Long-term caffeine consumption exacerbates renal failure in obese, diabetic, ZSF1 (fa-fa(cp)) rats

BACKGROUND: Our preliminary studies indicate that chronic caffeine consumption has adverse renal effects in nephropathy associated with high blood pressure and insulin resistance. The purpose of this study was to investigate the effects of early (beginning at 8 weeks of age) and long-term (30 weeks) caffeine treatment (0.1% solution) on renal function and structure in obese, diabetic ZSF1 rats. METHODS: Metabolic and renal function measurements were performed at six-week intervals and in a subset of animals (N = 6 per group) heart rate (HR) and mean arterial blood pressure (MABP) were monitored by a radiotelemetric technique. At the end of the study acute, measurements of renal hemodynamics and excretory function were conducted in anesthetized animals. RESULTS: Caffeine produced a very mild increase (4 to 5%) of MABP and HR, but greatly augmented proteinuria (P < 0.001), reduced creatinine clearance (P < 0.05) and had a mixed effect on metabolic status in obese ZSF1 rats. Caffeine significantly reduced body weight, glycosuria, fasting glucose and insulin levels and improved glucose tolerance, had no effect on elevated plasma triglycerides levels and significantly increased plasma cholesterol level (P < 0.001). Acute measurements of renal function revealed increased renal vascular resistance (95.1 +/- 11 vs. 50.7 +/- 2.4 mm Hg/mL/min/g kidney, P < 0.01) and decreased inulin clearance (0.37 +/- 0.11 vs. 0.97 +/- 0.13 mL/min/g kidney, P < 0.002) in caffeine-treated versus control animals, respectively. Caffeine potentiated the development of more severe tubulointerstitial changes (P < 0.05) and increased focal glomerulosclerosis (14.7 +/- 1.7 vs. 6.5 +/- 0.9%, caffeine vs. control, P < 0.002). CONCLUSION: The present study provides the first evidence that caffeine (despite improving insulin sensitivity) exacerbates renal failure in obese, diabetic ZSF1 rats. Further mechanistic studies of adverse renal effects of caffeine in chronic renal failure associated with metabolic syndrome are warranted.     

Early renal injury induced by caffeine consumption in obese, diabetic ZSF1 rats

Our previous studies indicate that prolonged caffeine consumption exacerbates renal failure in nephropathy associated with the metabolic syndrome. Reduced activity of the antioxidant defense system and beneficial effects of antioxidant therapy have been reported in diabetic rats and humans. The purpose of this study was to examine the early renal effects of caffeine consumption and the effects of concomitant antioxidant therapy in young obese, diabetic ZSF1 rats. Eleven-week-old male ZSF1 rats were randomized to drink tap water, caffeine (0.1%), tempol (1 mmol/L), or a solution containing caffeine and tempol for nine weeks. Caffeine significantly reduced body weight and glycosuria (weeks 2-9), improved glucose tolerance (week 9), had no effect on elevated plasma triglycerides, plasma cholesterol (week 9) and blood pressure (week 9), and significantly increased plasma cholesterol level (weeks 5 and 9). Yet, as early as after two weeks, caffeine greatly augmented proteinuria and increased renal vascular resistance (RVR) and heart rate (HR: week 9). Tempol had no effects on metabolic status and development of proteinuria, did not alter caffeine-induced metabolic changes and early proteinuria, and attenuated caffeine-induced increase in HR and RVR. Immunohistochemical analysis revealed significant glomerular and interstitial inflammation, proliferation, and fibrosis in control animals. Caffeine augmented the influx of glomerular and interstitial macrophages (ED1+ cells) influx, glomerular and tubular proliferative response, and glomerular collagen IV content. Tempol abolished the exacerbation of renal inflammation, proliferation, and fibrosis induced by caffeine. In conclusion, in nephropathy associated with the metabolic syndrome, caffeine--most likely through the interaction with adenosine receptors and interference with anti-inflammatory and/or glomerular hemodynamic effects of adenosine--augments proteinuria and stimulates some of the key proliferative mechanisms involved in glomerular remodeling and sclerosis. Tempol does not prevent early renal injury (i.e., proteinuria) induced by caffeine, yet abolishes late renal inflammatory, proliferative, and fibrotic change induced by chronic caffeine consumption in obese ZSF1 rats.     

Caffeine augments proteinuria in puromycin-aminonucleoside nephrotic rats

Several studies indicate that increased intrarenal adenosine concentrations may attenuate puromycin-aminonucleoside (PAN)-induced nephropathy in rats. The purpose of this study was to investigate the chronic effects of caffeine, a nonselective adenosine receptor antagonist, on renal function and structure in PAN-induced nephropathy. Animals were randomized to receive drinking water or 0.1% caffeine solution. PAN was administered in two doses to a subset from each group at 1 week (100 mg/kg, s.c.; Purom-1) and 15 wks (80 mg/kg, s.c.; Purom-2) after initiating caffeine treatment (PAN and CAFF-PAN groups). The remaining animals served as time controls (CON and CAFF groups). Renal excretory function was followed for 23 wks. Caffeine consumption significantly augmented PAN-induced proteinuria after both PAN injections (Purom-1 and Purom-2, p<0.05 and p<0.001 respectively; CAFF-PAN vs. PAN). In addition, caffeine potentiated the transient reduction in creatinine clearance (CrCl) induced by PAN. Caffeine consumption for 23 wks significantly reduced CrCl in conscious nephrotic animals (4.76 +/- 0.98 vs. 8.51 +/- 1.55 L/kg/day, CAFF-PAN vs. PAN). Seven days after both PAN injections, increased plasma renin activity was detected in animals that were consuming caffeine as compared with corresponding control groups (CAFF and CAFF + PAN vs CON and PAN, respectively). Eight weeks after the second injection of PAN, acute measures of renal hemodynamic and excretory function were compared in anesthetized animals and renal samples were analyzed for histological changes. In PAN-rats, caffeine treatment for 23 weeks significantly reduced inulin clearance (0.28 +/- 0.09 vs. 0.57 +/- 0.12 mL/min/gr kidney. CAFF-PAN vs PAN, p<0.05), tended to increase renal vascular resistance (59.0 +/- 9.5 vs. 42.9 +/- 5.5 mmHg/mL/min/gr kidney, CAFF-PAN vs. PAN, p < 0.06), potentiated the development of more severe tubulointerstitial damage (tubular atrophy, presence of proteinaceous material, tubular dilatation, interstitial inflammation, interstitial fibrosis), and tended to increase glomerulosclerosis. In conclusion, this study indicates that caffeine adversely affects renal function in PAN-nephrotic rats, and that this effect may be due, in part, to increased activity of the renin angiotensin system.     

Early Renal Injury Induced by Caffeine Consumption in Obese,Diabetic ZSF1 Rats

Our previous studies indicate that prolonged caffeine consumption exacerbates renal failure in nephropathy associated with the metabolic syndrome. Reduced activity of the antioxidant defense system and beneficial effects of antioxidant therapy have been reported in diabetic rats and humans. The purpose of this study was to examine the early renal effects of caffeine consumption and the effects of concomitant antioxidant therapy in young obese, diabetic ZSF1 rats. Eleven-week-old male ZSF1 rats were randomized to drink tap water, caffeine (0.1%), tempol (1 mmol/L), or a solution containing caffeine and tempol for nine weeks. Caffeine significantly reduced body weight and glycosuria (weeks 2–9), improved glucose tolerance (week 9), had no effect on elevated plasma triglycerides, plasma cholesterol (week 9) and blood pressure (week 9), and significantly increased plasma cholesterol level (weeks 5 and 9). Yet, as early as after two weeks, caffeine greatly augmented proteinuria and increased renal vascular resistance (RVR) and heart rate (HR: week 9). Tempol had no effects on metabolic status and development of proteinuria, did not alter caffeine-induced metabolic changes and early proteinuria, and attenuated caffeine-induced increase in HR and RVR. Immunohistochemical analysis revealed significant glomerular and interstitial inflammation, proliferation, and fibrosis in control animals. Caffeine augmented the influx of glomerular and interstitial macrophages (ED1+ cells) influx, glomerular and tubular proliferative response, and glomerular collagen IV content. Tempol abolished the exacerbation of renal inflammation, proliferation, and fibrosis induced by caffeine. In conclusion, in nephropathy associated with the metabolic syndrome, caffeine—most likely through the interaction with adenosine receptors and interference with anti-inflammatory and/or glomerular hemodynamic effects of adenosine—augments proteinuria and stimulates some of the key proliferative mechanisms involved in glomerular remodeling and sclerosis. Tempol does not prevent early renal injury (i.e., proteinuria) induced by caffeine, yet abolishes late renal inflammatory, proliferative, and fibrotic change induced by chronic caffeine consumption in obese ZSF1 rats.     

Renal function and structure in diabetic, hypertensive, obese ZDFxSHHF-hybrid rats

The obese ZDFxSHHF-fa/fa(cp) model was developed by crossing lean female Zucker Diabetic Fatty (ZDF +/fa) and lean male Spontaneously Hypertensive Heart Failure (SHHF/Mcc-fa(cp), +/fa) rats. The purpose of the present study was to determine renal function and morphology, hemodynamics, and metabolic status in ZDFxSHHF rats. Two sets of experiments were conducted. First, we evaluated heart and kidney function and metabolic status in aged (46 weeks old) male obese ZDFxSHHF and age matched obese SHHF rats, lean Spontaneously Hypertensive (SHR) and lean normotensive Wistar Kyoto (WKY) rats. In the second set of experiments, renal function and structure as well as metabolic and lipid status were determined in lean (LN) and obese (OB) adult (29-weeks of age) ZDFxSHHF rats. At 46 weeks of age ZDFxSHHF rats are hypertensive expressing marked cardiac hypertrophy associated with diastolic dysfunction and preserved contractile function. Fasted hyperglycemia and hyperinsulinemia are accompanied by moderate hypercholesterolemia and hypertriglyceridemia. Obese aged ZDFxSHHF have marked renal hypertrophy, a 3-8 fold decrease in creatinine clearance (compared with SHHF, SHR and WKY), a high percent of segmental + global glomerulosclerosis (59.8%+/-10.8), and severe tubulointerstitial and vascular changes. Obese ZDFxSHHF rats die at an early age (approximately 12 months) from end-stage renal failure. Studies conducted in 29-week animals showed that, although both LN and OB 29-week old animals are hypertensive, OB animals have more severely compromised renal function and structure as compared with lean litter-mates (kidney weight: 2.56+/-0.16 vs. 1.61+/-0.12 g; creatinine clearance: 0.42+/-0.04 vs. 1.24+/-0.13 L/g kid/day; renal vascular resistance 12.39+/-1.4 vs. 6.14+/-0.42 mmHg/mL/min/g kid; protein excretion: 556+/-16 vs. 159+/-9mg/day/g kid, p < 0.05, OB vs. LN, respectively). Obesity is also associated with hyperglycemia (424+/-37 vs. 115+/-11 mg/dL), hyperinsulinemia (117.2+/-8.8 vs. 42.3+/-3.5 microU/mL), hypertriglyceridemia (5200+/-702 vs. 194+/-23 mg/dL), hypercholesterolemia (632+/-39 vs. 109+/-4mg/dL), and presence of segmental + global glomerulosclerosis (20.1+/-3.2% vs. 0.1+/-0.1%) with prominent tubular and interstitial changes (p < 0.05, OB vs. LN, respectively). In summary, the present study indicates that the crossing of rat strains of nephropathy produces hybrids that carry a high risk for severe renal dysfunction. The ZDFxSHHF rats express insulin resistance, hypertension, dislipidemia and obesity and develop severe renal dysfunction. In addition, the hybrids do not develop some of the complications (hydronephrosis or congestive heart failure) common for the parental strains that may compromise studies of renal function and structure. Therefore, the ZDFxSHHF rat may be a useful model fore valuating risk factors and pharmacological interventions in chronic renal failure.     

Simultaneous hemodialysis during coronary angiography fails to prevent radiocontrast-induced nephropathy in chronic renal failure

BACKGROUND: Radiocontrast medium- (RM) associated nephrotoxicity continues to be a common cause of acute renal failure and may lead in patients with pre-existing chronic renal insufficiency even to end-stage renal failure requiring chronic dialysis. Since extracorporeal removal of RM after RM administration has been shown to be effective but does not prevent radiocontrast-induced nephropathy, the effect of a simultaneous dialysis during RM administration on renal function is not clear. METHODS: In a prospective, randomized and controlled trial, we studied the effect of a 4-hour online dialysis during RM (iomeprol) application in patients with advanced chronic renal failure (serum creatinine > or = 3 mg/dl) undergoing coronary angiography. All patients received hydration with saline before and after standardized coronary angiography and were randomized to receive a simultaneous high-flux hemodialysis (7 patients, HD group) or to control group (10 patients). 24-hour creatinine clearance (CrCl) was measured in all patients before, 1 week and 8 weeks after coronary angiography. The clinical follow-up comprised 8 weeks after RM application. RM plasma levels were measured in both groups 15, 30, 60 minutes, 2, 4, 12, 24, 48 and 72 hours after application by high-pressure liquid chromatography. RESULTS: At baseline, CrCl (19 +/- 10 vs 17 +/- 7 ml/min), percentage of diabetics (57 vs 70%) and dose of RM (77 +/- 27 vs 86 +/- 21 ml) were similar in both groups. Pharmacokinetics: Total clearance of iomeprol was significantly higher (54 +/- 15 vs 20 +/- 12 ml/min, p < 0.001) and the area under curve (AUC) was significantly lower (23 +/- 10 g x h/l vs 94 +/- 57 g x h/l, p < 0.001) in the HD group compared to control group. RM peak plasma levels 15 min after application were not different in both groups (3.0 +/- 1.1 vs 4.2 +/- 1.7 mmol/l, NS), however, significantly lower 60 min (1.6 +/- 0.4 vs 3.7 +/- 1.5 mmol/l, p < 0.01) and 240 min (0.7 +/- 0.3 vs 2.3 +/- 0.7 p < 0.001) after angiography. Clinical results: CrCl showed no difference 1 week (24 +/- 11 vs 19 +/- 9 ml/min, ns) and 8 weeks (24 +/- 5 vs 20 +/- 9 ml/min, NS) after angiography from baseline or between the groups. In each group, 2 patients developed end-stage renal disease and requested permanent dialysis during the 8-week follow-up. CONCLUSION: Simultaneous dialysis reduces AUC of iomeprol significantly, however, does not influence plasma peak concentration after angiography. Renal function and incidence of end-stage renal failure were not influenced by online-dialysis.     

The role of proinflammatory cytokine gene polymorphisms for development of insulin resistance after renal transplantation

BACKGROUND: Insulin resistance, a frequent prediabetic metabolic complication after renal transplantation, is generally linked to immunosuppressive drugs including corticosteroids, cyclosporine (CsA) or tacrolimus, as well as to age, cadaveric donors and ethnic factors. Cytokines are known to be inflammation modulatory substances that contribute to metabolic derangements after transplantation. The present study investigated the effects of cytokine gene polymorphisms on insulin resistance in renal transplant recipients. PATIENTS AND METHODS: Sixty-one renal transplant recipients (37 men, 24 women; mean age: 39.3 +/- 10.8 years) who attended regular clinical visits without a known history of diabetes were enrolled in the study. All patients were on a regimen of steroid, CsA, and mycophenolate mofetil. Venous blood samples were collected for biochemical analyses after an overnight fast at 08:00 pm. CsA trough levels, C-reactive protein, and fibrinogen were also estimated. Additional 10 mL of blood was withdrawn into an ethylenediamine tetraacetic acid-containing tube to determine cytokine genotypes (tumor necrosis factor-alpha [TNF-alpha] -238 G/A, transforming growth factor-beta [TGF-beta] codon 10 -869 T/C). Insulin resistance was calculated by the homeostasis model assessment (HOMA) method using the values of fasting blood glucose (FBG) and insulin levels. Anthropometric indices as well as body height, weight, waist and hip circumferences were measured simultaneously to calculate body mass index (kg/m2) and waist-to-hip ratio. Impaired fasting glucose (IFG) was described as an FBG > or = 110 but < 126 mg/dL. RESULTS: IFG was detected in 27.9% of this study group. The HOMA index was significantly higher among patients with IFG compared with normal FBG (NoGT) (6.3 +/- 4.5 vs 3.7 +/- 1.5; P = .01). Neither FBG and insulin nor HOMA values correlated with antrophometric, metabolic, or inflammatory parameters. Cytokine genotype allele frequencies, age, sex, immunosuppressive and antihypertensive drug type and doses, CsA trough levels, and donor source (cadaveric/living) were similar for patients with IFG and NoGT. Mutant allele carrier genotypes (AA + GA) for TNF-alpha -238 G/A showed higher fasting insulin (14.0 +/- 7.9 vs 34.1 +/- 17.7 microIU/mL; P = .04) and HOMA (4.01 +/- 2.01 vs 7.95 +/- 5.44; P = .002) levels than GG homozygote subjects. FBG, HOMA, and other metabolic and anthropometric indices were similar between TGF-beta codon 10 -869 T/C genotypes. The daily dose of steroid (mg/d) and A allele frequency for TNF-alpha -238 G/A genotype were significant predictors of HOMA index in linear regression analysis. CONCLUSION: The present study revealed that beside the daily dose of steroids, TNF-alpha -238 G/A genotype may contribute to insulin resistance in renal transplant recipients. Further investigations may highlight the effects of cytokine gene heterogenity on insulin resistance in those patients.     

Intraoperative glucose control in diabetic and nondiabetic patients during cardiac surgery

OBJECTIVE: The purpose of this study was to evaluate intraoperative glucose control. DESIGN: Prospective unblinded study. SETTING: Tertiary care center. PARTICIPANTS: Diabetic (n = 17) and nondiabetic (n = 23) patients undergoing elective cardiac surgery. INTERVENTIONS: Diabetics received a modified insulin regimen consisting of a fixed rate infusion of regular insulin, 10 U/m2/h, and a variable infusion of D10W, adjusted to maintain glucose between 101 to 140 mg/dL. MEASUREMENTS AND MAIN RESULTS: Baseline glucose was higher in diabetics versus nondiabetics (mean +/- standard error of the mean: 203 +/- 27 v 117 +/- 3 mg/dL, p < 0.005). After baseline, insulin levels were increased in diabetics to 410 to 568 microU/mL. Corresponding insulin levels in nondiabetics were 12 to 40 microU/mL. Compared with baseline, glucose was decreased by 10% +/- 29% in diabetics during hypothermic cardiopulmonary bypass and increased by 21% +/- 30% in nondiabetics (p < 0.005). After discontinuation of bypass, glucose was lower in diabetics (137 +/- 12 mg/dL) versus nondiabetics (162 +/- 8 mg/dL, p < 0.005). Nine diabetics had adequate intraoperative glycemic control during hypothermic bypass (glucose 123 +/- 8 mg/dL, insulin 550 +/- 68 microU/mL, glucose infusion rate 1.87 +/- 0.29 mg/kg/min), 6 approached adequate control near the end of surgery (glucose 147 +/- 8 mg/dL, insulin 483 +/- 86 microU/mL, glucose infusion rate 0.35 +/- 0.05 mg/kg/min), and 2 never achieved control. Diabetics with elevated initial glucose >300 mg/dL did not achieve adequate glycemic control. Four diabetics (3 with renal failure) required injection of 50% dextrose after bypass for hypoglycemia. CONCLUSION: Adequate glycemic control can be achieved in most diabetics during cardiac surgery using a modified insulin clamp technique provided initial glucose is <300 mg/dL.     

Insulin sensitivity and mitochondrial function are improved in children with burn injury during a randomized controlled trial of fenofibrate

OBJECTIVE: To determine some of the mechanisms involved in insulin resistance immediately following burn trauma, and to determine the efficacy of PPAR-alpha agonism for alleviating insulin resistance in this population. SUMMARY BACKGROUND DATA: Hyperglycemia following trauma, especially burns, is well documented. However, the underlying insulin resistance is not well understood, and there are limited treatment options. METHODS: Twenty-one children 4 to 16 years of age with >40% total body surface area burns were enrolled in a double-blind, prospective, placebo-controlled randomized trial. Whole body and liver insulin sensitivity were assessed with a hyperinsulinemic-euglycemic clamp, and insulin signaling and mitochondrial function were measured in muscle biopsies taken before and after approximately 2 weeks of either placebo (PLA) or 5 mg/kg of PPAR-alpha agonist fenofibrate (FEN) treatment, within 3 weeks of injury. RESULTS: The change in average daily glucose concentrations was significant between groups after treatment (146 +/- 9 vs. 161 +/- 9 mg/dL PLA and 158 +/- 7 vs. 145 +/- 4 FEN; pretreatment vs. posttreatment; P = 0.004). Insulin-stimulated glucose uptake increased significantly in FEN (4.3 +/- 0.6 vs. 4.5 +/- 0.7 PLA and 5.2 +/- 0.5 vs. 7.6 +/- 0.6 mg/kg per minute FEN; pretreatment vs. posttreatment; P = 0.003). Insulin trended to suppress hepatic glucose release following fenofibrate treatment (P = 0.06). Maximal mitochondrial ATP production from pyruvate increased significantly after fenofibrate (P = 0.001) and was accompanied by maintained levels of cytochrome C oxidase and citrate synthase activity levels. Tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 in response to insulin increased significantly following fenofibrate treatment (P = 0.04 for both). CONCLUSIONS: Fenofibrate treatment started within 1 week postburn and continued for 2 weeks significantly decreased plasma glucose concentrations by improving insulin sensitivity, insulin signaling, and mitochondrial glucose oxidation. Fenofibrate may be a potential new therapeutic option for treating insulin resistance following severe burn injury.     

Tacrolimus (FK506) versus cyclosporine microemulsion (neoral) as maintenance immunosuppression therapy in kidney transplant recipients

The effects of the calcineurin inhibitors tacrolimus (FK506) and cyclosporine (Neoral) on graft survival, function, and metabolic profile were evaluated in 69 patients receiving Neoral (group 1) and 54 patients receiving FK506 (group 2) for maintenance immunosuppression following kidney transplantation. Recipient and donor demographics and induction therapy were comparable, except for a higher number of sensitized patients in group 2 (n = 13). Acute rejection timing, severity, and infection rates and types were similar in both groups. During hospitalization, at 6 months, and at 1 year following transplantation, no significant differences were noted between groups in fasting glucose, serum cholesterol levels, triglyceride levels, or need for insulin or antihypertensive therapy. Mean serum creatinine levels on discharge (1.42 mg/dL +/- 0.14 vs 1.68 mg/dL +/- 0.3), at 1 month (1.45 mg/dL +/- 0.1 vs 1.39 mg/dL +/- 0.11), 3 months (1.46 mg/dL +/- 0.09 vs 1.32 mg/dL +/- 0.14), and 1 year (1.29 mg/dL +/- 0.08 vs 1.19 mg/dL +/- 0.09), but not at 6 months (1.42 +/- 0.37 vs 1.10 +/- 0.07; P = .001), were comparable between groups. The 1-year patient and graft survival rates were 98.3% for group 1 and 94.5% for group 2. When evaluated for acute rejection, infection, and metabolic differences, we conclude that both tacrolimus and cyclosporine are effective and safe calcineurin inhibitors for short-term use in kidney transplantation. A similar study is proposed to evaluate the long-term effects of both agents.     

RENAL FUNCTION AND STRUCTURE IN DIABETIC,HYPERTENSIVE, OBESE ZDFxSHHF-HYBRID RATS

The obese ZDFxSHHF-fa/fa^cp model was developed by crossing lean female Zucker Diabetic Fatty (ZDF +/fa) and lean male Spontaneously Hypertensive Heart Failure (SHHF/Mcc-fa^cp, +/fa) rats. The purpose of the present study was to determine renal function and morphology, hemodynamics, and metabolic status in ZDFxSHHF rats. Two sets of experiments were conducted. First, we evaluated heart and kidney function and metabolic status in aged (46 weeks old) male obese ZDFxSHHF and age matched obese SHHF rats, lean Spontaneously Hypertensive (SHR) and lean normotensive Wistar Kyoto (WKY) rats. In the second set of experiments, renal function and structure as well as metabolic and lipid status were determined in lean (LN) and obese (OB) adult (29-weeks of age) ZDFxSHHF rats. At 46 weeks of age ZDFxSHHF rats are hypertensive expressing marked cardiac hypertrophy associated with diastolic dysfunction and preserved contractile function. Fasted hyperglycemia and hyperinsulinemia are accompanied by moderate hypercholesterolemia and hypertriglyceridemia. Obese aged ZDFxSHHF have marked renal hypertrophy, a 3–8 fold decrease in creatinine clearance (compared with SHHF, SHR and WKY), a high percent of segmental + global glomerulosclerosis (59.8% ± 10.8), and severe tubulointerstitial and vascular changes. Obese ZDFxSHHF rats die at an early age (～12 months) from end-stage renal failure. Studies conducted in 29-week animals showed that, although both LN and OB 29-week old animals are hypertensive, OB animals have more severely compromised renal function and structure as compared with lean littermates (kidney weight: 2.56 ± 0.16 vs. 1.61 ± 0.12 g; creatinine clearance: 0.42 ± 0.04 vs. 1.24 ± 0.13 L/g kid/day; renal vascular resistance 12.39 ± 1.4 vs. 6.14 ± 0.42 mmHg/mL/min/g kid; protein excretion: 556 ± 16 vs. 159 ± 9 mg/day/g kid, p < 0.05, OB vs. LN, respectively). Obesity is also associated with hyperglycemia (424 ± 37 vs. 115 ± 11 mg/dL), hyperinsulinemia (117.2 ± 8.8 vs. 42.3 ± 3.5 μU/mL), hypertriglyceridemia (5200 ± 702 vs. 194 ± 23 mg/dL), hypercholesterolemia (632 ± 39 vs. 109 ± 4 mg/dL), and presence of segmental + global glomerulosclerosis (20.1 ± 3.2% vs. 0.1 ± 0.1%) with prominent tubular and interstitial changes (p < 0.05, OB vs. LN, respectively). In summary, the present study indicates that the crossing of rat strains of nephropathy produces hybrids that carry a high risk for severe renal dysfunction. The ZDFxSHHF rats express insulin resistance, hypertension, dislipidemia and obesity and develop severe renal dysfunction. In addition, the hybrids do not develop some of the complications (hydronephrosis or congestive heart failure) common for the parental strains that may compromise studies of renal function and structure. Therefore, the ZDFxSHHF rat may be a useful model fore valuating risk factors and pharmacological interventions in chronic renal failure.     

The influence of intravenous 1,25(OH)2D3 therapy on glucose metabolism in hemodialyzed patients with secondary hyperparathyroidism

Glucose intolerance, insulin resistance and hyperinsulinemia are common findings in end-stage renal disease patients. Parathormone (PTH) and vitamin D3 are linked with disturbances of glucose metabolism. Glycated hemoglobin (HbA1c) reflects long-term glycemic control. HbA1c is a marker of increased risk of death in diabetic patients but also in general population. The aim of the study was to investigate the influence of 1,25(OH)2D3 therapy on long-term control of glycemia in hemodialyzed (HD) patients with severe secondary hyperparathyroidism (SHP). Eight HD patients with SHP (PTH=1088.6+/-472.2) were given intravenous 1,25(OH)2D3 1-2 microg thrice a week, for 12 weeks (mean dose 4.5 microg/week). At baseline and after 12 weeks fasting blood was sampled for: glucose, insulin, HbA1c, PTH. Insulin/glucose ratio (I/G) was calculated as marker of insulin resistance. Results were compared with 14 healthy volunteers (controls) matched for age, sex and BMI. At baseline I/G was higher in HD vs controls 0.110+/-0.045 vs 0.073+/-0.021 (p = 0.02), and of borderline significance at follow-up (0.106+/-0.053, p=0.05 vs controls). PTH decreased significantly to 506.1+/-646.3 (p<0.02) during therapy. Significant decrease of HbA1c in HD patients was observed (5.84+/-0.40 vs 5.13+/-0.51; p=0.01), while fasting glucose, insulin and I/G did not change significantly. Intravenous 1,25(OH)2D3 therapy is successful, even in patients with severe secondary hyperparathyroidism. Significant decrease in HbA1c with stable insulin concentration may indicate positive impact of intravenous 1,25(OH)2D3 therapy on long-term glucose metabolism.     

Conversion from tacrolimus to cyclosporin is associated with a significant improvement of glucose metabolism in patients with new-onset diabetes mellitus after renal transplantation

BACKGROUND: The incidence of new-onset posttransplant diabetes mellitus (PTDM) is increased in renal transplant patients treated with tacrolimus. METHODS: We retrospectively analyzed fasting plasma glucose and HbA1c levels as well as the dose of glucose-lowering agents in 34 renal transplant patients converted from tacrolimus to cyclosporine (CsA) for PTDM. Diabetes was defined according to current guidelines as repeated fasting plasma glucose (FPG) levels > or =126 mg/dL. RESULTS: At conversion, 11 patients received insulin, 5 received oral agents, and 18 had no glucose-lowering therapy. Fasting plasma glucose levels decreased from 146 +/- 64 mg/dL at conversion to 111 +/- 26 mg/dL at 3 months and 104 +/- 21 mg/dL at 12 months (P < .001). HbA1c levels decreased from 6.8 +/- 0.8% at conversion to 6.0 +/- 0.6% at 12 months (P = .001). Insulin was stopped in 3, the dose reduced in 7, and remained stable in 1 of the patients. The average daily insulin dose among these patients was reduced from 31 +/- 17 units at conversion to 13 +/- 12 units at 12 months (P < .05). There was no significant change in the number of patients treated with oral glucose-lowering agents. Diabetes reversed (fasting plasma glucose < or = 125 mg/dL without glucose-lowering therapy) in 44% (95% confidence interval, 23% to 64%) of patients during the first year after conversion (P < .001). Graft function, blood pressure, and lipid levels remained stable after conversion but the proportion of patients receiving lipid-lowering therapy increased from 18% to 49% (P < .01). CONCLUSIONS: Conversion from tacrolimus to CsA for PTDM was associated with a marked improvement in glucose metabolism and frequent reversal of diabetes.     

Acute and short-term administration of a sulfonylurea (gliclazide) increases pulsatile insulin secretion in type 2 diabetes

The high-frequency oscillatory pattern of insulin release is disturbed in type 2 diabetes. Although sulfonylurea drugs are widely used for the treatment of this disease, their effect on insulin release patterns is not well established. The aim of the present study was to assess the impact of acute treatment and 5 weeks of sulfonylurea (gliclazide) treatment on insulin secretory dynamics in type 2 diabetic patients. To this end, 10 patients with type 2 diabetes (age 53 +/- 2 years, BMI 27.5 +/- 1.1 kg/m(2), fasting plasma glucose 9.8 +/- 0.8 mmol/l, HbA(1c) 7.5 +/- 0.3%) were studied in a double-blind placebo-controlled prospective crossover design. Patients received 40-80 mg gliclazide/placebo twice daily for 5 weeks with a 6-week washout period intervening. Insulin pulsatility was assessed by 1-min interval blood sampling for 75 min 1) under baseline conditions (baseline), 2) 3 h after the first dose (80 mg) of gliclazide (acute) with the plasma glucose concentration clamped at the baseline value, 3) after 5 weeks of treatment (5 weeks), and 4) after 5 weeks of treatment with the plasma glucose concentration clamped during the sampling at the value of the baseline assessment (5 weeks-elevated). Serum insulin concentration time series were analyzed by deconvolution, approximate entropy (ApEn), and spectral and autocorrelation methods to quantitate pulsatility and regularity. The P values given are gliclazide versus placebo; results are means +/- SE. Fasting plasma glucose was reduced after gliclazide treatment (baseline vs. 5 weeks: gliclazide, 10.0 +/- 0.9 vs. 7.8 +/- 0.6 mmol/l; placebo, 10.0 +/- 0.8 vs. 11.0 +/- 0.9 mmol/l, P = 0.001). Insulin secretory burst mass was increased (baseline vs. acute: gliclazide, 43.0 +/- 12.0 vs. 61.0 +/- 17.0 pmol. l(-1). pulse(-1); placebo, 36.1 +/- 8.4 vs. 30.3 +/- 7.4 pmol. l(-1). pulse(-1), P = 0.047; 5 weeks-elevated: gliclazide vs. placebo, 49.7 +/- 13.3 vs. 37.1 +/- 9.5 pmol. l(-1). pulse(-1), P < 0.05) with a similar rise in burst amplitude. Basal (i.e., nonoscillatory) insulin secretion also increased (baseline vs. acute: gliclazide, 8.5 +/- 2.2 vs. 16.7 +/- 4.3 pmol. l(-1). pulse(-1); placebo, 5.9 +/- 0.9 vs. 7.2 +/- 0.9 pmol. l(-1). pulse(-1), P = 0.03; 5 weeks-elevated: gliclazide vs. placebo, 12.2 +/- 2.5 vs. 9.4 +/- 2.1 pmol. l(-1). pulse(-1), P = 0.016). The frequency and regularity of insulin pulses were not modified significantly by the antidiabetic therapy. There was, however, a correlation between individual values for the acute improvement of regularity, as measured by ApEn, and the decrease in fasting plasma glucose during short-term (5-week) gliclazide treatment (r = 0.74, P = 0.014, and r = 0.77, P = 0.009, for fine and coarse ApEn, respectively). In conclusion, the sulfonylurea agent gliclazide augments insulin secretion by concurrently increasing pulse mass and basal insulin secretion without changing secretory burst frequency or regularity. The data suggest a possible relationship between the improvement in short-term glycemic control and the acute improvement of regularity of the in vivo insulin release process.     

Metabolic effects of a corticosteroid-free immunosuppressive regimen in recipients of pancreatic transplant

BACKGROUND: A corticosteroid (CS)-free immunosuppressive regimen may be considered less diabetogenic than treatments including CSs principally after pancreas transplantation. METHODS: To test whether a CS-free immunosuppressive treatment is metabolically superior to a regimen including CSs, we prospectively studied 19 CS-free simultaneous pancreas and kidney (SPK) transplant recipients (body mass index=22+/-1 kg/m2; cyclosporine dose=400+/-19 mg/kg/day; azathioprine dose=77+/-8 mg/day; basal plasma C-peptide=1.3+/-0.12 ng/mL) and 12 matched CS-treated SPK transplant recipients (prednisone dose=9+/-1 mg/day; basal C-peptide=2.2+/-0.2 ng/mL) by means of the 6,6-2H(2)-glucose infusion and the euglycemic insulin clamp (1 mU/kg/min, insulin infusion rate). In addition, six renal transplant recipients receiving a CS-free regimen were also studied as a control group. RESULTS: In the postabsorptive state, CS-treated SPK transplant recipients demonstrated comparable plasma glucose levels but higher plasma insulin levels than CS-free SPK transplant recipients. Plasma triglyceride levels were significantly higher in CS-treated SPK patients than in CS-free SPK patients (1.16+/-0.16 mg/dL vs. 0.88+/-0.08; P<0.05). High-density lipoprotein and apoprotein A(1) levels were similar in both groups. No difference was observed in pyruvate, lactate, beta-OH-butyrate, and basal endogenous glucose production in all three groups of patients studied. During euglycemic hyperinsulinemia, the inhibition of endogenous glucose production and the stimulation of tissue glucose disposal were not statistically different among the three groups. CONCLUSIONS: SPK recipients receiving chronic low-dose CS maintenance therapy do not present a lower glucose disposal than CS-free recipients. Nonetheless, this is obtained at the expense of a higher endogenous insulin secretion, which can cause an alteration of the triglyceride profile.     

The nutritional/metabolic and hormonal effects of 8 weeks of continuous ambulatory peritoneal dialysis with a 1% amino acid solution

Circulating intermediary metabolites, hormones and plasma amino acids (AA) were measured at intervals over 24 hours in seven non-diabetic patients with chronic renal failure treated by continuous ambulatory peritoneal dialysis (CAPD), before and after an 8-week period during which a 1% amino acid dialysis solution replaced two of the four dextrose exchanges. Mean 24-hour concentrations of plasma total and essential amino acid were higher following the AA dialysate (total pre: 2893 +/- 185; total post: 3357 +/- 244; p less than 0.05; essential pre: 751 +/- 47; essential post: 1064 +/- 57 mumol/l; p less than 0.001). Mean 24-hour concentrations of the branched chain amino acids leucine, isoleucine and valine were higher following the AA dialysate (valine pre: 201 +/- 18; valine post: 321 +/- 19; p less than 0.001; leucine pre: 102 +/- 6; leucine post: 127 +/- 9; p less than 0.01; isoleucine pre: 67 +/- 5; isoleucine post: 85 +/- 7 mumol/l; p less than 0.05). Serum albumin increased with use of the AA dialysate (pre: 36 +/- 1; 2 weeks, 40 +/- 1; 4 weeks, 40 +/- 1; 6 weeks, 41 +/- 1; 8 weeks, 38 +/- 2 g/l). 24-hour profiles and mean 24-hour concentrations of blood glucose, serum insulin, serum triglyceride, plasma non-esterified fatty acids (NEFA), plasma 3-hydroxybutyrate and plasma alanine were unchanged after the AA period. Plasma bicarbonate decreased with use of the amino acid solution (pre: 21 +/- 1; 2 weeks, 18 +/- 1; 4 weeks, 18 +/- 1; 6 weeks, 16 +/- 1; 8 weeks, 16 +/- 1 mmol/l). Use of a 1% amino acid solution over an 8-week period in CAPD patients improves the plasma amino acid profile but results in a metabolic acidosis. The other endocrine and metabolic abnormalities of uremia remain unchanged.     

Apolipoprotein C3 deficiency results in diet-induced obesity and aggravated insulin resistance in mice

Our aim was to study whether the absence of apolipoprotein (apo) C3, a strong inhibitor of lipoprotein lipase (LPL), accelerates the development of obesity and consequently insulin resistance. Apoc3(-/-) mice and wild-type littermates were fed a high-fat (46 energy %) diet for 20 weeks. After 20 weeks of high-fat feeding, apoc3(-/-) mice showed decreased plasma triglyceride levels (0.11 +/- 0.02 vs. 0.29 +/- 0.04 mmol, P < 0.05) and were more obese (42.8 +/- 3.2 vs. 35.2 +/- 3.3 g; P < 0.05) compared with wild-type littermates. This increase in body weight was entirely explained by increased body lipid mass (16.2 +/- 5.9 vs. 10.0 +/- 1.8 g; P < 0.05). LPL-dependent uptake of triglyceride-derived fatty acids by adipose tissue was significantly higher in apoc3(-/-) mice. LPL-independent uptake of albumin-bound fatty acids did not differ. It is interesting that whole-body insulin sensitivity using hyperinsulinemic-euglycemic clamps was decreased by 43% and that suppression of endogenous glucose production was decreased by 25% in apoc3(-/-) mice compared with control mice. Absence of apoC3, the natural LPL inhibitor, enhances fatty acid uptake from plasma triglycerides in adipose tissue, which leads to higher susceptibility to diet-induced obesity followed by more severe development of insulin resistance. Therefore, apoC3 is a potential target for treatment of obesity and insulin resistance.     

Characteristics and transplantation of the porcine neonatal pancreatic cell clusters isolated from 1- to 3-day-old versus 1-month-old pigs

Porcine neonatal pancreatic cell clusters (NPCCs) isolated from 1- to 3-day-old pigs (I-A) cured diabetic nude mice within 8 weeks after transplantation. To shorten the latent period between transplantation and reversal of hyperglycemia, we studied NPCCs isolated from 1-month-old pigs (I-B). One- to 3-day-old or 1-month-old pig pancreata were cut into fragments, digested by collagenase, and then studied for islet characteristics. In addition, 300 cultured NPCCs were transplanted under kidney capsule of nondiabetic nude mice. At 1 and 3 months after transplantation, the grafts were removed to measure the insulin content and beta-cell mass. Immediately after isolation, I-B was larger than I-A (0.211 +/- 0.006 vs 0.189 +/- 0.003 mm(2), P =.0003) and after a 6-day culture period, I-B contained more insulin than I-A (6.8 +/- 1.4 vs 2.3 +/- 0.2 microg/150 NPCCs, P =.02). However, the stimulation indices of I-A and I-B during static incubation with 500 mg/dL glucose (26.5 +/- 3.2 vs 23.9 +/- 1.7) or 500 mg/dL glucose plus 50 mol/L IBMX (41.9 +/- 4.4 vs 62.2 +/- 14.0) were not significantly different. Furthermore, neither I-A nor I-B showed first or second phase insulin secretion during sequential perifusion with 100 or 300 mg/dL glucose. In nondiabetic recipients, the insulin content of the graft at 1 month after transplantation was 0.3 +/- 0.0 and 0.3 +/- 0.1 microg, and the beta-cell mass of the graft at 3 months was 0.069 +/- 0.022 and 0.067 +/- 0.023 mg in mice receiving I-A or I-B, respectively (P >.05). Our data indicate NPCCs isolated from 1- to 3-day-old and 1-month-old pigs have different characteristics but similar transplantation effects.     

Does transrenal fixation of aortic endografts impair renal function?

OBJECTIVES: Transrenal fixation (TFX) of aortic endografts is thought to increase the risk for renal infarction and impaired renal function. We studied the late effects of TFX on renal function and perfusion. METHODS: Of 189 patients with commercial aortic endografts, which we inserted between 1995 and 2002, we reviewed data for 130 patients (112 men, 18 women) with available creatinine (Cr) concentration and contrast enhanced computed tomography (CT) scans preoperatively and 1 to 97 months after the procedure. Of the 130 patients, 69 patients had TFX and 61 patients had infrarenal fixation (IFX). Both groups were physiologically comparable. Average age was 76 +/- 8 years for patients with TFX and 75 +/- 8 years for patients with IFX. Presence of renal infarct or renal artery occlusion was determined by nephrograms on serial contrast-enhanced CT scans. RESULTS: Mean follow-up was 17 +/- 16 months (range, 1-54 months) for TFX and 21 +/- 21 months (range, 1-97 months) for IFX. Mean serum Cr concentration increased significantly during long-term follow-up in both groups (TFX, 1.3 +/- 0.5 mg/dL to 1.5 +/- 0.8 mg/dL, P <.01; IFX, 1.3 +/- 0.7 mg/dL to 1.4 +/- 0.8 mg/dL, P <.03). Creatinine clearance (CrCl) similarly decreased over long-term follow-up in both groups (TFX, 53.3 +/- 17.7 mL/min/1.73 m(2) to 47.9 +/- 16.2 mL/min/1.73 m(2), P <.01; IFX, 58.1 +/- 22.7 mL/min/1.73 m(2) to 53.1 +/- 23.4 mL/min/1.73 m(2), P <.02). There were no significant differences in the increase in Cr concentration (P =.19) or decrease in CrCl (P =.68) between TFX and IFX groups. Small renal infarcts were noted in four patients (5.8%) in the TFX group and one patient (1.6%) in the IFX group. No increase in Cr concentration or decrease in CrCl was noted in any patient with a renal infarct. Postoperative renal dysfunction developed in 7 of 69 patients (10.1%) in the TFX group and 7 of 61 patients (11.5%) in the IFX group. There were no statistically significant differences between groups with respect to number of patients with new renal infarcts (P =.37) or postoperative renal dysfunction (P =.81). CONCLUSION: There is a slight increase in serum Cr concentration and decrease in CrCl after aortic endografting. However, there was no significant difference in these changes between patients with TFX and IFX. Although TFX may produce a higher incidence of small renal infarcts, these do not impair renal function. Thus our midterm results suggest that TFX can be performed safely, with no greater change in renal function than observed after IFX.     

Rosiglitazone reduces glucose-stimulated insulin secretion rate and increases insulin clearance in nondiabetic, insulin-resistant individuals

Compensatory hyperinsulinemia permitting insulin-resistant individuals to maintain normal glucose tolerance is associated with a left shift in the glucose-stimulated insulin secretion rate (GS-ISR) dose-response curve and decrease in the insulin metabolic clearance rate (I-MCR). To see whether these changes would reverse with improvement in insulin sensitivity, 14 nondiabetic insulin-resistant subjects received rosiglitazone for 12 weeks (4 mg daily for 4 weeks and then 8 mg daily for 8 weeks). Insulin-mediated glucose uptake was quantified by measuring the steady-state plasma glucose concentration during the insulin suppression test. GS-ISR and I-MCR were determined during a 240-min graded intravenous glucose infusion. I-MCR was also calculated during the insulin suppression test. After rosiglitazone treatment, insulin sensitivity improved with significant fall in steady-state plasma glucose (means +/- SE from 13.5 +/- 0.62 to 9.8 +/- 1.02 mmol/l, P < 0.001). In response, the integrated GS-ISR decreased by 21% (P < 0.001), with a right shift in the dose-response curve. Calculated I-MCR increased by 34% (P = 0.008) during the insulin suppression test and by 21% (P = 0.03) during the graded glucose infusion. In conclusion, enhanced insulin sensitivity in rosiglitazone-treated nondiabetic insulin-resistant individuals was associated with a shift to the right in the GS-ISR dose-response curve and an increase in I-MCR.