Insulin resistance precedes microalbuminuria in patients with insulin-dependent diabetes mellitus

Background. Insulin resistance has been associated with hypertension and with renal complications in patients with type 1 diabetes mellitus. Causal relationships have not been fully explained. Methods. We investigated whether insulin resistance precedes microalbuminuria by measuring insulin resistance with a euglycaemic clamp in combination with indirect calorimetry in 16 uncomplicated type 1 diabetic patients and in six healthy control subjects. The patients had over 10 year duration of diabetes, and were expected to experience either a complication-free or complicated disease course within the next few years. They have thereafter been followed for the development of microalbuminuria for 3 years. Results. In a euglycaemic insulin clamp glucose disposal was lower in diabetic patients compared with control subjects (7.5±2.9 and 12.6±2.0 mg/kg LBM/min; P<0.002), mainly due to impaired glucose storage (4.3±2.3 vs 8.6±1.6 mg/kg LBM/min; P<0.001). Three years later seven IDDM patients had albumin excretion rate over 30 mg/24 h; glucose disposal (5.5±2.1 vs 9.0±2.2 mg/kg LBM/min; P<0.01) had been lower in patients who developed microalbuminuria compared with those who remained normoalbuminuric. Conclusions. Insulin resistance predicts the increment in urinary albumin excretion. Insulin resistance depends mainly on impaired glucose storage in uncomplicated IDDM.     

Portal Versus Systemic Venous Drainage of the Pancreatic Graft: The Effect on Glucose Metabolism in Pancreas and Kidney Transplant Recipients

Two different methods of graft venous drainage are used in pancreas transplantation: portal (PVD) and systemic (SVD). PVD is considered to be more physiologic due to its similarity to venous outflow of the native pancreas. The aim of our study was to compare glucose metabolism in Type 1 diabetic recipients of kidney and pancreatic grafts with PVD versus SVD by intravenous glucose tolerance test (IVGTT). We examined 28 insulin-independent patients after simultaneous pancreas and kidney transplantation: 14 recipients with PVD of the pancreatic graft and 14 with SVD after a mean post-transplant period of 1 year. All recipients had stable good function of the kidney graft. Fasting glycemia, insulin levels, glycosylated hemoglobin (HbA1c), and standard IVGTT with coefficient of glucose assimilation (K_G) calculation were assessed. Insulin sensitivity and production were evaluated using the homeostasis model assessment (homeostasis model assessment of insulin resistance [HOMA-IR], homeostasis model assessment of B-cell function [HOMA-B]). Total C-peptide and insulin secretions were calculated as areas under the curves (AUCs) from the serum levels during the IVGTT. PVD and SVD groups did not differ in age, body mass index (BMI) and duration of post-transplantation period (P ≥ .05). We did not find any significant difference in fasting glycemia, HbA1c, K_G, HOMA-IR, parameters of C-peptide level, fasting insulin level, and response during IVGTT. HOMA-B and AUC of insulin level were higher in the SVD group (45.1 ± 35.1 versus 19.8 ± 15.5, P =.03 and 1075 ± 612 versus 1799 ± 954 mIU/L/60 minutes, P < .03, respectively). In the PVD group, 1 patient had an abnormal response to the glucose stimulus, 8 patients had an impaired glucose tolerance, and 5 patients had a normal glucose tolerance. In the SVD group, an abnormal response was present in none, impaired glucose tolerance in 4, and normal glucose tolerance in 10 recipients. Athough this was not a prospectively randomized trial, we conclude that the change of surgical technique from SVD to PVD did not lead to any substantial change in terms of glucose tolerance.     

Glucose intolerance in renal transplant recipients is associated with increased urinary albumin excretion

ObjectiveNew-onset diabetes mellitus after transplantation (NODAT) is a common and serious complication of renal transplantation, and its incidence is known to be increased by immunosuppressive therapy. It has been reported that urinary albumin excretion is a potent predictor of NODAT. This study was conducted to investigate the relationship between glucose intolerance and urinary albumin excretion in renal transplant recipients.MethodsA cross-sectional study of 101 renal transplant recipients without prior evidence of diabetes was conducted. All patients underwent an oral glucose tolerance test with 75 g of glucose.ResultsThe patients with glucose intolerance had a significantly greater urinary albumin excretion than those with normal glucose tolerance. Multivariate logistic regression analysis revealed that the increase of urinary albumin excretion correlated significantly with the homeostasis model assessment of insulin resistance and systolic pressure.ConclusionThese results indicated that glucose intolerance is associated with increased albuminuria in renal transplant recipients. The rise in insulin resistance and systolic pressure may contribute to the increase of urinary albumin excretion in renal transplant recipients.     

Short-term treatment with rosiglitazone improves glucose tolerance, insulin sensitivity and endothelial function in renal transplant recipients.

BACKGROUND: Insulin resistance (IR) contributes to the development of glucose intolerance (post-transplant diabetes mellitus or impaired glucose tolerance) following renal transplantation. Furthermore, endothelial dysfunction (ED) is associated with IR. Glucose intolerance, IR and ED are all independent risk factors for cardiovascular disease. Therefore, treatment with insulin sensitizers may benefit glucose-intolerant renal transplant recipients. The main objectives of the present study were to investigate the effect of 4 weeks' treatment with the PPAR-gamma agonist rosiglitazone on insulin sensitivity, plasma glucose and endothelial function in renal transplant recipients with glucose intolerance. Safety parameters were also addressed. METHODS: A total of 10 glucose-intolerant renal transplant recipients were treated with rosiglitazone (initially 4 mg/day increasing to 8 mg/day after 1 week). A hyperinsulinaemic euglycaemic glucose clamp, an oral glucose tolerance test and endothelial function assessment with laser Doppler flowmetry were performed both at baseline and at follow-up. RESULTS: Treatment with rosiglitazone was followed by a significantly improved mean glucose disposal rate (from 6.5 to 9.1 g/kg/min; P = 0.02) and a significant decline in fasting and 2 h plasma glucose (from 6.4 to 5.8 mmol/l, P = 0.01 and from 14.2 to 10.6 mmol/l, P = 0.03, respectively). Furthermore, a significant improvement in endothelial function was demonstrated (AUC(ACh); from 389 to 832 AU x min, P = 0.04). No serious adverse events or hypoglycaemic episodes were observed. CONCLUSIONS: Four weeks' treatment with rosiglitazone was associated with increased insulin sensitivity, lowered fasting and 2 h plasma glucose and improved endothelial function in renal transplant recipients with glucose intolerance. The drug was well tolerated and may be a good alternative for treating these patients.     

A 6-year prospective study on new onset diabetes mellitus, insulin release and insulin sensitivity in renal transplant recipients.

BACKGROUND: It is well known that both insulin resistance and insulin deficiency are involved in the pathogenesis of post-transplant diabetes mellitus (PTDM), but the relative importance of the two different mechanisms is still under debate. The present prospective longitudinal study was performed over 6 years to investigate the impact of impaired insulin secretion (ISec) and insulin sensitivity (IS) in the development of PTDM in renal transplant recipients. METHODS: A total of 95 non-diabetic patients underwent a 75 g oral glucose tolerance test (OGTT) 10 weeks post-transplant. Six years later, 63 of these recipients were re-examined, the majority (n = 58) with an OGTT. Fasting, 1- and 2-h insulin and glucose levels were measured and used to estimate the insulin secretory response and IS both at baseline and at follow-up. RESULTS: The proportion of recipients with normal glucose tolerance (NGT) rose from 46% (baseline) to 65% (follow-up) (P = 0.008), and median fasting and 2-h serum glucose were reduced by 0.7 mmol/l (P < 0.001) and 1.3 mmol/l (P = 0.039), respectively. The recipients with PTDM at follow-up had a significant decline in the estimated median first and second phase ISec (-58 and -47%, respectively, P = 0.005 for both). The patients who normalized their glucose tolerance from PTDM or IGT at baseline to NGT at follow-up increased their IS significantly (68%, P = 0.002) without significant alterations in ISec. CONCLUSIONS: Impaired ISec seems to be the dominant mechanism in the development of PTDM after renal transplantation. In contrast, normalization of glucose intolerance is associated with improved IS.     

The dynamics of glucose metabolism under calcineurin inhibitors in the first year after renal transplantation in nonobese patients

BACKGROUND: The incidence of glucose metabolism disturbances after transplantation often is based on the use of hypoglycemic agents and not on the results of glucose tolerance tests (GTTs), which may camouflage the real incidence. A lack of information also exists regarding the profile of glucose metabolism during the first year after transplant. METHODS: Oral GTT along with insulin measurements and drugs pharmacokinetics were prospectively performed at days 30, 60, 180, and 360 after transplant to diagnose disturbances of glucose metabolism after renal transplantation, in nonobese patients receiving either tacrolimus (n=55) or cyclosporine (n=29), along with mycophenolate mofetil and steroids. RESULTS: The incidence of impaired glucose tolerance or diabetes mellitus reached a peak at 60 days and decreased at 1 year. It could not be adequately diagnosed using fasting plasma glucose in a decreased abnormal (>99 ng/mL) range. In both groups, insulin secretion, evaluated by the Homeostasis Model Assesment (HoMA-beta), decreased (P<0.005) from the condition of normal GTT (101+/-56%) to impaired glucose tolerance (72+/-35%) and diabetes mellitus (54+/-25%). In the cyclosporine group, insulin secretion was normal and stable throughout the study period, but in the tacrolimus group, insulin secretion recovered over time and was inversely correlated with tacrolimus exposure. Insulin resistance (HoMA-IR) did not change. CONCLUSIONS: This study shows the need to perform an oral GTT at 60 days and at the end of the first year of renal transplantation to adequately diagnose impaired glucose metabolism.     

Risk factors for the development of new-onset diabetes mellitus in a living related renal transplant program

New-onset diabetes mellitus is associated with considerable morbidity after transplantation. We evaluated 78 living related renal transplant recipients due to all causes except diabetic nephropathy a waiting a living related renal transplantation. We evaluated demographic characteristics, pretransplant glycemic profile, fasting C-peptide levels, plasma insulin levels, pretransplant insulin resistance, and immunosuppression protocols. Among the 16.7% of patients developing diabetes mellitus at the end of 1 year, age, family history, and impaired glucose tolerance at the time of transplantation corelated with the development of diabetes mellitus in the posttransplant period.     

The impact of impaired insulin release and insulin resistance on glucose intolerance after renal transplantation

The current knowledge of the pathogenesis of post-transplant glucose intolerance is sparse. This study was undertaken to assess the relative importance of insulin secretion (ISec) and insulin sensitivity (IS) in the pathogenesis of post-transplant diabetes mellitus (PTDM), impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) after renal transplantation. An oral glucose tolerance test (OGTT) was performed in 167 non-diabetic recipients 10 wk after renal transplantation. Fasting, 1-h and 2-h insulin and glucose levels were used to estimate the insulin secretory response and IS. One year after transplantation 89 patients were re-examined with an OGTT including measurements of fasting and 2 h glucose. Ten weeks after transplantation the PTDM-patients had significantly lower ISec and IS than patients with IGT/IFG, who again had lower ISec and IS than those with normal glucose tolerance (NGT). One year later, a similar difference in baseline ISec was observed between the three groups, whereas baseline IS did not differ significantly. Patients who improved their glucose tolerance during the first year, were mainly characterized by a significantly greater baseline ISec, and they received a significantly higher median prednisolone dose at baseline with a subsequent larger dose reduction during the first year, than the patients who had their glucose tolerance unchanged or worsened. In conclusion, both impaired ISec and IS characterize patients with PTDM and IGT/IFG in the early course after renal transplantation. The presence of defects in insulin release, rather than insulin action, indicates a poor prognosis regarding later normalization of glucose tolerance.     

Minimal model analysis in nondiabetic renal transplant recipients with hepatitis C

INTRODUCTION: Epidemiological data suggest that hepatitis C virus (HCV) infection may contribute to the development of posttransplantation diabetes mellitus (PTDM). METHODS: We investigated the glucose metabolism in 19 renal transplant recipients with antiHCV antibodies and without DM according to World Health Organization criteria before or after transplantation. We measured insulin sensitivity (SI), glucose effectiveness (SG), and pancreatic insulin response using the frequently sampled intravenous glucose tolerance test (FSIGTT). SI and SG were estimated using the Bergman minimal model method and pancreatic insulin response was expressed as the area under insulin curve (AUIC) between 0 and 19 minutes. RESULTS: Impaired glucose tolerance was shown in 42% of patients, some (31.5%) in the range of glucose intolerance (KG: 1-1.5) and others (10.5%) in the diabetes range (KG < 1). SI and SG were decreased in 39% and 63% of patients, respectively. Pancreatic insulin response revealed high variation among patients although showing a tendency to be enhanced. CONCLUSIONS: A high number of HCV-positive renal transplant recipients without clinically manifest PTDM have impaired glucose tolerance, which suggests the future development of diabetes in these patients.     

Predictability and other aspects of post-transplant diabetes mellitus in heart transplant recipients.

BACKGROUND: Diabetes mellitus that develops after organ transplantation may predispose patients to further complications. We studied the value of pre-transplant oral glucose tolerance testing or maximum random plasma glucose, and HLA-DR3 and/or DR4 phenotype as predictors of post-transplantation diabetes mellitus in heart transplant recipients. PATIENTS AND METHODS: In 228 cardiac allograft recipients (median age, 50 years; mean follow-up, 4.77 years), we used either pre-transplant oral glucose tolerance testing results (Group I, n = 141)-excluding patients with pre-existing diabetes (n = 9)--or maximum random plasma glucose values (Group II, n = 78) to study predictability of post-transplant diabetes. In addition, we investigated its relation to rejection treatment and clinical course. RESULTS: Cumulative incidence of post-transplant diabetes (n = 43) was 19.6%, 83% of which became manifest within 3 months post-transplant; pre-transplant body mass index was higher (p < 0.01) in this group. Mortality did not increase. Of 123 patients in Group I who survived > 3 months, post-transplant diabetes occurred in 32% vs 16% of those with impaired and normal glucose tolerance respectively (ns), and in 55% of patients with isolated post-load hyperglycemia (p < 0.05 vs normal). Maximum random glucose values (Group II) did not predict post-transplant diabetes. Prevalence of the HLA-DR3, DR4, and DR3DR4 phenotypes did not increase in post-transplant diabetes; relation to rejection treatment was likely in 30%. Approximately 50% of posttransplant diabetes patients required only temporary drug treatment. CONCLUSIONS: The risk of post-transplant diabetes increased parallel to pre-transplant degree of glucose intolerance, but was considerable even in normal glucose tolerance. HLA-DR3 and/or DR4 phenotype was not a predisposing factor.     

Metabolic cardiovascular syndrome after renal transplantation.

BACKGROUND: Cardiovascular disease (CVD) is the major cause of death in renal transplant recipients. Traditional risk factors like hypertension, dyslipidaemia and diabetes mellitus are common, but cannot completely account for the high prevalence of CVD in this population. The aim of the present study was to assess whether post-transplant glucose intolerance, defined as post-transplant diabetes mellitus, impaired glucose tolerance, or impaired fasting glucose, is associated with metabolic disturbances known to increase risk of cardiovascular disease, similar to what has been observed in the general population. METHODS: One hundred and seventy-three consecutive patients were prospectively examined 10 weeks after transplantation. An oral glucose tolerance test was completed in 167 patients. Questionnaires, medical records, and the results of various blood tests were used to evaluate a number of known cardiovascular risk factors in all patients. RESULTS: Glucose intolerance was present in about one-half the recipients and was associated with age, a positive family history of ischaemic heart disease, acute rejection, higher levels of serum triglycerides, apolipoprotein B and 2-h insulin, and lower levels of serum HDL cholesterol. After adjustment for age and sex, lower HDL cholesterol (P=0.005), higher serum triglycerides (P<0.001), apolipoprotein B (P=0.039) and 2-h insulin (P<0.001) were still associated with post-transplant glucose intolerance. CONCLUSIONS: Ten weeks after renal transplantation glucose intolerance is associated with a clustering of cardiovascular risk factors and metabolic abnormalities, consistent with a post-transplant metabolic cardiovascular syndrome.     

Glucose metabolism in the first 3 years after renal transplantation in patients receiving tacrolimus versus cyclosporine-based immunosuppression.

The long-term effects of tacrolimus and cyclosporine on pancreatic islet cell function in renal transplant recipients are unclear. Therefore, a prospective, randomized, longitudinal study was performed that compared glucose metabolism in adult kidney allograft recipients on tacrolimus versus cyclosporine-based immunosuppression. Twenty-three white renal allograft recipients, randomized for either therapy with cyclosporine or tacrolimus, underwent intravenous glucose tolerance tests 6 times during the first 3 yr after transplantation. Concomitant therapy (low-dose steroids and azathioprine) was the same in both groups. Insulin sensitivity index (kG), insulin resistance (insulin/glucose ratio and homeostasis model assessment), and C-peptide and insulin secretion were calculated. Trough levels of tacrolimus and cyclosporine were measured. The occurrence of posttransplantation diabetes mellitus was prospectively monitored. Statistical analysis was performed by ANOVA for repeated measures, and parametric and nonparametric tests were also performed. Although only one patient treated with cyclosporine developed posttransplantation diabetes mellitus, kG levels were below normal in up to one-third of both patients who received tacrolimus and cyclosporine. The only significant difference between patients who received tacrolimus and those who received cyclosporine was in pancreatic secretion capacity at week 3 after transplantation, when the increment of C-peptide secretion was 57% lower and the increment of insulin secretion was 48% lower for patients receiving tacrolimus. In both groups, from week 3 to month 6, there was a tendency toward an increase in kG, despite a significant increase in fasting glucose and insulin resistance calculated by homeostasis model assessment. After month 6, there were no significant changes in any of the parameters of glucose metabolism, indicating that long-term use of either tacrolimus or cyclosporine does not cause chronic, cumulative pancreatic toxicity.     

Visceral fat is strongly associated with post‐transplant diabetes mellitus and glucose metabolism 1 year after kidney transplantation

Body composition after kidney transplantation is linked to glucose metabolism, and impaired glucose metabolism is associated with increased risk of cardiovascular events and death. One year after transplantation, we examined 150 patients for post‐transplant diabetes performing oral glucose tolerance tests and body composition measurements including visceral adipose tissue (VAT) content from dual‐energy X‐ray absorptiometry scans. We found that glucose metabolism was generally improved over the first year post‐transplant, and that the levels of VAT and percentage VAT of total body fat mass (VAT_%totBFM) were lowest in those with normal glucose tolerance and highest in those with post‐transplant diabetes mellitus. In a multivariable linear regression analysis, 87.4% of the variability in fasting glucose concentration was explained by insulin resistance (P<.001, HOMA‐IR index), beta cell function (P<.001, HOMA‐beta), VAT_%totBFM (P=.007), and body mass index (BMI; P=.015; total model P<.001), while insulin resistance (P<.001) and beta cell function (P<.001) explained 31.9% of the variability in 2‐hour glucose concentration in a multivariable model (total model P<.001). VAT was associated with glucose metabolism to a larger degree than BMI. In conclusion, VAT is associated with hyperglycemia one year after kidney transplantation, and insulin resistance and beta cell function estimates are the most robust markers of glucose metabolism.     

Calcineurin inhibitor effects on glucose metabolism and endothelial function following renal transplantation

Abstract: Background:  Calcineurin inhibitors (CNI) are involved in the development of post-transplant diabetes mellitus (PTDM). Changes in insulin secretion and sensitivity contribute to the development of PTDM and are associated with endothelial function.
Methods:  In a pre-defined substudy of a previously published randomized trial in renal transplant recipients we compared the effect of CNI treatment (n = 23) with complete CNI-avoidance (n = 21) on insulin secretion and sensitivity (oral glucose tolerance test) as well as endothelial function (laser Doppler flowmetry), 10 wk and 12 months following transplantation.
Results:  Insulin sensitivity differed 10 wk post-transplant and was significantly better after 12 months in patients never treated with CNI drugs [0.091 (0.050) vs. 0.083 (0.036) μmol/kg/min/pmol/L, p = 0.043]. Insulin secretion tended to be higher in CNI treated patients at both time points (p = 0.068). Endothelial function was not significantly different at week 10 [540 (205) vs. 227 (565) arbitary units × minutes, p = 0.35] or month 12 [510 (620) vs. 243 (242), p = 0.33].
Conclusions:  Findings in the present study indicate that long-term CNI treatment negatively affects glucose metabolism and this may contribute to the increased risk for premature cardiovascular disease in CNI treated renal transplant recipients. Further studies to elucidate this hypothesis are, however, needed.     

Syngeneic transplantation of fetal rat pancreas. I. Effect of insulin treatment of the reversal of alloxan diabetes.

Sixty-nine alloxan-diabetic male Fischer rats received syngeneic transplants of eight 18-days-postcoitum fetal pancreases at the renal subcapsular site. One half of the recipients were given 2 to 4 U. protamine-zinc insulin for seven days immediately after transplantation. This insulin-treatment regimen effectively normalized blood glucose rapidly. Forty-seven transplant recipients survived, and diabetes was reversed in all. Insulin treatment had no effect on recovery time or glucose tolerance. Those animals requiring longer periods to reach normoglycemia had impaired glucose tolerance. Some insulin-treated recipients returned to normoglycemia rapidly while others required an extended period. Those animals that showed rapid reversal exhibited elevated concentrations of plasma insulin both in the fasting state and during glucose tolerance tests. No pretransplant parameters could be identified as predictors of rapid reversal.     

Insulin resistance and insulin deficiency in the pathogenesis of posttransplantation diabetes in man.

Although steroids can induce insulin resistance, it is not known whether additional defects in insulin secretion are necessary for the development of diabetes. To address this question, we measured insulin sensitivity (euglycemic insulin clamp in combination with indirect calorimetry and infusion of tritiated glucose) and insulin secretion (hyperglycemic clamp) in three groups of subjects: (1) 10 kidney transplant patients with normal oral glucose tolerance, (2) 14 patients who developed diabetes after kidney transplantation, and (3) 10 healthy controls. Glucose utilization, primarily storage of glucose as glycogen, was reduced by 34% in kidney transplant patients with normal glucose tolerance when compared with healthy control subjects (18.2 +/- 2.9 vs. 27.5 +/- 2.7 microM/L; P less than 0.05). Insulin secretion was normal in relation to the degree of insulin resistance in transplanted non-diabetic patients, thus maintaining a normal oral glucose tolerance. Development of transplantation diabetes was associated with only minor further deterioration of glucose storage (14.7 +/- 2.7 microM/L; P less than 0.001 vs. control subjects), whereas first-phase, second-phase, and glucagon-stimulated insulin secretion measured during hyperglycemic clamping (incremental area under the insulin curve 287 +/- 120, 1275 +/- 419, and 3515 +/- 922 pM) became impaired as compared with nondiabetic kidney transplant patients (769 +/- 216, 3084 +/- 545, and 6293 +/- 533 pM; P less than 0.05). We conclude that both insulin resistance and insulin deficiency are necessary for the development of diabetes in kidney transplant patients.     

Role of insulin resistance indices in predicting new‐onset diabetes after kidney transplantation

New‐onset diabetes mellitus (NODAT) is a serious complication following renal transplantation. In this cohort study, we studied 118 nondiabetic renal transplant recipients to examine whether indices of insulin resistance and secretion calculated before transplantation and at 3 months post‐transplantation are associated with the development of NODAT within 1 year. We also analysed the long‐term impact of early diagnosed NODAT. Insulin indices were calculated using homeostasis model assessment (HOMA) and McAuley's Index. NODAT was diagnosed using fasting plasma glucose. Median follow‐up was 11 years. The cumulative incidence of NODAT at 1 year was 37%. By logistic regression, recipient age (per year) was the only significant pretransplant predictor of NODAT (OR 1.04, CI 1.009–1.072), while age (OR 1.04, CI 1.005–1.084) and impaired fasting glucose (OR 2.97, CI 1.009–8.733) were significant predictors at 3 months. Pretransplant and 3‐month insulin resistance and secretion indices did not predict NODAT. All‐cause mortality was significantly higher in recipients developing NODAT within 1 year compared with those remaining nondiabetic (44% vs. 22%, log‐rank P = 0.008). By Cox's regression analysis, age (HR 1.075, CI 1.042–1.110), 1‐year creatinine (HR 1.007, CI 1.004–1.010) and NODAT within 3 months (HR 2.4, CI 1.2–4.9) were independent predictors of death. In conclusion, NODAT developing early after renal transplantation was associated with poor long‐term patient survival. Insulin indices calculated pretransplantation using HOMA and McAuley's Index did not predict NODAT.     

The influence of hyperinsulinaemia on calcium-phosphate metabolism in renal failure

Background. Patients with renal failure are characterized by impaired insulin-mediated glucose uptake. Insulin plays a major role in the maintenance of phosphate homeostasis but it remains to be determined whether in uraemia insulin-dependent renal and extrarenal phosphate disposal is also affected. Methods. The effects of hyperinsulinaemia on serum concentrations of phosphate, ionized calcium and intact PTH as well as renal excretion of calcium and phosphate was studied under euglycaemic conditions (glucose clamp technique) in patients with advanced renal failure and in healthy subjects. Fifteen patients with renal failure (mean serum creatinine 917 &mgr;mol/l) and 12 control subjects were included. All subjects underwent a 3-h euglycaemic clamp with constant infusion of insulin (50 mU/m²/min) following a priming bolus. The urine was collected for 3 h before and throughout the clamp. Results. The tissue insulin sensitivity (M/I) was lower in patients with renal failure than in control subjects (5.3±2.4 vs 6.7±1.8 mg/kg/min per mU/ml, P=0.001) but the phosphate lowering action of insulin was larger in patients with renal failure than in control subjects. Urinary calcium excretion increased (P<0.05) and phosphate excretion did not change during the clamp in both groups. Despite a decrease of serum ionized calcium in the group of patients with renal failure and no change in the control group, plasma PTH fell significantly in both groups but this effect was still significant after 180 min only in the renal failure group. A significant correlation was observed between changes in serum phosphate and PTH induced by hyperinsulinaemia (r=0.48, P<0.01). Conclusions. Phosphate-lowering effect of insulin is well preserved in severe renal failure despite the resistance to insulin-stimulated glucose uptake. The decrease of serum PTH observed during hyperinsulinaemia appears to be independent of serum ionized calcium.     

Post-transplant diabetes mellitus: risk factors, frequency of transplant rejections, and long-term prognosis

Background Estimates of the incidence of new-onset diabetes after renal transplantation vary between 2% and 54%. It was the aim of the present trial to study the prevalence of post-transplant diabetes mellitus (DM), the risk factors, the frequency of transplant rejections, and the long-term prognosis.Methods We studied all consecutive patients with endstage renal disease, but without DM who received kidney transplantation at our center since 1992 (n = 253; age, 52.2 ± 12.6 years; body mass index, 22.0 ± 7.9 kg/m²). Follow up was 3.3 ± 1.6 years (range, 0.1–17.7) years.Results In total, 43/253 patients (17%) developed new-onset DM after transplantation. Patients with new-onset diabetes were significantly older (58.3 ± 11.4 vs 50.9 ± 12.5 years; P < 0.01) and had a tendency to a higher body mass index (24.0 ± 8.5 vs 21.6 ± 7.8 kg/m²; P = 0.077). There were no differences between the groups in respect of blood pressure control (137.7 ± 19.0/81.8 ± 14.2 vs 137.1 ± 21.9/83.9 ± 13.1 mmHg; P = 0.89/0.39), glomerular filtration rate (58.0 ± 28.1 vs 64.1 ± 22.1 ml/min per 1.73 m²; P = 0.13), steroid dosage (4.5 ± 1.2 [n = 21] vs 4.6 ± 2.2 [n = 135] mg/day; P = 0.13), or the frequency and dosage of immunosuppressive drugs such as cyclosporine, tacrolimus, and sirolimus during the follow up. However, more patients with post-transplant diabetes received steroids (83.7% vs 64.3%; P = 0.021) and azathioprine (41.9% vs 24.3%; P = 0.030). Patients with new-onset diabetes had higher serum creatinine values (163.4 ± 67.9 vs 138.7 ± 59.5 µmol/l; P = 0.017). The mean hemoglobin (Hb)A1c in patients with DM was 6.28 ± 1.29% (Tosho HPLC; mean normal, 5.15%). In 18 patients (7.1%) transplant rejections occurred (16 patients without DM [7.6%] vs 2 patients with new-onset DM [4.7%]; P = 0.39). On performing multivariate analysis, the only parameter found to be associated with new-onset DM was the body mass index (R² = 0.05; β = 0.23; P = 0.02), and the only factor associated with transplant rejection was fasting blood glucose (R² = 0.07; β = 0.28; P = 0.02). None of the other parameters included in the models (age, duration after transplantation, diabetes duration, immunosuppressive therapy, HbA1c, HLA mismatches) showed any associations.Conclusions The prevalence of new-onset DM after renal transplantation was 17%. The most important parameter associated with new-onset diabetes was a higher body mass index, and the most important parameter associated with transplant rejection was an elevated fasting blood glucose level. To prevent transplant rejections and to improve patients’ outcome, in addition to providing optimal immunosuppressive therapy and HLA matching, good blood pressure control and HbA1c, but also near normal fasting blood glucose levels, should be achieved.     

New-onset diabetes after transplantation in tacrolimus-treated, living kidney transplantation: long-term impact and utility of the pre-transplant OGTT

Background

To evaluate the role of the oral glucose tolerance test (OGTT) before transplantation and to examine the risk factors for new-onset diabetes after transplantation (NODAT) during long-term follow-up of renal transplant recipients receiving FK-based therapy.

Methods

The study evaluated 378 patients pre-transplantation using the OGTT and assigned them to one of three groups: Group 1, normal pattern; Group 2, impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) pattern (IFG/IGT); and Group 3, DM pattern.

Results

Although the incidence of NODAT was higher in Group 3 than in groups 1 and 2, no significant difference was found between the three groups with regard to graft survival during long-term follow-up. Multivariate analysis showed that only a family history of diabetes was a significant factor determining NODAT progression.

Conclusions

Impaired glucose tolerance appears to be a threshold influencing NODAT; however, it was not a significant factor in graft survival. Careful monitoring and management based on the result of the pre-transplantation OGTT appear to prevent the deterioration of impaired glucose tolerance in renal transplant recipients receiving FK-based therapy, even when a pre-operative OGTT shows impaired glycemic control.