1Department of Medicine, Section of Nephrology and 2Department of Clinical Chemistry, Rikshospitalet, Oslo, Norway
Correspondence and offprint requests to: Monica Hagen, Department of Medicine, Section of Nephrology, Laboratory for Renal Physiology, Rikshospitalet, 0027 Oslo, Norway. Email: monica.hagen{at}rikshospitalet.no
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
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.
Keywords: insulin release; insulin sensitivity; post-transplant diabetes mellitus; renal transplantation
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Impaired insulin secretion (ISec) and peripheral insulin resistance have both been identified as potential mechanisms in the pathogenesis of PTDM. It has been argued that the former may be more important than the latter [6]. We have shown recently that defects in insulin release as assessed 10 weeks after renal transplantation indicate a poor prognosis regarding normalization of glucose tolerance during the following year [7]. Moreover, in non-transplanted type 2 diabetics, like the Pima Indians, worsening of glucose tolerance from normal glucose tolerance (NGT) to IGT, and from IGT to diabetes mellitus, is accompanied by a progressive decline in the acute insulin secretory response and an increase in body weight [8]. In contrast, the subjects who remain normoglycaemic over time are characterized by maintained acute insulin response and glucose disposal.
Long-term studies of renal transplant patients are scarce, still questioning whether PTDM may persist over several years in these patients, and whether late-onset diabetes may develop in the individuals who are normoglycaemic shortly after transplantation. The objectives of the present single-centre prospective observational study were first, to assess the glucose tolerance and the occurrence of PTDM in a group of renal transplant recipients over a period of 6 years after transplantation. Secondly, we tested the hypothesis of whether impaired insulin release is more important than insulin resistance in the development of PTDM.
![]() |
Subjects and methods |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
Stratification of the patients
The recipients were divided into different categories of glucose tolerance according to the criteria given by the Expert Committee [4]: PTDM with fasting serum glucose 7.0 mmol/l or 2-h serum glucose
11.1 mmol/l; IGT with fasting glucose <7.0 mmol/l and 2-h glucose 7.811.0 mmol/l; impaired fasting glucose (IFG) with fasting glucose 6.16.9 mmol/l and 2-h glucose <7.8 mmol/l; and NGT with fasting serum glucose <6.1 mmol/l and 2-h serum glucose <7.8 mmol/l.
Immunosuppressive therapy
Ten weeks after renal transplantation, all patients (n = 63) were treated with prednisolone and cyclosporin A (CsA) (Sandimmun Neoral®), and 81% with azathioprine. During the follow-up period, six recipients were switched to tacrolimus and two to mycophenolate mofetil, and three patients had their prednisolone treatment withdrawn. Excluding the subjects who changed immunosuppressive therapy from the statistical analyses did not change the overall findings.
Analytical procedures
The analysis of baseline serum glucose was performed using a glucose dehydrogenase method (Cobas Mira, Roche, Switzerland). At follow-up, whole blood glucose was measured with a HemocueAB® B-glucose Analyser (Angelholm, Sweden) in 54 recipients, whereas glucose was analysed in venous serum directly in nine recipients. Whole blood glucose values were recalculated to venous serum values [9].
Serum insulin was determined by a commercial radioimmunoassay (Coat-A-CountTM, Diagnostic Products Corporation, Los Angeles, CA) at baseline and by a fluoroimmunoassay (Auto DELFIATM Insulin, Wallac Oy, Turku, Finland) at follow-up. Creatinine clearance was calculated according to the Cockcroft and Gault formula [10].
Insulin release and sensitivity indices
Insulin release was estimated by the use of three OGTT-derived indices. These equations have been validated in patients with varying degrees of glucose tolerance and correlate well with the results from hyperglycaemic clamp studies [11,12].
Using the trapezoid rule, the area under the curve (AUC) insulin and the AUC glucose during the OGTT were calculated and implemented in the insulin release index: SecrAUC = AUCIns/AUCGluc [11,12]. The first and second phase insulin release were estimated according to the following equations: Secr1.phase = 1194 + 4.724 x Ins0 117.0 xGluc1 + 1.414 x Ins1; Secr2.phase = 295 + 0.349 x Ins1 25.72 xGluc1 + 1.107 x Ins0, where Ins0 and Ins1 are serum insulin levels at 0 and 1 h after an OGTT, respectively, and Gluc1 represents serum glucose 1 h post-load [12].
The OGTT-derived insulin sensitivity (IS) index [ISITX =0.208 0.0032 x body mass index (BMI) 0.0000645 x Ins2 0.00375 x Gluc2], which is a modification of the IS index proposed by Stumvoll et al. [12], was implemented as the surrogate estimate of IS [11,13]. The ISITX has recently been validated in renal transplant recipients and correlated closely with the results from hyperinsulinaemic euglycaemic clamp (r = 0.58, P < 0.001) [13].
Statistical analyses
Results are given as median and range. For continuous data, the MannWhitney or the Wilcoxon matched pairs signed rank sum test was used, whereas Pearson 2 or McNemars test was implemented for categorical data as appropriate. Linear regression was implemented in the analysis of potential independent continuous variables, with 2-h serum glucose or IS as the dependent variables. Multiple linear regression was used to assess any independent predictor of change in glucose tolerance or IS. All variables associated with 2-h serum glucose or IS in the univariate analyses with P-values <0.1 were included in the multiple regression model. Two tailed P-values are reported, and values <0.05 considered significant. The analyses were performed using the Statistical Package for the Social Sciences (SPSS version 10.0 for Windows, Chicago, IL).
![]() |
Results |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
None of the five recipients who improved their glucose tolerance from PTDM to either IGT (n = 1) or NGT (n = 4) were on glucose-lowering drugs at baseline.
One recipient, who deteriorated from IGT to PTDM, was on a combination treatment with insulin and metformin at follow-up.
None of the recipients who were using hypoglycaemic therapy at follow-up went through the OGTT.
Insulin secretion (ISec) and insulin sensitivity (IS)
Calculated indices of ISec and IS for all recipients are given in Table 2. All the indices of ISec were significantly reduced 6 years after renal transplantation (Secr1.phase, P < 0.001; Secr2.phase, P < 0.001; SecrAUC, P < 0.001), whereas median IS increased significantly (ISITX, P = 0.033).
|
None of these parameters were associated with changes in ISec.
Association of changes in ISec and IS with
changes in glucose tolerance 6 years after
renal transplantation
To assess the relative importance of ISec and IS on changes in glucose tolerance during the follow-up, the recipients were divided into two groups (Table 3). The group of patients who had PTDM at follow-up (n = 14) was labelled diabetic. The group of recipients who normalized their glucose tolerance, from PTDM or IGT at baseline to NGT at follow-up (n = 15), was labelled normoglycaemic. At baseline, these two groups were not significantly different in terms of IS, ISec, BMI, fasting and post-prandial serum glucose, kidney function and treatment with antihypertensive medication (P > 0.117).
|
The patients who had NGT both at baseline and at follow-up (n = 26) tended to increase their IS [8.8 (6.110.6) vs 9.3 (5.012.1) x 102; P = 0.101]. All the ISec indices were significantly reduced during the period (P < 0.001).
![]() |
Discussion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Insulin sensitivity
The IS improved significantly in the cohort in general over the 6 years. We previously have reported that tapering off prednisolone during the first year after renal transplantation is significantly associated with improved glucose tolerance [3]. The present findings of a significant association between prednisolone tapering and improvement in IS may explain and support our previous data [3].
The group of recipients with PTDM or IGT at baseline who normalized their glucose tolerance was characterized by a significant increase in IS and preserved ISec. Interestingly, they also used higher daily doses of prednisolone than the progressors did in the early course. The subsequent greater dose reduction can be one plausible explanation for the improvement in IS [3]. Furthermore, hyperglycaemia itself predisposes for insulin resistance [16] and, as these patients gradually became normoglycaemic, they may have improved their IS by reducing the glucose exposure in insulin-sensitive tissue. However, the weight gain in both groups may have counteracted the improvement in IS.
Insulin secretion
The OGTT-derived first and second phase ISec decreased by half in the total patient population. Older age is known to be an important determinant of impaired ß-cell function [2,17]. However, we were not able to show a significant association between estimated ISec and age in the present study (data not shown). Since the glucose tolerance was improved during the period, the reduction in ISec seems mainly to be caused by increased IS.
It is widely believed that diminution of first phase ISec is the earliest detectable defect of ß-cell function in the non-transplant human population [18]. Further, in the Pima Indians, the reduction in ISec is more pronounced than the fall in IS among subjects developing type 2 diabetes [9]. In the present study, the group of patients who developed PTDM during the follow-up suffered from a steep decline in ISec. Both the estimated acute and late phase insulin responses were diminished to a similar degree (Table 3). Thus, impaired ISec seems to be a prerequisite for the development of both PTDM and type 2 diabetes.
A positive family history of diabetes is well known to be associated with increased risk of developing IGT [2,18,19]. The inability of the ß-cells to compensate for a decrease in insulin action distinguishes individuals who develop diabetes from those who retain NGT [18]. Five of the 14 diabetic recipients at follow-up reported diabetes mellitus in first-degree relatives, whereas this was the case in only one of the 15 non-diabetics. The immunosuppressive therapy, and particularly high doses of steroids in the early course, has probably revealed early glucose intolerance in predisposed pre-transplant non-diabetic individuals [2,6,13,20]. Although it has been suggested that the mechanism behind the diabetogenic effect of CsA is impaired insulin release, we were not able to find any association between the change in whole blood CsA trough levels and the change in estimated insulin secretion from baseline to follow-up. If any such an effect exists, it cannot be strictly dose dependent [3].
A limitation of the present study is that the surrogate estimates for ISec and IS may be inferior compared with insulin measures derived from hyperglycaemic and euglycaemic clamp studies. However, the ISec indices have been validated extensively in patients with different degrees of glucose tolerance and are strongly correlated with results from clamp studies [11,12]. In addition, the ISITX has recently been validated in renal transplant subjects and found to correlate well with results from hyperinsulinaemic euglycaemic clamp [13].
Moreover, one should be aware that 32 patients were lost to follow-up, of whom 18 died. We do not know the glucose tolerance status of these recipients over the years. This may have biased our conclusions on the transitions between normoglycaemia and hyperglycaemia in the cohort. However, the fact that the persons lost to follow-up were not significantly different from the subjects included in the study at baseline makes it less likely that this is a major flaw of the study.
In conclusion, a decline in insulin secretion seems to be the most important factor for the development of long-term PTDM. On the other hand, improvement in insulin sensitivity together with sufficient insulin release is associated with improved glucose tolerance during the first 6 years after renal transplantation.
![]() |
Acknowledgments |
---|
Conflict of interest statement. None declared.
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|