD患者长期生存率的重：要环节。
第二部分
吡格列酮对维持性腹膜透析患者代谢紊乱及炎症反应的治疗作用——随机交叉设计研究
背景
本文的第一部分研究表明胰岛素抵抗、脂代谢紊乱在维持性PD患者中常见而严重,并与心脑血管事件发生密切相关,是PD患者死亡的危险因素。但是,对PD患者代谢紊乱的治疗,尤其是对高甘油三酯血症的治疗一直是个棘手的问题。研究发现被广泛用于治疗2型糖尿病的吡格列酮不仅能恢复胰岛素敏感性,降低血糖并且对于2型糖尿病患者的血脂和炎症反应也有积极的治疗作用。所以,可以设想吡格列酮在代谢紊乱严重的腹膜透析人群中有良好的应有前景。本研究的目的是研究口服吡格列酮对腹膜透析患者脂代谢紊乱、IR、炎症反应以及脂肪因子代谢紊乱的治疗作用。
方法
随机交叉设计研究：入选36例血清甘油三酯水平>1.8mmol/L的维持性PD患者,随机分成两组。第一阶段(12周)A组先用口服吡格列酮15mg/天治疗,B组作为空白对照；第二阶段(12周)A组作为空白对照,B组用口服吡格列酮15mg/天治疗；两个阶段之间的洗脱期为4周。每6周随访一次,进行人体测量和检测空腹血清甘油三酯、其它血脂水平、空腹血糖、胰岛素(计算HOMA-IR用)、C反应蛋白、肝功能、脂肪因子等水平。
结果
所有36例受试对象(10例有糖尿病,26例非糖尿病)完成本研究。虽然12周的吡格列酮治疗并没有显著改善血甘油三酯水平和低密度脂蛋白水平,但治疗后高密度脂蛋白水平有所上升,差异有统计学意义(治疗前：0.94±0.20mmol/L,治疗后1.00±0.21mm0l/L,P=0.0038)。治疗后,胰岛素抵抗指数HOMA-IR(治疗前6.23(1.39-29.03),治疗后5.28(0.97-14.95),P=0.0060)和空腹血糖(治疗前7±2.35mm0l/L,治疗后6.6±2.45mmol/L,P=0.0106)水平下降,差异有统计学意义；糖化血红蛋白水平变化不明显。毗格列酮治疗后血C反应蛋白水平明显下降,差异有统计学意义(治疗前：11.30(0.18-53)mg/L,治疗后：3.36(0.17-26.30)mg/L(P=0.0049))；血总脂联素水平上升而血抵抗素水平下降,差异均有统计学意义(脂联素：治疗前13.38±8.86ug/ml,治疗后49.87±33.34ug/ml,P<0.0001；抵抗素：治疗前33.09±16.81ng/ml,治疗后28.89±10.76ng/ml,P=0.0219).治疗前后体重指数无明显变化。整个试验期间除了1例有残肾功能的患者出现下肢水肿外,无心血管事件、低血糖、肝功能受损、骨折等不良反应发生。
结论
尽管12周的毗格列酮治疗(15mg/天)并没有降低维持性PD患者血甘油三酯水平,但却降低了该人群的胰岛素抵抗水平和炎症反应、改善了脂肪因子代谢紊乱。提示吡格列酮在该人群代谢紊乱治疗方面有很好的应用前景。
Insulin Resistance and Lipid Metabolic Disorder in Peritoneal Dialysis Patients:Prognosis and Therapy
Part I
Insulin Resistance as a Predictor of Cardiocerebrovascular Morbidity and All Cause Mortality in Peritoneal Dialysis Patients: A Prospective Cohort Study
Background
Insulin resistance (IR) contributes to metabolic disorder. The overload of glucose aggravates IR in PD patients. Whereas IR, metabolic disorder, obesity are the established risk factors for increased morbidity and mortality in the general population, epidemiological studies and clinical trials in end stage renal disease patients have created uncertainties with regards to the impact of metabolic disorder on mortality. Prospective study about the relationship between IR, metabolic disorder and cardiocerebrovascular morbidity and mortality in nondiabetic PD patients is limited. We hypothesized that high level of insulin resistance is associated with dysmetabolism development and cardiocerebrovascular morbidity and mortality in nondiabetic PD patients.
Methods
A cohort of 69 nondiabetic uremic patients was prospectively enrolled. They had been treated by regular peritoneal dialysis for more than 3 months. At baseline, the HOMA-IR (fasting serum insulinμU/mL×fasting serum glucose mmol/L/22.5) formula was used to determine the insul in resistance. The cut-off point for IR was established by the median. According to it, the patients were divided into two groups:High IR group (IR-H group) if HOMA-IR was greater than or equal to the median and low IR group(IR-L group) if less than this level. The differences of dysmetabolism parameters (BMI, serum cholesterol, triglyceride, HDL, LDL, CRP, total adiponectin, leptin, resistin) and development of new onset diabetes mellitus, cardiocerebrovascular morbidity and all-cause mortality were investigated between the two groups.
Results
At the beginning of the study, average age was 61.95±16.06years, 37 were female, and the median time on PD was 15.17months. The average follow-up period was 22.82±11.07 months. The cut-off point of IR was 2.86: IR-H group, HOMA-IR(?)2.86(n=35);IR-L group, HOMA-IR<2.86 (n=34). Average age, PD duration,24 hour peritoneal dialysate glucose absorption, average blood pressure, the distribution of primary renal disease and residue renal function did not differ between the two groups. The level of BMI, average fasting serum glucose, average ferritin, median triglyceride, median CRP, median leptin were statistically significantly higher in IR-H group than those in IR-L group. However, median HDL, median adiponectin levels were statistically significantly lower in IR-H group than those in IR-L group. There were positive correlations between HOMA-IR and CRP, leptin, triglycerides. Inverse associations were observed between HOMA-IR and HDL, HOMA-IR and adiponectin.
There were 10 patients in IR-H group but no patient in IR-L group developed diabetes mellitus (P=0.001). During the follow-up period,11 Cardiocerebrovascular events (including cerebral infarction 4, cerebral hemorrhage 2, myocardial infarction 1, left heart failure 2, pulmonary infarction 1, and phlebothrombosis in lower limb 1) were occurred in IR-H group but only 1 event (angina pectoris) occurred in IR-L group. HOMA-IR were found to be significant predictors of cardiocerebrovascular events even after adjusted for age and gender (RR=16.35; 95%CI:4.75-56.29; P=0.O11). There were 9 patients died (cardiocerebrovascular events 5, cancer 1, serious peritonitisl, unknown reason 2) in IR-H group but only 2 patients died (serious pneumonia 1, intestinal perforationl) in IR-L group. The survival curves estimated by the Kaplan-Meier method and log rank test showed that patients in IR-H group had a significantly lower survival rate compared with those in IR-L group (x2=4.76, P=0.0291) HOMA-IR remained to be significant predictors of all cause mortality even after adjusted for age, gender, residue renal function, serum albumin (RR=3.28;95%CI:1.32-8.16;P=0.O11). The percentage of patients who died because of cardiocerebrovascular disease in IR-H group were higher than that in IR-L group (IR-H group:5/35, IR-L:0/34; P=0.029)
Conclusions
Insulin resistance is particularly prevalent in PD patients. PD patients who had higher IR level had more serious metabolic disorders, higher rates of diabetes development, cardiocerebrovascular morbidity and all cause mortality. It was accepted that being able to correct the insulin resistance could be a novel therapeutic approach to reduce mortality in this cohort.
PartⅡ
Twelve weeks of pioglitazone therapy significantly attenuates dysmetabolism and reduces inflammation in prevalent peritoneal dialysis patients:A randomized, cross-over trial
Backgrounds
In the first part, we have demonstrated that cardiocerebrovascular disease is the major cause of mortality in PD patients, which is attributable to a higher prevalence of insulin resistance and metabolic disturbance. However, treatment for metabolic disorder, esp. hypertriglyceride is difficult in PD patients in China where the icodextrin dialysate has still been unavailable. The aim of this study is to investigate the effect of oral pioglitazone on lipid metabolism, insulin resistance, inflammation and adipokine metabolism in PD patients.
Methods
We randomly assigned 36 prevalent PD patients with serum triglyceride levels> 1.8mmol/L to receive either oral pioglitazone (15mg once daily) or no medication for 12 weeks. After a four weeks wash out, patients then continued with the alternative therapy. Anthropometrics and fasting serum triglycerides, low density lipoprotein(LDL), high density lipoprotein(HDL), glucose, insulin (for calculation of HOMA-IR), C-reactive protein(CRP), liver function tests, leptin, total adiponectin and resistin were measured every six weeks.
Results
All 36 patients (10 diabetes,26 non-diabetes) completed the study. Although no significant differences of 12 weeks therapy of pioglitazone on serum TG and LDL were recorded, pioglitazone significantly increased HDL level (0.94±0.20 to.1.00±0.21mmol/L, p=0.0038). HOMA-IR level (6.23(1.39-29.03) to 5.28(0.97-14.95), p=0.0060) and fasting serum glucose level (7±2.35 to 6.6±2.45mmol/L, p=0.0106) were decreased significantly, whereas no significant change was occurred in HbAlc level. Pioglitazone significantly reduced median CRP level from 11.30(0.18-53) to 3.36 (0.17-26.30) mg/L (p=0.0049). Total adiponectin level (13.38±8.86 to.49.87±33.34, p<0.0001) increased and resistin level decreased (33.09±16.81 to.28.89±10.76, p=0.0219) significantly. There were also no significant changes in BMI after treatment. Pioglitazone was well tolerated that no adverse effects as hypoglycemia, hepatic impairment and heart failure were observed during the study period except that 1 patient with significant residue renal function developed lowered-extremity edema.
Conclusion
12 weeks of pioglitazone (15mg once daily) did not alter serum triglycerides in prevalent PD patients, but decreased insulin resistance, inflammation and attenuated adipokine imbalance. Pioglitazone may be a beneficial therapy for this patient group.
引文
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1. Pennell P, Rojas C, Asif A, Rossini E. Managing metabolic complications of peritoneal dialysis. Clin Nephrol. Jul 2004;62(1):35-43.
2. Ohnishi H, Saitoh S, Ura N, et al. Relationship between insulin resistance and accumulation of coronary risk factors. Diabetes Obes Metab. Nov 2002; 4(6):388-393.
3. Haffner SM, D'Agostino R, Mykkanen L, et al. Proinsulin and insulin concentrations in relation to carotid wall thickness:Insulin Resistance Atherosclerosis Study. Stroke. Aug 1998;29(8):1498-1503.
4. Bressler P, Bailey SR, Matsuda M, DeFronzo RA. Insulin resistance and coronary artery disease. Diabetologia. Nov 1996:39(11):1345-1350.
5. Wang AY. Cardiovascular risk factors in peritoneal dialysis patients revisited. Perit Dial Int. Jun 2007;27 Suppl 2:S223-227.
6. Mak RH. Impact of end-stage renal disease and dialysis on glycemic control. Semin Dial. Jan-Feb 2000;13(1):4-8.
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9. Mak RH.1,25-Dihydroxyvitamin D3 corrects insulin and lipid abnormalities in uremia. Kidney Int. May 1998;53(5):1353-1357.
10. DeFronzo RA, Alvestrand A, Smith D, Hendler R, Hendler E, Wahren J. Insulin resistance in uremia. J Clin Invest. Feb 1981;67(2):563-568.
11. Friedman JE, Dohm GL, Elton CW, et al. Muscle insulin resistance in uremic humans:glucose transport, glucose transporters, and insulin receptors. Am J Physiol. Jul 1991;261(1 Pt 1):E87-94.
12. Dzurik R, Spustova V, Lajdova I. Inhibit ion of glucose utilization in isolated rat soleus muscle by pseudouridine:implications for renal failure. Nephron.1993;65(1):108-110.
13. Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors. Endocr Rev. May 2005; 26 (3):439-451.
14. Gannage-Yared MH, Khalife S, Semaan M, Fares F, Jambart S, Halaby G. Serum adiponectin and leptin levels in relation to the metabolic syndrome, androgenic profile and somatotropic axis in healthy non-diabetic elderly men. Eur J Endocrinol. Jul 2006;155(1):167-176.
15. Abdella NA, Mojiminiyi OA, Moussa MA, et al. Plasma leptin concentration in patients with Type 2 diabetes:relationship to cardiovascular disease risk factors and insulin resistance. Diabet Med. Mar 2005; 22 (3):278-285.
16. Correia ML, Rahmouni K. Role of leptin in the cardiovascular and endocrine complications of metabolic syndrome. Diabetes Obes Metab. Nov 2006;8(6):603-610.
17. Sentinelli F, Romeo S, Arca M, et al. Human resistin gene, obesity, and type 2 diabetes:mutation analysis and population study. Diabetes. Mar 2002;51(3):860-862.
18. Lee JH, Chan JL, Yiannakouris N, et al. Circulating resistin levels are not associated with obesity or insulin resistance in humans and are not regulated by fasting or leptin administration: cross-sectional and interventional studies in normal, insulin-resistant, and diabetic subjects. J Clin Endocrinol Metab. Oct 2003:88(10):4848-4856.
19. Axelsson J, Bergsten A, Qureshi AR, et al. Elevated resistin levels in chronic kidney disease are associated with decreased glomerular filtration rate and inflammation, but not with insulin resistance. Kidney Int. Feb 2006;69(3):596-604.
20. Prichard SS. Impact of dyslipidemia in end-stage renal disease.J Am Soc Nephrol. Sep 2003;14(9 Suppl 4):S315-320.
21. Garcia-Lopez E, Carrero JJ, Suliman ME, Lindholm B, Stenvinkel P. Risk factors for cardiovascular disease in patients undergoing peritoneal dialysis. Perit Dial Int. Jun 2007;27 Suppl 2:S205-209.
22. Sane T, Taskinen MR. Does familial hypertriglyceridemia predispose to NIDDM? Diabetes Care. Nov 1993;16(11):1494-1501.
23. Valdivielso P, Sanchez-Chaparro MA, Calvo-Bonacho E, et al. Association of moderate and severe hypertriglyceridemia with obesity, diabetes mellitus and vascular disease in the Spanish working population:Results of the ICARIA study. Atherosclerosis. May 27 2009.
24. Cordeiro AC, Carrero JJ, Abensur H, Lindholm B, Stenvinkel P. Systemic and local inflammation in peritoneal dialysis:mechanisms, biomarkers and effects on outcome. Contrib Nephrol. 2009:163:132-139.
25. Fortes PC, de Moraes TP, Mendes JG, Stinghen AE, Ribeiro SC, Pecoits-Filho R. Insulin resistance and glucose homeostasis in peritoneal dialysis. Perit Dial Int. Feb 2009;29 Suppl 2:S145-148.
26. Bredie SJ, Bosch FH, Demacker PN, Stalenhoef AF, van Leusen R. Effects of peritoneal dialysis with an overnight icodextrin dwell on parameters of glucose and lipid metabolism. Perit Dial Int. May-Jun 2001;21 (3):275-281.
27. Kramer D, Shapiro R, Adler A, Bush E, Rondinone CM. Insulin-sensitizing effect of rosiglitazone (BRL-49653) by regulation of glucose transporters in muscle and fat of Zucker rats. Metabolism. Nov 2001;50(11):1294-1300.
28. Tan GD, Fielding BA, Currie JM, et al. The effects of rosiglitazone on fatty acid and triglyceride metabolism in type 2 diabetes. Diabetologia. Jan 2005;48(1):83-95.
29. Sarafidis PA, Lasaridis AN, Nilsson PM, et al. The effect of rosiglitazone on novel atherosclerotic risk factors in patients with type 2 diabetes mellitus and hypertension. An open-label observational study. Metabolism. Sep 2005;54(9):1236-1242.
30. Kalaitzidis RG, Sarafidis PA, Bakris GL. Effects of thiazolidinediones beyond glycaemic control. Curr Pharm Des. 2009;15(5):529-536.
31. Karal liedde J, Buckingham R, Starkie M, Lorand D, Stewart M, Viberti G. Effect of various diuretic treatments on rosiglitazone-induced fluid retention. J Am Soc Nephrol. Dec 2006;17(12):3482-3490.
32. Stafylas PC, Sarafidis PA, Lasaridis AN. The controversial effects of thiazolidinediones on cardiovascular morbidity and mortality. Int J Cardiol. Jan 24 2009;131(3):298-304.
2. Fortes PC, de Moraes TP, Mendes JG, Stinghen AE, Ribeiro SC, Pecoits-Filho R. Insulin resistance and glucose homeostasis in peritoneal dialysis. Perit Dial Int. Feb 2009;29 Suppl 2:S145-148.
3. Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. Dec 1988;37(12):1595-1607.
4. Kaplan NM. The deadly quartet. Upper-body obesity, glucose intolerance, hypertriglyceridemia, and hypertension. Arch Intern Med. Jul 1989:149(7):1514-1520.
5. DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care. Mar 1991;14(3):173-194.
6. Pennell P, Rojas C, Asif A, Rossini E. Managing metabolic complications of peritoneal dialysis. Clin Nephrol. Jul 2004:62(1):35-43.
7. Ohnishi H, Saitoh S, Ura N, et al. Relationship between insulin resistance and accumulation of coronary risk factors. Diabetes Obes Metab. Nov 2002; 4(6):388-393.
8. Haffner SM, D'Agostino R, Mykkanen L, et al. Proinsulin and insulin concentrations in relation to carotid wall thickness:Insulin Resistance Atherosclerosis Study. Stroke. Aug 1998:29(8):1498-1503.
9. Bressler P, Bailey SR, Matsuda M, DeFronzo RA. Insulin resistance and coronary artery disease. Diabetologia. Nov 1996:39(11):1345-1350.
10. Chmielewski M, Carrero JJ, Nordfors L, Lindholm B, Stenvinkel P. Lipid disorders in chronic kidney disease:reverse epidemiology and therapeutic approach. J Nephrol. Sep-Oct 2008;21(5):635-644.
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12. Kovesdy CP, Anderson JE, Kalantar-Zadeh K. Inverse association between lipid levels and mortality in men with chronic kidney disease who are not yet on dialysis:effects of case mix and the malnutrition-inflammation-cachexia syndrome. J Am Soc Nephrol. Jan 2007;18(1):304-311.
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