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Rosiglitazone improves glucose metabolism in nondiabetic uremic patients on CAPD
Rosiglitazone Improves Glucose Metabolism in Nondiabetic Uremic Patients on CAPD Shih-Hua Lin, MD, Yuh-Feng Lin, MD, Shi-Wen Kuo, MD, Yu-Juei Hsu, MD, and Yi-Jen Hung, MD ● Background: Insulin resistance, a strong risk factor for atherosclerotic vascular disease, is present in uremic patients without diabetes on continuous ambulatory peritoneal dialysis (CAPD) therapy. Amelioration of insulin resistance may reduce associated long-term cardiovascular complications. The aim of the study is to investigate the effects of rosiglitazone (ROS), an insulin sensitizer, on glucose metabolism in CAPD patients without diabetes. Methods: Fifteen uremic patients without diabetes on CAPD therapy were enrolled. All were administered ROS, 4 mg/d, for 12 weeks. A control group consisted of 15 age- and sex-matched healthy subjects. Oral glucose tolerance test (OGTT) results, fasting glucose and insulin levels, related blood biochemistry results, and C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor–␣ (TNF-␣) levels were determined before initiation and at 4 and 12 weeks of therapy. Insulin resistance was evaluated using the homeostasis model assessment method (HOMAIR). A whole-body insulin sensitivity index (ISI) and insulinogenic index for insulin production were calculated from OGTT results. Results: CAPD patients showed significantly greater HOMA-IR and glucose intolerance compared with healthy controls. After 4 and 12 weeks of ROS therapy, there were no significant changes in body weight, blood pressure, dialysis adequacy, hemoglobin level, hemoglobin A1c level, liver function, lipid profile, or intact parathyroid hormone, CRP, IL-6, or TNF-␣ levels. There was a significant decrease in HOMA-IR (3.2 ⴞ 0.6, 2.2 ⴞ 0.4, and 2.1 ⴞ 0.4; P < 0.05). During the OGTT, there was a significant decrease in the area under the glucose curve and a significant increase in ISI (3.5 ⴞ 0.4, 5.0 ⴞ 0.7, and 5.3 ⴞ 0.7; P < 0.05), but no significant change in insulinogenic index. Conclusion: ROS improved insulin resistance in CAPD patients without diabetes. Whether long-term use of ROS reduces cardiovascular risk needs further study. Am J Kidney Dis 42:774-780. © 2003 by the National Kidney Foundation, Inc. INDEX WORDS: Continuous ambulatory peritoneal dialysis (CAPD); glucose tolerance; insulin resistance; rosiglitazone (ROS); uremia.
I
NSULIN RESISTANCE and/or glucose intolerance have been shown uniformly in uremic patients.1 The exact mechanisms responsible for these metabolic disturbances have not been fully elucidated. Factors implicated in their pathogenesis included uremic toxins, metabolic acidosis, secondary hyperparathyroidism, and vitamin D deficiency.2 Despite renal replacement therapy, insulin resistance persists. In uremic patients treated with continuous ambulatory peritoneal dialysis (CAPD), fast and continuous absorption of glucose from standard or highly concentrated glucose-containing peritoneal dialysate causes chronic stimulation of insulin secretion in patients without diabetes. One hypothesis is that From the Department of Medicine, Division of Nephrology; and Department of Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC. Received March 31, 2003; accepted in revised form June 3, 2003. Address reprint requests to Shih-Hua Lin, MD, Division of Nephrology, Department of Medicine, Tri-Service General Hospital, No. 325, Section 2, Cheng-Kung Rd, Neihu 114, Taipei, Taiwan, ROC. E-mail: [email protected] © 2003 by the National Kidney Foundation, Inc. 0272-6386/03/4204-0008$30.00/0 doi:10.1053/S0272-6386(03)00844-8 774
this leads to reduced tissue insulin sensitivity because of downregulation of tissue receptor expression, mimicking a prediabetic state.3 Of interest, hyperinsulinemia and other disorders of glucose metabolism may be associated with increased cardiovascular mortality in CAPD patients.4 The thiazolidinediones (TZDs) are a new class of agents developed for the treatment of type 2 diabetes mellitus and insulin resistance.5 These drugs activate peroxisome proliferator-activated receptor gamma (PPAR␥), a nuclear receptor that regulates the expression of several genes involved in insulin resistance.6 Specifically, TZDs improve insulin action and decrease insulin resistance. TZDs also are active in lipid metabolism, fibrinolysis, coagulation, platelet aggregation, albuminuria, endothelial function, anti-inflammation, and other metabolic processes.7 At present, there are no reports on the use of TZDs in CAPD patients without diabetes. To elucidate the possible favorable effects of TZDs on CAPD-related glucose tolerance and insulin resistance, we designed a study to investigate glucose metabolism in CAPD patients without diabetes administered an insulin sensitizer, rosiglitazone (ROS).
American Journal of Kidney Diseases, Vol 42, No 4 (October), 2003: pp 774-780
ROSIGLITAZONE IMPROVES INSULIN RESISTANCE IN CAPD PATIENTS Table 1.
Medications of 15 CAPD Patients Without Diabetes Medication
No. of Patients (%)
Antihypertensive drugs Angiotensin II receptor blockers Angiotensin-converting enzyme inhibitors Calcium blockers ␣-Blockers 1-Blockers Antihyperuricemic agents Antiplatelet agents Active vitamin D Loop diuretics Oral nitrate Oral iron supplement Phosphate binders Erythropoietin dose (3,870 ⫾ 290 IU/wk)
5 (33) 2 (13) 3 (20) 4 (27) 4 (27) 7 (47) 12 (80) 5 (33) 4 (27) 2 (13) 6 (40) 15 (100) 15 (100)
PATIENTS AND METHODS
Patients The study protocol was approved by the Ethics Committee on Human Studies at Tri-Service General Hospital, Taipei, Taiwan, ROC. Informed consent was obtained from each patient. Fifteen uremic patients undergoing CAPD with standard glucose solutions for more than 6 months were enrolled in this study. They were 7 men and 8 women with ages ranging from 27 to 75 years (47.1 ⫾ 3.3 years). Duration of CAPD treatment ranged from 8 to 52 months (mean, 24.6 months). Causes of renal failure were chronic glomerulonephritis in 5 patients, polycystic kidney disease in 1 patient, chronic interstitial nephropathy in 4 patients, hypertensive nephropathy in 2 patients, obstructive nephropathy in 1 patient, and idiopathic in 2 patients. No patient had diabetes or had experienced peritonitis in the past 6 months. Patients with acute illnesses were excluded. All patients performed three 4-hour 2-L exchanges of 1.5% glucose solution during the day and one 9-hour 2-L exchange of 2.5% glucose solution while sleeping at night. They continued their regular medications, such as antihypertensives, erythropoietin, and phosphate binders, except for lipidlowering agents. Their current medications are listed in Table 1. Patients were administered ROS (Avandia; GlaxoSmithKline Pharmaceuticals, Philadelphia, PA), 4 mg/d, daily for 12 weeks. The control group consisted of 15 healthy subjects with sex, age, and relative body weight distributions similar to those of the patient group. They were not administered medications that might affect carbohydrate or lipid metabolism. Fasting blood sampling and oral glucose tolerance test (OGTT) results were determined at baseline and 4 and 12 weeks after ROS therapy. Adequacy of dialysis (Kt/V and creatinine clearance), normalized protein catabolic rate, and residual renal function were evaluated at baseline, 4 weeks, and 12 weeks after ROS therapy. Transport characteristics of the peritoneum-peritoneal equilibration test (PET) also were assessed at baseline and 12 weeks after ROS therapy.
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Methods Assessment of insulin resistance. Insulin resistance was assessed using the homeostasis model assessment (HOMAIR) originally described by Matthews et al,8 in which HOMA-IR (mmol/L ⫻ IU/mL) ⫽ fasting glucose (mmol/L) ⫻ fasting insulin ( IU/mL)/ 22.5. The HOMA-IR correlates closely with the insulin sensitivity index (ISI) measured by the gold standard euglycemic hyperinsulinemic clamp. This index can be applied to subjects with renal failure.9 OGTT. Patients were instructed to drain the peritoneal dialysate before midnight and hold off on peritoneal dialysis treatments the next day. After an overnight fast, an OGTT was begun at 8:00 AM. Seventy-five grams of glucose was administered in 150 mL of lemon-flavored water. Venous blood samples were obtained through an indwelling catheter before glucose ingestion and at 30, 60, 90, and 120 minutes after glucose ingestion. The insulinogenic index (measure of insulin production during the OGTT) was calculated as the total increase in plasma insulin level divided by the total increase in plasma glucose level during the 2-hour period of the OGTT (insulin area above baseline/glucose area above baseline).10 From plasma and insulin concentrations during the OGTT, a whole-body ISI is calculated as previously described.11 Assays. Whole blood was used for hemoglobin A1c assays; EDTA-plasma was used for glucose, insulin, and lipid assays; and serum was used for other biochemical assays. Glucose was measured using a glucose oxidase method. Hemoglobin A1c was measured by using ion exchange in EDTA-anticoagulated whole blood (BioRad Diamat, Richmond, CA). Insulin was measured by means of radioimmunometric assay (Insulin RIA-BEAD II; Dinabot Co, Tokyo, Japan). C-Peptide level was measured by means of radioimmunoassay (Diagnostic Systems Laboratories Inc, TX). Intact parathyroid hormone (PTH) was measured by means of radioimmunoassay using the Intact PTH-Parathyroid Hormone Immunoassay kit (Nichols Institute Diagnostics, San Juan Capistrano, CA). C-Reactive protein (CRP) was measured using the Tina-quant (Latex) ultrasensitive assay (Roche Diagnostics GmbH, Mannheim, Germany). Serum interleukin-6 (IL-6), and tumor necrosis factor-␣ (TNF-␣) were determined using enzyme-linked immunosorbent assay (R&D, Minneapolis, MN). Other measurements were performed using routine methods.
Statistical Analysis Results are expressed as mean ⫾ SEM. For comparison of variables between the 2 groups (CAPD patients and healthy subjects), unpaired Student’s t-test was performed. Mann-Whitney U test was used when variables were not normally distributed between the 2 groups. A within-group comparison of posttreatment and baseline values was analyzed by using repeated-measures analysis of variance with Bonferroni correction for multiple comparisons. Coefficients of correlation between HOMA-IR and ISI in the 2 groups were calculated by linear regression. Differences are considered significant at P less than 0.05.
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LIN ET AL Table 2.
Characteristics of Healthy Controls and CAPD Patients on ROS Therapy CAPD Patients
Body weight (kg) Body mass index (kg/m2) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Hemoglobin (g/dL) Hemoglobin A1c (%) C-Peptide (ng/mL) Triglycerides (mg/dL) Cholesterol (mg/dL) Aspartate aminotransferase (U/L) Alanine aminotransferase (U/L) Albumin (g/dL) Urea nitrogen (mg/dL) Creatinine (mg/dL) Bicarbonate (mEq/L) Alkaline phosphatase (U/L) Intact PTH (pg/mL) CRP (mg/dL) IL-6 (pg/mL) TNF-␣ (ng/mL)
Controls
Baseline
4 wk
12 wk
58.0 ⫾ 2.8 22.0 ⫾ 0.8 126 ⫾ 12 74 ⫾ 8 13.8 ⫾ 0.8* 4.9 ⫾ 0.3* 1.2 ⫾ 0.2* 112 ⫾ 13* 187 ⫾ 9* 21 ⫾ 2 20 ⫾ 2 4.2 ⫾ 0.2* 14 ⫾ 1* 1.0 ⫾ 0.1* 25.4 ⫾ 0.3 90 ⫾ 7* 24 ⫾ 6* 0.09 ⫾ 0.02* 1.4 ⫾ 0.2* 0.4 ⫾ 0.2*
58.4 ⫾ 3.0 22.0 ⫾ 0.8 125 ⫾ 13 78 ⫾ 9 9.7 ⫾ 1.2 5.3 ⫾ 0.4 7.5 ⫾ 1.0 174 ⫾ 20 218 ⫾ 13 19 ⫾ 2 17 ⫾ 2 3.9 ⫾ 0.3 72 ⫾ 4 11.8 ⫾ 3.4 25.0 ⫾ 0.3 151 ⫾ 17 317 ⫾ 66 0.17 ⫾ 0.03 7.7 ⫾ 1.2 4.0 ⫾ 0.2
58.6 ⫾ 2.9 22.0 ⫾ 0.8 130 ⫾ 16 81 ⫾ 7 9.4 ⫾ 1.3 5.5 ⫾ 0.1 7.6 ⫾ 0.9 212 ⫾ 20 232 ⫾ 13 15 ⫾ 1 15 ⫾ 1 3.8 ⫾ 0.1 71 ⫾ 4 11.5 ⫾ 3.0 25.2 ⫾ 0.3 143 ⫾ 16 288 ⫾ 80 0.16 ⫾ 0.02 8.9 ⫾ 1.2 3.9 ⫾ 0.2
58.5 ⫾ 2.9 22.1 ⫾ 0.8 121 ⫾ 17 79 ⫾ 12 9.2 ⫾ 1.4 5.4 ⫾ 0.1 8.1 ⫾ 1.0 195 ⫾ 18 236 ⫾ 14 16 ⫾ 1 16 ⫾ 1 3.8 ⫾ 0.1 69 ⫾ 4 11.9 ⫾ 2.7 24.8 ⫾ 0.3 138 ⫾ 13 258 ⫾ 91 0.16 ⫾ 0.02 7.5 ⫾ 1.0 4.2 ⫾ 0.2
NOTE. Data expressed as mean ⫾ SEM. To convert hemoglobin and albumin in g/dL to g/L, multiply by 10; hemoglobin A1c in percentage of total hemoglobin to proportion of glucose of total hemoglobin, multiply by 0.01; C-peptide in ng/mL to nmol/L, multiply by 0.333; triglycerides in mg/dL to mmol/L, multiply by 0.0113; cholesterol in mg/dL to mmol/L, multiply by 0.0259; urea nitrogen in mg/dL to mmol/L, multiply 0.357; creatinine in mg/dL to mol/L, multiply by 88.4; bicarbonate in mEq/L to mmol/L, multiply by 1.0; iPTH in pg/mL to ng/L, multiple by 1.0; CRP in mg/dL to mg/L, multiply by 10. *P ⬍ 0.05, control versus baseline, 4 weeks, and 12 weeks.
RESULTS
Clinical Characteristics As listed in Table 2, there were significant differences in plasma creatinine, urea nitrogen, albumin, triglyceride, cholesterol, hemoglobin, hemoglobin A1c, C-peptide, alkaline phosphatase, and intact PTH levels between CAPD patients and healthy subjects. Serum CRP, IL-6, and TNF-␣ levels were markedly elevated in CAPD patients. After 4 and 12 weeks of ROS therapy, there were no significant changes in body weight, body mass index, blood pressure, hemoglobin level, hemoglobin A1c level, liver function, triglyceride level, or cholesterol level. There also were no significant changes in serum CRP, IL-6, and TNF-␣ levels after ROS treatment (Table 2). Weekly Kt/V (2.2 ⫾ 0.1 versus 2.1 ⫾ 0.1 versus 2.1 ⫾ 0.1; P ⫽ not significant [NS]), weekly creatinine clearance (76 ⫾ 3 versus 74 ⫾ 3 versus 75 ⫾ 4 L/wk/ 1.73 m2; P ⫽ NS), residual renal function (2.7 ⫾ 0.4 versus 2.6 ⫾ 0.4 versus 2.6 ⫾ 0.4
mL/min; P ⫽ NS), and normalized protein catabolic rate (1.25 ⫾ 0.05 versus 1.27 ⫾ 0.04 versus 1.27 ⫾ 0.05 g/kg/d; P ⫽ NS) were not significantly changed at baseline, 4 weeks, and 12 weeks of ROS therapy. For the PET test, dialysate to plasma creatinine (0.67 ⫾ 0.02 versus 0.65 ⫾ 0.02; P ⫽ NS) and dialysate to plasma urea nitrogen (0.94 ⫾ 0.01 versus 0.93 ⫾ 0.01; P ⫽ NS) were not significantly changed between baseline and 12 weeks of ROS therapy. No significant side effects were observed during ROS therapy except that 1 patient developed lower-extremity edema. No patient was found to have abnormal liver function during ROS therapy. HOMA-IR Uremic patients on CAPD therapy showed no significant difference in fasting glucose concentrations, but significantly greater serum insulin concentrations (13.5 ⫾ 2.2 IU/mL [93.8 ⫾ 15.3 pmol/L] versus 8.0 ⫾ 1.2 IU/mL [55.6 ⫾ 8.3
ROSIGLITAZONE IMPROVES INSULIN RESISTANCE IN CAPD PATIENTS Table 3.
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Glucose and Insulin Profiles During OGTTs in Healthy Controls and CAPD Patients on ROS Therapy CAPD Patients
Fasting glucose (mg/dL) Fasting insulin (IU/mL) HOMA-IR ISI Insulinogenic index (IU/mg)
Controls
Baseline
4 wk
12 wk
91.4 ⫾ 1.7 8.0 ⫾ 1.2§ 1.8 ⫾ 0.3§ 6.2 ⫾ 0.5§ 134 ⫾ 29
92.6 ⫾ 2.3 13.5 ⫾ 2.2 3.2 ⫾ 0.6 3.5 ⫾ 0.4 114 ⫾ 15
89.1 ⫾ 1.5* 9.5 ⫾ 1.7* 2.2 ⫾ 0.4* 5.0 ⫾ 0.7* 127 ⫾ 20
87.3 ⫾ 1.2†‡ 9.1 ⫾ 1.2‡ 2.1 ⫾ 0.4‡ 5.3 ⫾ 0.7‡ 116 ⫾ 16
NOTE. Data expressed as mean ⫾ SEM. To convert glucose in mg/dL to mmol/L, multiply by 0.0555; insulin in IU/mL to pmol/L, multiply by 6.945. *P ⬍ 0.05, 4 weeks versus baseline. †P ⬍ 0.05, control versus 12 weeks. ‡P ⬍ 0.05, 12 weeks versus baseline. §P ⬍ 0.05, control versus baseline.
pmol/L]; P ⬍ 0.05) compared with healthy controls (Table 3). HOMA-IR also was significantly greater (3.2 ⫾ 0.6 versus 1.8 ⫾ 1.2; P ⬍ 0.05), suggesting the presence of insulin resistance in uremic patients on CAPD therapy. After 4 and 12 weeks of ROS therapy, there were significant decreases in fasting glucose levels, insulin levels, and HOMA-IR (Table 3). There were no longer significant differences in insulin levels and HOMA-IR, except for plasma glucose levels, between healthy subjects and CAPD patients after 12 weeks of ROS therapy (Table 3). OGTT Results Uremic patients on CAPD therapy showed significant glucose intolerance, seen by the area under the glucose curve, compared with healthy controls (Fig 1). The increase in area under the insulin curve also was significantly greater in CAPD patients (Fig 2). After 4 and 12 weeks of ROS treatment, CAPD patients showed improved glucose tolerance, with a significant decrease in the area under the glucose curve and a concomitant significant decrease in the area under the insulin curve (Figs 1 and 2). Insulinogenic index was not significantly changed after ROS treatment (Table 3), whereas whole-body ISI increased significantly. There were no significant differences in insulinogenic index and insulin sensitivity between healthy subjects and CAPD patients after 12 weeks of ROS therapy. Correlation There was a negative correlation between ISI and fasting HOMA-IR during OGTT in healthy
subjects (ISI ⫽ 8.7 ⫺ 1.4 * HOMA-IR; r ⫽ ⫺0.81; P ⬍ 0.001) and CAPD patients before (ISI ⫽ 5.1 ⫺ 0.5 * HOMA-IR; r ⫽ ⫺0.73; P ⬍ 0.01) and 4 (ISI ⫽ 7.5 ⫺ 1.1 * HOMAIR; r ⫽ ⫺0.72; P ⬍ 0.01) and 12 weeks (ISI ⫽ 7.9 ⫺ 1.2 * HOMA-IR; r ⫽ ⫺0.70; P ⬍ 0.01) after ROS therapy. DISCUSSION
In this study, uremic patients without diabetes on CAPD therapy showed a significantly higher HOMA-IR (an index of insulin resistance), impaired glucose tolerance, and preserved insulin secretory ability during glucose loading. Although CAPD may improve the insulin resistance and glucose intolerance associated with
Fig 1. Plasma glucose concentrations during OGTTs in healthy subjects (open circle) and CAPD patients without diabetes before (filled circle) and 4 (open triangle) and 12 weeks (filled triangle) after ROS treatment. Values expressed as mean ⴞ SEM. To convert glucose in mg/dL to mmol/L, multiply by 0.0555.
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Fig 2. Plasma insulin concentrations during OGTT in healthy subjects (open circle) and CAPD patients without diabetes before (filled circle) and 4 (open triangle) and 12 weeks (filled triangle) after ROS treatment. Values expressed as mean ⴞ SEM. To convert insulin in IU/mL to pmol/L, multiply by 6.945.
uremia,12,13 it does not completely correct this abnormality. Some hypotheses have been proposed to explain the persistence of insulin resistance in uremic patients on CAPD therapy.14 First, CAPD may be unable to remove unknown circulating factors that impair glucose use during renal failure. Second, the secondary hyperparathyroidism, active vitamin D deficiency, hyperlipidemia, and metabolic acidosis present in uremia may persist in CAPD and contribute to insulin resistance. Third, a decrease in fat-free mass secondary to protein malnutrition and an increase in adiposity may occur during the course of CAPD. Regardless of the possible mechanisms, insulin resistance is associated with arterial wall changes, coronary artery disease, and cardiovascular mortality in patients with chronic renal failure.15,16 A recent study found HOMA-IR was an independent predictor of cardiovascular mortality in a cohort of uremic patients without diabetes on hemodialysis therapy.17 Intuitively, these findings may be generalized to CAPD patients without diabetes. Thus, amelioration of insulin resistance in uremic patients has the potential to impact on mortality. To date, therapy has been aimed at correction of the contributory factors stated in the hypotheses, and use of ROS as an insulin sensitizer to treat uremic insulin resistance has not been reported in the literature. After 4 and 12 weeks of ROS therapy, a significant decrease in
LIN ET AL
fasting glucose levels, insulin levels, and HOMA-IR coupled with a significant increase in ISI during OGTTs indicated improvement in insulin resistance. Nevertheless, insulin secretion ability was not affected; pancreatic beta cell function appeared to be preserved. Because there was close correlation between HOMA-IR and ISI during OGTTs both before and after ROS therapy, HOMA-IR alone may be used an index of insulin resistance if patients cannot tolerate the OGTT during ROS therapy. There were no hypoglycemic episodes, abnormal liver function, or significant body weight changes during ROS therapy. However, there was a trend to increased total cholesterol and triglyceride levels, which deserves cautious monitoring. Despite the successful use of ROS as an insulin sensitizer in CAPD patients without diabetes, its specific mechanism of action remains uncertain. Impaired peripheral sensitivity to insulin has been studied extensively in patients with uremia and been shown to reside primarily in muscle and adipose tissue.1,2 Because PPAR␥ is expressed abundantly in adipose tissue, fat cells have been implicated as a primary target for TZDs, perhaps through suppression of resistin expression.18 Resistin is a newly discovered adipocyte-secreted hormone that appears to have a role in the pathogenesis of insulin resistance.19 PPAR␥ also is expressed in skeletal muscle,20 increasing the expression of adipocyte lipid binding protein and muscle fatty acid binding protein in this tissue.21 Fatty acids are key regulators of insulin sensitivity and decreased glucose use in skeletal muscle. The PPAR␥-induced increase in fatty acid uptake by adipocyte lipid binding protein and muscle fatty acid binding protein may be partially responsible for enhanced insulin sensitivity by ROS. Furthermore, ROS may increase glucose transporter 4 expression, facilitating glucose uptake into skeletal muscle.22 Insulin resistance also may develop in the presence of inflammation.23 Uremia per se is a state of proinflammation24 reflected by greater circulating CRP, TNF-␣, and IL-6 levels compared with healthy subjects, as in this study. TZD-PPAR complexes have been shown to reduce TNF-␣–induced insulin resistance, suggesting another mechanism for TZD action.25 However, in this study, ROS did not significantly reduce circulating CRP, TNF-␣, and IL-6 levels.
ROSIGLITAZONE IMPROVES INSULIN RESISTANCE IN CAPD PATIENTS
Interestingly, the schedule of ROS administration has been shown to greatly influence its effects, specifically, the 2-mg twice-daily regimen resulted in a greater reduction in insulin resistance than 4 mg once daily despite the same total daily milligram exposure.26 The protocol in our study was ROS, 4 mg once daily, as a half of the maximal recommended dose.27 Because of its high molecular weight of 474 daltons, high protein binding (⬎98%), and predominantly hepatic metabolism, ROS pharmacokinetics does not differ between patients with normal function or chronic renal failure or those on hemodialysis therapy.28 Because no completed pharmacokinetics of ROS are available in uremic patients on CAPD therapy, dose adjustment of ROS in uremic patients on CAPD therapy awaits further study. However, given the difference seen between once-daily and twice-daily ROS dosing, as well as the lack of anti-inflammatory effects at the 4-mg once-daily dose, more creative dosing schedules merit further investigation. In conclusion, CAPD patients show increased glycemic and insulinemic responses to oral glucose, suggesting an insulin-resistant state. Chronic use of ROS can reduce serum fasting glucose and insulin levels, as well as insulin resistance, in CAPD patients. Because insulin resistance is a modifiable risk factor, additional prospective studies are warranted to determine whether longterm use of PPAR␥ agonists can reduce cardiovascular morbidity in uremic patients. REFERENCES 1. DeFronzo RA, Tobin JD, Rowe JW, Andres R: Glucose intolerance in uremia: Quantification of pancreatic beta cell sensitivity to glucose and tissue sensitivity to insulin. J Clin Invest 62:425-435, 1978 2. DeFronzo RA, Alvestrand A, Smith D, Hendler R, Hendler E, Wahren J: Insulin resistance in uremia. J Clin Invest 67:63-68, 1981 3. Delarue J, Maingourd C: Acute metabolic effects of dialysis fluids during CAPD. Am J Kidney Dis 37:S103S107, 2001 (suppl 1) 4. Prichard S: Major and minor risk factors for cardiovascular disease in peritoneal dialysis. Perit Dial Int 20:S154S159, 2000 (suppl 2) 5. Mayerson AB, Hundal RS, Dufour S, et al: The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes 51:797-802, 2002 6. Parulkar AA, Pendergrass ML, Grand-Ayala R, Lee TR, Fonseca VA: Nonhypoglycemic effects of thiazolidinediones. Ann Intern Med 134:61-71, 2001
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7. Martens FM, Visseren FL, Lemay J, de Koning EJ, Rabelink TJ: Metabolic and additional vascular effects of thiazolidinediones. Drugs 62:1463-1480, 2002 8. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC: Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412-419, 1985 9. Shoji T, Emoto M, Nishizawa Y: HOMA index to assess insulin resistance in renal failure patients. Nephron 89:348-349, 2001 10. 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 87: 533-538, 1994 11. Matsuda M, DeFronzo RA: Insulin sensitivity indices obtained from oral glucose tolerance testing: Comparison with the euglycemic clamp. Diabetes Care 22:1462-1470, 1999 12. Mak RH: Insulin resistance in uremia: Effect of dialysis modality. Pediatr Res 40:304-308, 1996 13. Kobayashi S, Maejima S, Ikeda T, Nagase M: Impact of dialysis therapy on insulin resistance in end-stage renal disease: Comparison of haemodialysis and continuous ambulatory peritoneal dialysis. Nephrol Dial Transplant 15:65-70, 2000 14. Delarue J, Maingourd C, Couet C, Vidal S, Bagros P, Lamisse F: Effects of oral glucose on intermediary metabolism in continuous ambulatory patients versus healthy subjects. Perit Dial Int 18:505-511, 1998 15. Stenvinkel P, Heimburger O, Paultre F, et al: Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int 55:1899-1911, 1999 16. Shoji T, Emoto M, Shinohara K, et al: Diabetes mellitus, aortic stiffness, and cardiovascular mortality in endstage renal disease. J Am Soc Nephrol 12:2117-2124, 2001 17. Shinohara K, Shoji T, Emoto M, et al: Insulin resistance as an independent predictor of cardiovascular mortality in patients with end-stage renal disease. J Am Soc Nephrol 13:1894-1900, 2002 18. Shuldiner AR, Yang R, Gong DW: Resistin, obesity and insulin resistance: The emerging role of the adipocyte as an endocrine organ. N Engl J Med 345:1345-1346, 2001 19. Steppan CM, Brown EJ, Wright CM, et al: A family of tissue-specific resistin-like molecules. Proc Natl Acad Sci U S A 98:502-506, 2002 20. Park KS, Ciaraldi TP, Abrams-Carter L, Mudaliar S, Nikoulina SE, Henry RR: PPARr gene expression is elevated in skeletal muscle of obese and type II diabetic subjects. Diabetes 46:1230-1234, 1997 21. Park KS, Ciaraldi TP, Lindgren K, et al: Troglitazone effects on gene expression in human skeletal muscle of type II diabetes involve up-regulation of peroxisome proliferatorsactivated receptor-gamma. J Clin Endocrinol Metab 83:28302835, 1998 22. Yonemitsu S, Nishimura H, Shintani M, et al: Troglitazone induces GLUT4 translocation in L6 myotubes. Diabetes 50:1093-1101, 2001 23. Lang CH, Dobrescu C, Bagby GJ: Tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic glucose output. Endocrinology 130:43-52, 1992
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24. Pereira BJ, Shapiro L, King AJ, Falagas ME, Strom JA, Dinarello CA: Plasma levels of IL-1beta, TNF alpha and their specific inhibitors in undialyzed chronic renal failure, CAPD and hemodialysis patients. Kidney Int 45:890-896, 1994 25. Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI: Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 106:679-684, 2002
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26. Phillips LS, Grunberger G, Miller E, Patwardhan R, Rappaport EB, Salzman A: Once- and twice daily dosing with rosiglitazone improves glycemic control in patients with type 2 diabetes. Diabetes Care 24:308-315, 2001 27. Wagstaff AJ, Goa KL: Rosiglitazone: A review of its use in the management of type 2 diabetes mellitus. Drugs 62:1805-1837, 2002 28. Thompson-Culkin K, Zussman B, Miler AK, Freed MI: Pharmacokinetics of rosiglitazone in patients with endstage renal disease. J Int Med Res 30:391-9, 2002
I
NSULIN RESISTANCE and/or glucose intolerance have been shown uniformly in uremic patients.1 The exact mechanisms responsible for these metabolic disturbances have not been fully elucidated. Factors implicated in their pathogenesis included uremic toxins, metabolic acidosis, secondary hyperparathyroidism, and vitamin D deficiency.2 Despite renal replacement therapy, insulin resistance persists. In uremic patients treated with continuous ambulatory peritoneal dialysis (CAPD), fast and continuous absorption of glucose from standard or highly concentrated glucose-containing peritoneal dialysate causes chronic stimulation of insulin secretion in patients without diabetes. One hypothesis is that From the Department of Medicine, Division of Nephrology; and Department of Medicine, Division of Endocrinology and Metabolism, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC. Received March 31, 2003; accepted in revised form June 3, 2003. Address reprint requests to Shih-Hua Lin, MD, Division of Nephrology, Department of Medicine, Tri-Service General Hospital, No. 325, Section 2, Cheng-Kung Rd, Neihu 114, Taipei, Taiwan, ROC. E-mail: [email protected] © 2003 by the National Kidney Foundation, Inc. 0272-6386/03/4204-0008$30.00/0 doi:10.1053/S0272-6386(03)00844-8 774
this leads to reduced tissue insulin sensitivity because of downregulation of tissue receptor expression, mimicking a prediabetic state.3 Of interest, hyperinsulinemia and other disorders of glucose metabolism may be associated with increased cardiovascular mortality in CAPD patients.4 The thiazolidinediones (TZDs) are a new class of agents developed for the treatment of type 2 diabetes mellitus and insulin resistance.5 These drugs activate peroxisome proliferator-activated receptor gamma (PPAR␥), a nuclear receptor that regulates the expression of several genes involved in insulin resistance.6 Specifically, TZDs improve insulin action and decrease insulin resistance. TZDs also are active in lipid metabolism, fibrinolysis, coagulation, platelet aggregation, albuminuria, endothelial function, anti-inflammation, and other metabolic processes.7 At present, there are no reports on the use of TZDs in CAPD patients without diabetes. To elucidate the possible favorable effects of TZDs on CAPD-related glucose tolerance and insulin resistance, we designed a study to investigate glucose metabolism in CAPD patients without diabetes administered an insulin sensitizer, rosiglitazone (ROS).
American Journal of Kidney Diseases, Vol 42, No 4 (October), 2003: pp 774-780
ROSIGLITAZONE IMPROVES INSULIN RESISTANCE IN CAPD PATIENTS Table 1.
Medications of 15 CAPD Patients Without Diabetes Medication
No. of Patients (%)
Antihypertensive drugs Angiotensin II receptor blockers Angiotensin-converting enzyme inhibitors Calcium blockers ␣-Blockers 1-Blockers Antihyperuricemic agents Antiplatelet agents Active vitamin D Loop diuretics Oral nitrate Oral iron supplement Phosphate binders Erythropoietin dose (3,870 ⫾ 290 IU/wk)
5 (33) 2 (13) 3 (20) 4 (27) 4 (27) 7 (47) 12 (80) 5 (33) 4 (27) 2 (13) 6 (40) 15 (100) 15 (100)
PATIENTS AND METHODS
Patients The study protocol was approved by the Ethics Committee on Human Studies at Tri-Service General Hospital, Taipei, Taiwan, ROC. Informed consent was obtained from each patient. Fifteen uremic patients undergoing CAPD with standard glucose solutions for more than 6 months were enrolled in this study. They were 7 men and 8 women with ages ranging from 27 to 75 years (47.1 ⫾ 3.3 years). Duration of CAPD treatment ranged from 8 to 52 months (mean, 24.6 months). Causes of renal failure were chronic glomerulonephritis in 5 patients, polycystic kidney disease in 1 patient, chronic interstitial nephropathy in 4 patients, hypertensive nephropathy in 2 patients, obstructive nephropathy in 1 patient, and idiopathic in 2 patients. No patient had diabetes or had experienced peritonitis in the past 6 months. Patients with acute illnesses were excluded. All patients performed three 4-hour 2-L exchanges of 1.5% glucose solution during the day and one 9-hour 2-L exchange of 2.5% glucose solution while sleeping at night. They continued their regular medications, such as antihypertensives, erythropoietin, and phosphate binders, except for lipidlowering agents. Their current medications are listed in Table 1. Patients were administered ROS (Avandia; GlaxoSmithKline Pharmaceuticals, Philadelphia, PA), 4 mg/d, daily for 12 weeks. The control group consisted of 15 healthy subjects with sex, age, and relative body weight distributions similar to those of the patient group. They were not administered medications that might affect carbohydrate or lipid metabolism. Fasting blood sampling and oral glucose tolerance test (OGTT) results were determined at baseline and 4 and 12 weeks after ROS therapy. Adequacy of dialysis (Kt/V and creatinine clearance), normalized protein catabolic rate, and residual renal function were evaluated at baseline, 4 weeks, and 12 weeks after ROS therapy. Transport characteristics of the peritoneum-peritoneal equilibration test (PET) also were assessed at baseline and 12 weeks after ROS therapy.
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Methods Assessment of insulin resistance. Insulin resistance was assessed using the homeostasis model assessment (HOMAIR) originally described by Matthews et al,8 in which HOMA-IR (mmol/L ⫻ IU/mL) ⫽ fasting glucose (mmol/L) ⫻ fasting insulin ( IU/mL)/ 22.5. The HOMA-IR correlates closely with the insulin sensitivity index (ISI) measured by the gold standard euglycemic hyperinsulinemic clamp. This index can be applied to subjects with renal failure.9 OGTT. Patients were instructed to drain the peritoneal dialysate before midnight and hold off on peritoneal dialysis treatments the next day. After an overnight fast, an OGTT was begun at 8:00 AM. Seventy-five grams of glucose was administered in 150 mL of lemon-flavored water. Venous blood samples were obtained through an indwelling catheter before glucose ingestion and at 30, 60, 90, and 120 minutes after glucose ingestion. The insulinogenic index (measure of insulin production during the OGTT) was calculated as the total increase in plasma insulin level divided by the total increase in plasma glucose level during the 2-hour period of the OGTT (insulin area above baseline/glucose area above baseline).10 From plasma and insulin concentrations during the OGTT, a whole-body ISI is calculated as previously described.11 Assays. Whole blood was used for hemoglobin A1c assays; EDTA-plasma was used for glucose, insulin, and lipid assays; and serum was used for other biochemical assays. Glucose was measured using a glucose oxidase method. Hemoglobin A1c was measured by using ion exchange in EDTA-anticoagulated whole blood (BioRad Diamat, Richmond, CA). Insulin was measured by means of radioimmunometric assay (Insulin RIA-BEAD II; Dinabot Co, Tokyo, Japan). C-Peptide level was measured by means of radioimmunoassay (Diagnostic Systems Laboratories Inc, TX). Intact parathyroid hormone (PTH) was measured by means of radioimmunoassay using the Intact PTH-Parathyroid Hormone Immunoassay kit (Nichols Institute Diagnostics, San Juan Capistrano, CA). C-Reactive protein (CRP) was measured using the Tina-quant (Latex) ultrasensitive assay (Roche Diagnostics GmbH, Mannheim, Germany). Serum interleukin-6 (IL-6), and tumor necrosis factor-␣ (TNF-␣) were determined using enzyme-linked immunosorbent assay (R&D, Minneapolis, MN). Other measurements were performed using routine methods.
Statistical Analysis Results are expressed as mean ⫾ SEM. For comparison of variables between the 2 groups (CAPD patients and healthy subjects), unpaired Student’s t-test was performed. Mann-Whitney U test was used when variables were not normally distributed between the 2 groups. A within-group comparison of posttreatment and baseline values was analyzed by using repeated-measures analysis of variance with Bonferroni correction for multiple comparisons. Coefficients of correlation between HOMA-IR and ISI in the 2 groups were calculated by linear regression. Differences are considered significant at P less than 0.05.
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LIN ET AL Table 2.
Characteristics of Healthy Controls and CAPD Patients on ROS Therapy CAPD Patients
Body weight (kg) Body mass index (kg/m2) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Hemoglobin (g/dL) Hemoglobin A1c (%) C-Peptide (ng/mL) Triglycerides (mg/dL) Cholesterol (mg/dL) Aspartate aminotransferase (U/L) Alanine aminotransferase (U/L) Albumin (g/dL) Urea nitrogen (mg/dL) Creatinine (mg/dL) Bicarbonate (mEq/L) Alkaline phosphatase (U/L) Intact PTH (pg/mL) CRP (mg/dL) IL-6 (pg/mL) TNF-␣ (ng/mL)
Controls
Baseline
4 wk
12 wk
58.0 ⫾ 2.8 22.0 ⫾ 0.8 126 ⫾ 12 74 ⫾ 8 13.8 ⫾ 0.8* 4.9 ⫾ 0.3* 1.2 ⫾ 0.2* 112 ⫾ 13* 187 ⫾ 9* 21 ⫾ 2 20 ⫾ 2 4.2 ⫾ 0.2* 14 ⫾ 1* 1.0 ⫾ 0.1* 25.4 ⫾ 0.3 90 ⫾ 7* 24 ⫾ 6* 0.09 ⫾ 0.02* 1.4 ⫾ 0.2* 0.4 ⫾ 0.2*
58.4 ⫾ 3.0 22.0 ⫾ 0.8 125 ⫾ 13 78 ⫾ 9 9.7 ⫾ 1.2 5.3 ⫾ 0.4 7.5 ⫾ 1.0 174 ⫾ 20 218 ⫾ 13 19 ⫾ 2 17 ⫾ 2 3.9 ⫾ 0.3 72 ⫾ 4 11.8 ⫾ 3.4 25.0 ⫾ 0.3 151 ⫾ 17 317 ⫾ 66 0.17 ⫾ 0.03 7.7 ⫾ 1.2 4.0 ⫾ 0.2
58.6 ⫾ 2.9 22.0 ⫾ 0.8 130 ⫾ 16 81 ⫾ 7 9.4 ⫾ 1.3 5.5 ⫾ 0.1 7.6 ⫾ 0.9 212 ⫾ 20 232 ⫾ 13 15 ⫾ 1 15 ⫾ 1 3.8 ⫾ 0.1 71 ⫾ 4 11.5 ⫾ 3.0 25.2 ⫾ 0.3 143 ⫾ 16 288 ⫾ 80 0.16 ⫾ 0.02 8.9 ⫾ 1.2 3.9 ⫾ 0.2
58.5 ⫾ 2.9 22.1 ⫾ 0.8 121 ⫾ 17 79 ⫾ 12 9.2 ⫾ 1.4 5.4 ⫾ 0.1 8.1 ⫾ 1.0 195 ⫾ 18 236 ⫾ 14 16 ⫾ 1 16 ⫾ 1 3.8 ⫾ 0.1 69 ⫾ 4 11.9 ⫾ 2.7 24.8 ⫾ 0.3 138 ⫾ 13 258 ⫾ 91 0.16 ⫾ 0.02 7.5 ⫾ 1.0 4.2 ⫾ 0.2
NOTE. Data expressed as mean ⫾ SEM. To convert hemoglobin and albumin in g/dL to g/L, multiply by 10; hemoglobin A1c in percentage of total hemoglobin to proportion of glucose of total hemoglobin, multiply by 0.01; C-peptide in ng/mL to nmol/L, multiply by 0.333; triglycerides in mg/dL to mmol/L, multiply by 0.0113; cholesterol in mg/dL to mmol/L, multiply by 0.0259; urea nitrogen in mg/dL to mmol/L, multiply 0.357; creatinine in mg/dL to mol/L, multiply by 88.4; bicarbonate in mEq/L to mmol/L, multiply by 1.0; iPTH in pg/mL to ng/L, multiple by 1.0; CRP in mg/dL to mg/L, multiply by 10. *P ⬍ 0.05, control versus baseline, 4 weeks, and 12 weeks.
RESULTS
Clinical Characteristics As listed in Table 2, there were significant differences in plasma creatinine, urea nitrogen, albumin, triglyceride, cholesterol, hemoglobin, hemoglobin A1c, C-peptide, alkaline phosphatase, and intact PTH levels between CAPD patients and healthy subjects. Serum CRP, IL-6, and TNF-␣ levels were markedly elevated in CAPD patients. After 4 and 12 weeks of ROS therapy, there were no significant changes in body weight, body mass index, blood pressure, hemoglobin level, hemoglobin A1c level, liver function, triglyceride level, or cholesterol level. There also were no significant changes in serum CRP, IL-6, and TNF-␣ levels after ROS treatment (Table 2). Weekly Kt/V (2.2 ⫾ 0.1 versus 2.1 ⫾ 0.1 versus 2.1 ⫾ 0.1; P ⫽ not significant [NS]), weekly creatinine clearance (76 ⫾ 3 versus 74 ⫾ 3 versus 75 ⫾ 4 L/wk/ 1.73 m2; P ⫽ NS), residual renal function (2.7 ⫾ 0.4 versus 2.6 ⫾ 0.4 versus 2.6 ⫾ 0.4
mL/min; P ⫽ NS), and normalized protein catabolic rate (1.25 ⫾ 0.05 versus 1.27 ⫾ 0.04 versus 1.27 ⫾ 0.05 g/kg/d; P ⫽ NS) were not significantly changed at baseline, 4 weeks, and 12 weeks of ROS therapy. For the PET test, dialysate to plasma creatinine (0.67 ⫾ 0.02 versus 0.65 ⫾ 0.02; P ⫽ NS) and dialysate to plasma urea nitrogen (0.94 ⫾ 0.01 versus 0.93 ⫾ 0.01; P ⫽ NS) were not significantly changed between baseline and 12 weeks of ROS therapy. No significant side effects were observed during ROS therapy except that 1 patient developed lower-extremity edema. No patient was found to have abnormal liver function during ROS therapy. HOMA-IR Uremic patients on CAPD therapy showed no significant difference in fasting glucose concentrations, but significantly greater serum insulin concentrations (13.5 ⫾ 2.2 IU/mL [93.8 ⫾ 15.3 pmol/L] versus 8.0 ⫾ 1.2 IU/mL [55.6 ⫾ 8.3
ROSIGLITAZONE IMPROVES INSULIN RESISTANCE IN CAPD PATIENTS Table 3.
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Glucose and Insulin Profiles During OGTTs in Healthy Controls and CAPD Patients on ROS Therapy CAPD Patients
Fasting glucose (mg/dL) Fasting insulin (IU/mL) HOMA-IR ISI Insulinogenic index (IU/mg)
Controls
Baseline
4 wk
12 wk
91.4 ⫾ 1.7 8.0 ⫾ 1.2§ 1.8 ⫾ 0.3§ 6.2 ⫾ 0.5§ 134 ⫾ 29
92.6 ⫾ 2.3 13.5 ⫾ 2.2 3.2 ⫾ 0.6 3.5 ⫾ 0.4 114 ⫾ 15
89.1 ⫾ 1.5* 9.5 ⫾ 1.7* 2.2 ⫾ 0.4* 5.0 ⫾ 0.7* 127 ⫾ 20
87.3 ⫾ 1.2†‡ 9.1 ⫾ 1.2‡ 2.1 ⫾ 0.4‡ 5.3 ⫾ 0.7‡ 116 ⫾ 16
NOTE. Data expressed as mean ⫾ SEM. To convert glucose in mg/dL to mmol/L, multiply by 0.0555; insulin in IU/mL to pmol/L, multiply by 6.945. *P ⬍ 0.05, 4 weeks versus baseline. †P ⬍ 0.05, control versus 12 weeks. ‡P ⬍ 0.05, 12 weeks versus baseline. §P ⬍ 0.05, control versus baseline.
pmol/L]; P ⬍ 0.05) compared with healthy controls (Table 3). HOMA-IR also was significantly greater (3.2 ⫾ 0.6 versus 1.8 ⫾ 1.2; P ⬍ 0.05), suggesting the presence of insulin resistance in uremic patients on CAPD therapy. After 4 and 12 weeks of ROS therapy, there were significant decreases in fasting glucose levels, insulin levels, and HOMA-IR (Table 3). There were no longer significant differences in insulin levels and HOMA-IR, except for plasma glucose levels, between healthy subjects and CAPD patients after 12 weeks of ROS therapy (Table 3). OGTT Results Uremic patients on CAPD therapy showed significant glucose intolerance, seen by the area under the glucose curve, compared with healthy controls (Fig 1). The increase in area under the insulin curve also was significantly greater in CAPD patients (Fig 2). After 4 and 12 weeks of ROS treatment, CAPD patients showed improved glucose tolerance, with a significant decrease in the area under the glucose curve and a concomitant significant decrease in the area under the insulin curve (Figs 1 and 2). Insulinogenic index was not significantly changed after ROS treatment (Table 3), whereas whole-body ISI increased significantly. There were no significant differences in insulinogenic index and insulin sensitivity between healthy subjects and CAPD patients after 12 weeks of ROS therapy. Correlation There was a negative correlation between ISI and fasting HOMA-IR during OGTT in healthy
subjects (ISI ⫽ 8.7 ⫺ 1.4 * HOMA-IR; r ⫽ ⫺0.81; P ⬍ 0.001) and CAPD patients before (ISI ⫽ 5.1 ⫺ 0.5 * HOMA-IR; r ⫽ ⫺0.73; P ⬍ 0.01) and 4 (ISI ⫽ 7.5 ⫺ 1.1 * HOMAIR; r ⫽ ⫺0.72; P ⬍ 0.01) and 12 weeks (ISI ⫽ 7.9 ⫺ 1.2 * HOMA-IR; r ⫽ ⫺0.70; P ⬍ 0.01) after ROS therapy. DISCUSSION
In this study, uremic patients without diabetes on CAPD therapy showed a significantly higher HOMA-IR (an index of insulin resistance), impaired glucose tolerance, and preserved insulin secretory ability during glucose loading. Although CAPD may improve the insulin resistance and glucose intolerance associated with
Fig 1. Plasma glucose concentrations during OGTTs in healthy subjects (open circle) and CAPD patients without diabetes before (filled circle) and 4 (open triangle) and 12 weeks (filled triangle) after ROS treatment. Values expressed as mean ⴞ SEM. To convert glucose in mg/dL to mmol/L, multiply by 0.0555.
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Fig 2. Plasma insulin concentrations during OGTT in healthy subjects (open circle) and CAPD patients without diabetes before (filled circle) and 4 (open triangle) and 12 weeks (filled triangle) after ROS treatment. Values expressed as mean ⴞ SEM. To convert insulin in IU/mL to pmol/L, multiply by 6.945.
uremia,12,13 it does not completely correct this abnormality. Some hypotheses have been proposed to explain the persistence of insulin resistance in uremic patients on CAPD therapy.14 First, CAPD may be unable to remove unknown circulating factors that impair glucose use during renal failure. Second, the secondary hyperparathyroidism, active vitamin D deficiency, hyperlipidemia, and metabolic acidosis present in uremia may persist in CAPD and contribute to insulin resistance. Third, a decrease in fat-free mass secondary to protein malnutrition and an increase in adiposity may occur during the course of CAPD. Regardless of the possible mechanisms, insulin resistance is associated with arterial wall changes, coronary artery disease, and cardiovascular mortality in patients with chronic renal failure.15,16 A recent study found HOMA-IR was an independent predictor of cardiovascular mortality in a cohort of uremic patients without diabetes on hemodialysis therapy.17 Intuitively, these findings may be generalized to CAPD patients without diabetes. Thus, amelioration of insulin resistance in uremic patients has the potential to impact on mortality. To date, therapy has been aimed at correction of the contributory factors stated in the hypotheses, and use of ROS as an insulin sensitizer to treat uremic insulin resistance has not been reported in the literature. After 4 and 12 weeks of ROS therapy, a significant decrease in
LIN ET AL
fasting glucose levels, insulin levels, and HOMA-IR coupled with a significant increase in ISI during OGTTs indicated improvement in insulin resistance. Nevertheless, insulin secretion ability was not affected; pancreatic beta cell function appeared to be preserved. Because there was close correlation between HOMA-IR and ISI during OGTTs both before and after ROS therapy, HOMA-IR alone may be used an index of insulin resistance if patients cannot tolerate the OGTT during ROS therapy. There were no hypoglycemic episodes, abnormal liver function, or significant body weight changes during ROS therapy. However, there was a trend to increased total cholesterol and triglyceride levels, which deserves cautious monitoring. Despite the successful use of ROS as an insulin sensitizer in CAPD patients without diabetes, its specific mechanism of action remains uncertain. Impaired peripheral sensitivity to insulin has been studied extensively in patients with uremia and been shown to reside primarily in muscle and adipose tissue.1,2 Because PPAR␥ is expressed abundantly in adipose tissue, fat cells have been implicated as a primary target for TZDs, perhaps through suppression of resistin expression.18 Resistin is a newly discovered adipocyte-secreted hormone that appears to have a role in the pathogenesis of insulin resistance.19 PPAR␥ also is expressed in skeletal muscle,20 increasing the expression of adipocyte lipid binding protein and muscle fatty acid binding protein in this tissue.21 Fatty acids are key regulators of insulin sensitivity and decreased glucose use in skeletal muscle. The PPAR␥-induced increase in fatty acid uptake by adipocyte lipid binding protein and muscle fatty acid binding protein may be partially responsible for enhanced insulin sensitivity by ROS. Furthermore, ROS may increase glucose transporter 4 expression, facilitating glucose uptake into skeletal muscle.22 Insulin resistance also may develop in the presence of inflammation.23 Uremia per se is a state of proinflammation24 reflected by greater circulating CRP, TNF-␣, and IL-6 levels compared with healthy subjects, as in this study. TZD-PPAR complexes have been shown to reduce TNF-␣–induced insulin resistance, suggesting another mechanism for TZD action.25 However, in this study, ROS did not significantly reduce circulating CRP, TNF-␣, and IL-6 levels.
ROSIGLITAZONE IMPROVES INSULIN RESISTANCE IN CAPD PATIENTS
Interestingly, the schedule of ROS administration has been shown to greatly influence its effects, specifically, the 2-mg twice-daily regimen resulted in a greater reduction in insulin resistance than 4 mg once daily despite the same total daily milligram exposure.26 The protocol in our study was ROS, 4 mg once daily, as a half of the maximal recommended dose.27 Because of its high molecular weight of 474 daltons, high protein binding (⬎98%), and predominantly hepatic metabolism, ROS pharmacokinetics does not differ between patients with normal function or chronic renal failure or those on hemodialysis therapy.28 Because no completed pharmacokinetics of ROS are available in uremic patients on CAPD therapy, dose adjustment of ROS in uremic patients on CAPD therapy awaits further study. However, given the difference seen between once-daily and twice-daily ROS dosing, as well as the lack of anti-inflammatory effects at the 4-mg once-daily dose, more creative dosing schedules merit further investigation. In conclusion, CAPD patients show increased glycemic and insulinemic responses to oral glucose, suggesting an insulin-resistant state. Chronic use of ROS can reduce serum fasting glucose and insulin levels, as well as insulin resistance, in CAPD patients. Because insulin resistance is a modifiable risk factor, additional prospective studies are warranted to determine whether longterm use of PPAR␥ agonists can reduce cardiovascular morbidity in uremic patients. REFERENCES 1. DeFronzo RA, Tobin JD, Rowe JW, Andres R: Glucose intolerance in uremia: Quantification of pancreatic beta cell sensitivity to glucose and tissue sensitivity to insulin. J Clin Invest 62:425-435, 1978 2. DeFronzo RA, Alvestrand A, Smith D, Hendler R, Hendler E, Wahren J: Insulin resistance in uremia. J Clin Invest 67:63-68, 1981 3. Delarue J, Maingourd C: Acute metabolic effects of dialysis fluids during CAPD. Am J Kidney Dis 37:S103S107, 2001 (suppl 1) 4. Prichard S: Major and minor risk factors for cardiovascular disease in peritoneal dialysis. Perit Dial Int 20:S154S159, 2000 (suppl 2) 5. Mayerson AB, Hundal RS, Dufour S, et al: The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes 51:797-802, 2002 6. Parulkar AA, Pendergrass ML, Grand-Ayala R, Lee TR, Fonseca VA: Nonhypoglycemic effects of thiazolidinediones. Ann Intern Med 134:61-71, 2001
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7. Martens FM, Visseren FL, Lemay J, de Koning EJ, Rabelink TJ: Metabolic and additional vascular effects of thiazolidinediones. Drugs 62:1463-1480, 2002 8. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC: Homeostasis model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412-419, 1985 9. Shoji T, Emoto M, Nishizawa Y: HOMA index to assess insulin resistance in renal failure patients. Nephron 89:348-349, 2001 10. 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 87: 533-538, 1994 11. Matsuda M, DeFronzo RA: Insulin sensitivity indices obtained from oral glucose tolerance testing: Comparison with the euglycemic clamp. Diabetes Care 22:1462-1470, 1999 12. Mak RH: Insulin resistance in uremia: Effect of dialysis modality. Pediatr Res 40:304-308, 1996 13. Kobayashi S, Maejima S, Ikeda T, Nagase M: Impact of dialysis therapy on insulin resistance in end-stage renal disease: Comparison of haemodialysis and continuous ambulatory peritoneal dialysis. Nephrol Dial Transplant 15:65-70, 2000 14. Delarue J, Maingourd C, Couet C, Vidal S, Bagros P, Lamisse F: Effects of oral glucose on intermediary metabolism in continuous ambulatory patients versus healthy subjects. Perit Dial Int 18:505-511, 1998 15. Stenvinkel P, Heimburger O, Paultre F, et al: Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int 55:1899-1911, 1999 16. Shoji T, Emoto M, Shinohara K, et al: Diabetes mellitus, aortic stiffness, and cardiovascular mortality in endstage renal disease. J Am Soc Nephrol 12:2117-2124, 2001 17. Shinohara K, Shoji T, Emoto M, et al: Insulin resistance as an independent predictor of cardiovascular mortality in patients with end-stage renal disease. J Am Soc Nephrol 13:1894-1900, 2002 18. Shuldiner AR, Yang R, Gong DW: Resistin, obesity and insulin resistance: The emerging role of the adipocyte as an endocrine organ. N Engl J Med 345:1345-1346, 2001 19. Steppan CM, Brown EJ, Wright CM, et al: A family of tissue-specific resistin-like molecules. Proc Natl Acad Sci U S A 98:502-506, 2002 20. Park KS, Ciaraldi TP, Abrams-Carter L, Mudaliar S, Nikoulina SE, Henry RR: PPARr gene expression is elevated in skeletal muscle of obese and type II diabetic subjects. Diabetes 46:1230-1234, 1997 21. Park KS, Ciaraldi TP, Lindgren K, et al: Troglitazone effects on gene expression in human skeletal muscle of type II diabetes involve up-regulation of peroxisome proliferatorsactivated receptor-gamma. J Clin Endocrinol Metab 83:28302835, 1998 22. Yonemitsu S, Nishimura H, Shintani M, et al: Troglitazone induces GLUT4 translocation in L6 myotubes. Diabetes 50:1093-1101, 2001 23. Lang CH, Dobrescu C, Bagby GJ: Tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic glucose output. Endocrinology 130:43-52, 1992
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24. Pereira BJ, Shapiro L, King AJ, Falagas ME, Strom JA, Dinarello CA: Plasma levels of IL-1beta, TNF alpha and their specific inhibitors in undialyzed chronic renal failure, CAPD and hemodialysis patients. Kidney Int 45:890-896, 1994 25. Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI: Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 106:679-684, 2002
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26. Phillips LS, Grunberger G, Miller E, Patwardhan R, Rappaport EB, Salzman A: Once- and twice daily dosing with rosiglitazone improves glycemic control in patients with type 2 diabetes. Diabetes Care 24:308-315, 2001 27. Wagstaff AJ, Goa KL: Rosiglitazone: A review of its use in the management of type 2 diabetes mellitus. Drugs 62:1805-1837, 2002 28. Thompson-Culkin K, Zussman B, Miler AK, Freed MI: Pharmacokinetics of rosiglitazone in patients with endstage renal disease. J Int Med Res 30:391-9, 2002