Consequences on ß-Cell Function and Reserve After Long-Term Pancreas Transplantation
R. Paul Robertson
From the Pacific Northwest Research Institute, Seattle, Washington
 |
ABSTRACT
|
---|
ß-Cell replacement in diabetes using pancreatic islets or ß-cell surrogates is a research area undergoing intense scrutiny. Once this approach is demonstrated to be reproducibly successful, the next major issue will be the length of time that success will be sustained. Whole and segmental pancreas transplants are now successful for up to two decades. Study of these grafts can provide insight into and predictions about ß-cell function and reserve when islet transplantation becomes a routine. The studies described herein investigated 102 human whole and segmental transplant recipients and control subjects to address the following five questions. 1) Is the usual reciprocal relationship between the acute insulin response to intravenous glucose (AIRgluc) and the level of fasting plasma glucose (FPG) maintained in pancreas transplant recipients? 2) Do recipients who have no AIRgluc have an acute insulin response to intravenous arginine (AIRarg)? 3) Do recipients of whole pancreata from cadaveric donors have twice the amount of insulin secretory reserve as that found in recipients of 50% segmental grafts from living, related donors? 4) What clinically accessible measure of insulin secretion best correlates with glucose potentiation of arginine-induced insulin secretion (GPAIS)? 5) Do successful pancreas transplant recipients evince time-dependent declines in ß-cell function and glycemic regulation when studied long term and longitudinally? The results demonstrate that 1) the normal relationship between AIRgluc and fasting glucose levels is maintained despite systemic venous drainage of allografts and consequent hyperinsulinemia; 2) AIRgluc and AIRarg decrease in parallel as fasting glucose levels rise, although AIRarg is still present after AIRgluc disappears; 3) AIRarg and AIRgluc are strongly predictive of ß-cell mass; 4) AIRarg and AIRgluc are strongly predictive of insulin secretory reserve; and 5) transplant recipients who have successfully maintained normoglycemia for an average of 10 years and up to 22 years nonetheless experience time-related declines in ß-cell function.
Whether evaluating long-term success of pancreas or islet transplantation, the essential information regarding health of the transplant evolves from studies of ß-cell function and insulin secretory reserve. Stimulation of insulin secretion and measurement of ß-cell mass are direct and reliable approaches to assessing the secretory reserve of pancreatic islet ß-cells. Modes of stimulation include meal ingestion, oral glucose, intravenous glucose, and arginine given alone as single pulse or during hyperglycemia induced by an antecedent glucose infusion. The latter, termed glucose potentiation of arginine-induced insulin secretion (GPAIS), has been used as an in vivo metabolic test of insulin secretory reserve in animals and in humans (16). Animal models are valuable because they allow manipulation of ß-cell mass through various means, such as alloxan or streptozotocin-induced killing of ß-cells and through surgical removal of varying amounts of pancreatic mass. The strength of these approaches is that the residual ß-cell mass can be estimated by histology and immunochemistry and used to generate correlations with metabolic data from the animals. A limitation to using toxins is that they can cause functional damage to residual ß-cells that look normal by histochemistry (5). A weakness of using laboratory animals is the assumption that relationships between ß-cell mass and insulin secretory responses in nonhuman models precisely reflect human metabolism.
Pancreas transplantation in humans provides a unique research model that finesses the problems inherent in using toxic drugs and laboratory animals. Pancreas transplantation as treatment for type 1 diabetes is usually performed after 20 years of the disease in patients with secondary complications who are unable to attain satisfactory glycemic control without recurrent hypoglycemia. The most frequent procedure is simultaneous pancreas and kidney transplantation, wherein the rationale is that the transplanted pancreas will establish euglycemia and will thus protect the transplanted kidney from exposure to hyperglycemia. Simultaneous pancreas and kidney transplantation does not involve a decision about using immunosuppressive drugs because the recipient is in renal failure, is scheduled for kidney transplantation, and has already committed to chronic immunosuppression. Pancreata are also transplanted after kidney transplantation, using the same rationale. Much less frequently, pancreas transplants (PTXs) alone are provided to patients unable to attain satisfactory glucose control using insulin-based regimens without frequent episodes of serious hypoglycemia. Donation of a pancreas segment by a family member who undergoes distal hemipancreatectomy provides a variation on these procedures. Overall pancreas survival rates at 1 year posttransplant are 82% for simultaneous pancreas and kidney transplantation, 74% for PTX after kidney transplantation, and 76% for PTX alone (7). Long-term outcomes that specifically focus on quantification of ß-cell functional reserve in pancreas recipients are rarely reported. The most extensive previous study (8) reported acute insulin responses to arginine and to glucose and assessment of insulin secretory reserve in recipients who were studied in a cross-sectional but not longitudinal manner.
This work addresses five questions. 1) Is the reciprocal relationship between the acute insulin response to intravenous glucose (AIRgluc) and the level of fasting plasma glucose (FPG) that is normally found in humans maintained in whole and segmental PTX recipients? 2) Do recipients who have no AIRgluc have an acute insulin response to intravenous arginine (AIRarg), as is the case in type 2 diabetes? 3) Do recipients of whole pancreata from brain-dead donors maintained on life support have twice the amount of insulin secretory reserve as that found in recipients of 50% segmental grafts from healthy, living, and related donors? 4) What routine, clinically accessible, and brief measure of insulin secretion best correlates with and can be used as a surrogate for GPAIS, a labor-intensive metabolic measure that requires admittance to a hospital for a full morning? 5) Do successful PTX recipients who maintain euglycemia without exogenous insulin treatment nonetheless evince time-dependent declines in ß-cell function and glycemic regulation when studied long term and longitudinally?
 |
RESEARCH DESIGN AND METHODS
|
---|
Patients.
This work reports data from 102 individuals (63 pancreas recipients and 39 control subjects). The recipients all received their transplants at the University of Minnesota, but most lived in other states. The 153 successful recipients were asked to participate in these studies, and those who had failed transplants were not studied. Although the need to travel to one of the two study sites was a major disincentive, 63 recipients agreed to be studied on one occasion and 21 agreed to return for repeat studies. All patients had either received a whole pancreas from a brain-dead, heart-beating donor or a 50% segment of pancreas from living family members for at least 1 year and for as long as 22 years before the studies. Some patients had also received a kidney transplant simultaneously with or before the PTX. The studies were performed between 1994 and 2003. Recipients and control subjects were studied at the University of Minnesota General Clinical Research Center in Minneapolis and at the University of Washington General Clinical Research Center in Seattle. All clinical studies and laboratory assays were performed in the laboratory of the same investigator (R.P.R.). In some cases, the costs of transportation and lodging were paid for; however, no stipends were paid to the patients for participating. The experimental protocol was approved by the Institutional Review Boards of the University of Minnesota and the University of Washington. Insulin secretory reserve data from 16 patients have previously appeared in a small cross-sectional study (8), and acute insulin response data have appeared in other small cross-sectional studies (9,10); however, no cumulative analysis of the entire series of patients with emphasis on longitudinal studies (the focus of this work) has previously been published. The subgroup of 21 patients who were studied longitudinally successfully maintained a PTX for at least 2 and up to 22 years. These patients were studied at least twice and up to four times after transplantation. None of the patients were using insulin or other hypoglycemic agents for glucose control. The control subjects were sex-, age-, and BMI-matched to some of the pancreas recipients and were paid a modest stipend, which was approved by the two Institutional Review Boards.
Experimental studies.
All studies were preceded by an overnight fast from food and caloric drink and were performed fasting at bed rest the following day between 7:00 A.M. and noon. Intravenous cannulae were inserted into peripheral veins in both arms for the purposes of infusing fluids and drawing blood samples. Baseline blood samples were drawn for glucose, HbA1c, and insulin. Arginine-induced insulin secretion was assessed by injecting at time 0 an intravenous pulse of arginine, 5 g in 40 ml saline, and samples were drawn 2, 3, 4, 5, 7, 10, 25, and 30 min following the injection (Fig. 1). Immediately thereafter, glucose-induced insulin secretion and glucose disappearance rates were assessed by injecting an intravenous pulse of glucose, 20 g in 40 ml saline, after which samples were collected at 3, 4, 5, 7, 10, 15, 20, 25, 30, 115, and 120 min. Insulin secretory reserve was assessed by the method of glucose potentiation of arginine-induced insulin secretion (13). This technique involves a 67-min infusion of a glucose solution (900 mg/min), a rate previously determined to maximally potentiate the insulin response to nonglucose stimuli, with arginine pulse given at 60 min and sample collections at 50, 55, 60, 62, 63, 64, 65, and 67 min (13). Glucose levels were determined by an automated glucose analyzer (11), HbA1c levels were determined by high-performance liquid chromatography, and insulin and C-peptide levels were determined by radioimmunoassay (2).

View larger version (18K):
[in this window]
[in a new window]
|
FIG. 1. An example of insulin responses during a study of GPAIS is shown. AIRgluc is calculated from the response to intravenous glucose, AIRarg is calculated from the first response to intravenous arginine, and insulin secretory reserve is calculated from the second response to intravenous arginine. See RESEARCH DESIGN AND METHODS for details.
|
|
Calculations and statistics.
AIRarg was calculated as the mean of the three highest insulin levels obtained within 5 min after the arginine pulse less the prestimulus insulin level. AIRgluc was calculated as the mean of the insulin levels obtained 3, 4, and 5 min after the glucose pulse less the prestimulus level. AIRargmax, the measure of GPAIS, was calculated as the mean of the three highest insulin levels obtained within 5 min after the second arginine pulse less the prestimulus insulin level after 5060 min of glucose infusion. Similar calculations were made for the acute C-peptide response to arginine (ACRarg), the acute C-peptide response to glucose (ACRgluc), and the acute C-peptide response to GPAIS (ACRargmax). Kg was calculated as the slope of the linear correlation between time and the natural log of the glucose concentration obtained at 10, 15, 20, 25, and 30 min following the pulse of intravenous glucose. Although Kg is traditionally termed a glucose disappearance rate, it is recognized that it actually results from a combination of glucose disappearance and endogenous glucose production. All data are expressed as means ± SE. Statistical analyses were performed by Students t tests, by ANOVA, and by Pearson product linear correlations. Significance was ascribed to P < 0.05.
 |
RESULTS
|
---|
Cross-sectional studies.
Of the 63 recipients studied, 13 were transplanted with segmental pancreata from living, related donors and 50 with whole pancreata from brain-dead, heart-beating donors (Table 1). On average the segmental recipients had been transplanted twice as long (P < 0.001), but there were no significant differences between the two groups of recipients in age, BMI, FPG, Kg, fasting insulin, or fasting C-peptide levels. The whole PTX group, but not the segmental PTX group, had significantly higher fasting insulin and fasting C-peptide levels than the control group (both P < 0.001), but no significant differences were found in BMI, FPG, or Kg.
View this table:
[in this window]
[in a new window]
|
TABLE 1 Clinical profile of PTX recipients and control subjects in the combined sectional and longitudinal groups
|
|
An inverse relationship was observed within the segmental and whole PTX groups between the FPG level and the magnitude of the AIRgluc (Table 2) (Fig. 2). To place into context the reciprocal relationship between AIRgluc and FPG, the AIRgluc responses in the two transplant groups were compared with those of the control group. This comparison required expression of the AIRgluc data as a function of fasting insulin because the transplanted pancreata were drained by the systemic venous circuit, thereby bypassing first-pass hepatic degradation of insulin and causing hyperinsulinemia (12), which is in contrast to the control group, whose insulin secretion was delivered into the hepatic portal vein before appearance in the systemic venous circulation. This calculation is justified by the statistically significant correlations between AIRgluc and fasting insulin for both groups (r = 0.43, P < 0.001 and r = 0.56, P < 0.001 for the transplant and control groups, respectively). The AIRgluc in the control group fell within the distribution of values of the transplant recipients (Fig. 3). AIRgluc values became 0 at FPG levels >115 mg/dl. However, those recipients with no AIRgluc still demonstrated an AIRarg, although the AIRarg also diminished progressively as FPG values rose (Table 2). To assess whether differences existed between the segmental and the whole PTX groups, recipients within a narrower FPG range were segregated to avoid outliers (four in each group) and to create a more homogeneous group. In this analysis, the segmental PTX group had secretion values that were
50% smaller and statistically significantly different from the whole PTX group for AIRgluc, AIRarg, ACRgluc, ACRarg, and AIRargmax (Table 3). The level of glycemia reached by the 60th minute of the 1-h glucose infusion during the GPAIS portion of the studies did not differ between the segmental and whole PTX groups (segmental, 330 ± 31, and whole, 292± 14 mg/dl; mean ± SE; P = NS).

View larger version (23K):
[in this window]
[in a new window]
|
FIG. 3. AIRgluc plotted as a function of fasting glucose levels. A: Comparison of segmental and whole PTX recipients using absolute insulin values is shown. Linear correlation after log transformation [log(AIRgluc) = (5.26 - 10.8) x log(FPG)] was used to provide r and P values. B: PTX recipient and control subject insulin values expressed as the percentage of basal insulin values to normalize insulin response data. This is necessary because PTX recipients are hyperinsulinemic due to venous drainage from the allograft into the systemic rather than portal circuit. See text for details.
|
|
View this table:
[in this window]
[in a new window]
|
TABLE 3 PTX recipients with FPG in the range of 88110 mg/dl subgrouped according to transplantation of a 50% segment or a whole pancreas
|
|
For the segmental PTX group, highly statistically significant correlations were observed between AIRarg and AIRargmax, AIRgluc and AIRargmax, and AIRarg and AIRgluc (Fig. 4). Lesser degrees of statistical significance were observed for the relationships between ACRarg and ACRargmax, ACRgluc and ACRargmax, and ACRarg and ACRgluc in the segmental PTX group (Table 4). In the recipients of whole pancreata, highly statistical correlations were found between all relationships except ACRarg and fasting C-peptide (Fig. 4) (Table 4).


View larger version (40K):
[in this window]
[in a new window]
|
FIG. 4. A: Correlations between AIRarg and insulin secretory reserve. B: Correlations between AIRgluc and insulin secretory reserve. C: Correlations between AIRarg and AIRgluc.
|
|
Longitudinal studies.
Of the 21 recipients studied longitudinally, 11 were men and 10 were women (Table 5). Six received segmental PTX, and 15 received whole PTX. Six of the procedures involved pancreas transplantation alone, 11 involved simultaneous pancreas and kidney transplantation, and 4 involved pancreas after kidney transplantation. The average age of the recipients at the time of the procedure was 35 ± 1 years, and the average length of follow-up was 10 ± 1 years, with a maximum of 22 years. The most frequent immunosuppressive drug regimen was cyclosporine, azathioprine, and prednisone (15 of 21 patients). Fasting glucose levels remained generally stable and in the normal range, with only one recipient developing a level >126 mg/dl by 22 years after segmental PTX (Fig. 5A). No significant trend was observed when the data were expressed as change from initial value (Fig. 5B). AIRgluc and AIRarg tended to be lower in the recipients who had been transplanted the longest (Figs. 6 and 7). These patients were also the recipients who tended to have segmental rather than whole PTX. When these data were expressed as change in AIRgluc and change in AIRarg from the initial value obtained, the trends toward smaller values over time were not statistically significant for AIRarg (P = 0.0546) (Fig. 6B) but were for AIRgluc (P < 0.01) (Fig. 7B). A similar trend toward lesser values in AIRargmax over time was observed (Fig. 8A), but when the data were examined as change from the initial value, no statistical difference was observed (Fig. 8B). The levels of glycemia in the final studies at the 60th minute of the 1-h glucose infusion were 296 ± 13 mg/dl and showed no significant trend upwards or downwards from the initial studies. Glucose disappearance rates after intravenous glucose injection generally were in the normal range, although seven recipients had levels slightly below normal on at least one occasion (Fig. 9A). When the Kg data were expressed as change from the initial values, no significant trend was observed (Fig. 9B). HbA1c values were generally stable and within the normal range, although five recipients had slightly elevated values on at least one occasion (Fig. 10A). When the HbA1c data were expressed as change from the initial values, no statistical trends toward higher values were observed (Fig. 10B).

View larger version (23K):
[in this window]
[in a new window]
|
FIG. 5. A: FPG levels in recipients followed longitudinally. B: The change in FPG levels observed when comparing values from the first study and the final study.
|
|

View larger version (23K):
[in this window]
[in a new window]
|
FIG. 6. A: AIRarg in recipients followed longitudinally. B: The change in AIRarg observed when comparing values from the first study and the final study.
|
|

View larger version (25K):
[in this window]
[in a new window]
|
FIG. 7. A: AIRgluc in recipients followed longitudinally. B: The change in AIRgluc observed when comparing values from the first study and the final study.
|
|

View larger version (26K):
[in this window]
[in a new window]
|
FIG. 8. A: Insulin secretory reserve in recipients followed longitudinally. B: The change in insulin secretory reserve observed when comparing values from the first study and the final study.
|
|

View larger version (24K):
[in this window]
[in a new window]
|
FIG. 9. A: Glucose disappearance rates after injection of intravenous glucose in recipients followed longitudinally. B: Change in glucose disappearance rates observed when comparing values from the first study and the final study.
|
|

View larger version (22K):
[in this window]
[in a new window]
|
FIG. 10. A: HbA1c values in recipients followed longitudinally. B: The change in HbA1c values observed when comparing values from the first study and the final study.
|
|
 |
DISCUSSION
|
---|
This report provides both cross-sectional and long-term, longitudinal metabolic data from a large cohort of PTX patients studied for up to 22 years posttransplantation. The cross-sectional study provides novel information indicating that the physiologic reciprocal relationship between the magnitude of the AIRgluc and the fasting glucose level normally observed in diabetic and nondiabetic humans (13) is maintained in successful recipients of PTXs. This is of interest because insulin from transplanted pancreata is delivered directly into the systemic venous circulation, thereby bypassing first-pass hepatic degradation, which leads to hyperinsulinemia in both the fasting and stimulated states (11). It might be anticipated that this could lead to hypoglycemia, and indeed mild postprandial hypoglycemia has been documented in some cases (1416). However, this study demonstrates that the normal relationship between levels of glycemia and insulin secretion is generally maintained after pancreas transplantation and explains why hyperinsulinism in PTX recipients does not usually lead to hypoglycemia. Restored glucagon responses to hypoglycemia clearly also plays an important role in preventing hypoglycemia (17,18). This study also documents that the deterioration in insulin responses to glucose that accompanies development of higher fasting glucose levels is accompanied parri passu by deterioration in insulin responses to arginine, as is the case in patients with type 2 diabetes (1). The finding that both of these responses are diminished by
50% in recipients of segmental PTXs compared with recipients of whole organs is consistent with previous reports (4,5) suggesting that ß-cell mass is an important determinant of the magnitude of glucose- and nonglucose-stimulated insulin responses. While seemingly intuitively self-evident, this need not have been the outcome because the former procedure uses fresh tissue obtained shortly before transplantation, whereas the latter involves procurement of a pancreas from a brain-dead donor on life-support measures and transportation of the pancreas from distant geographic sites. At a more pragmatic level, the highly statistically significant correlations between AIRarg and AIRargmax, as well as AIRgluc and AIRargmax, demonstrate that either measure can be used as accurate surrogates for GPAIS, the much more labor-intensive measurement of insulin secretory reserve. In certain clinical situations, such as the period immediately following pancreatic islet transplantation, when it may be desirable to avoid hyperglycemia, AIRarg may be preferred to AIRgluc as a test of insulin secretory reserve. In other cases, AIRgluc will be preferred because intravenous preparations of glucose are less expensive and more readily available. Generally, C-peptide measurements provided the same information as insulin measurements, so they can be used instead of insulin measurements in partially successful recipients who receive small doses of insulin to manage glycemia.
The longitudinal study of segmental and whole PTX recipients was designed to ascertain whether the passage of time posttransplantation would be accompanied with steady deterioration in glycemic control and in ß-cell function. The novelty and strength of this study lay in its exclusive use of paired data from 21 individual recipients studied for an average of 10 years and for up to 22 years posttransplant. A previous long-term study (8) reported paired data for FPG only, and not for AIRarg, AIRgluc, AIRargmax, Kg, or HbA1c and, therefore, did not provide an assessment of the stability of ß-cell function over time posttransplantation. The results herein demonstrate remarkable stability in levels of FPG and intravenous glucose disappearance rates despite the diminution of AIRgluc. This result emphasizes the sensitivity of AIRgluc as a marker for altered ß-cell responsivity because AIRarg, AIRargmax, intravenous glucose tolerance, and HbA1c did not change significantly.
Figures 510 portray islet function in individual subjects studied more than once, but not every year, during the years portrayed. A limitation of these data is that they are therefore only longitudinal to a limited extent. Over the years studied, there were substantial changes in case selection, pancreas procurement, pancreas transplantation technique, immunosuppression, and graft survival. Successful subjects shown functioning 15 years after transplantation, for example, are not representative of cohort islet function 15 years after transplantation, some members of which have subsequently experienced loss of graft function through chronic rejection. Since subjects whose graft function was lost were excluded from this analysis, the rate of decline of islet function for a given years cohort shown in these studies is unavoidably higher than shown. This bias is inevitable because studies could not be carried out in subjects with graft failure. Moreover, islet function in subjects transplanted 15 years ago may not predict long-term islet function in subjects transplanted more recently. With improved organ procurement, surgical techniques and less toxic immunosuppression, it is reasonable to predict that the decline in islet function may not be as marked within individual subjects.
This information from PTX recipients can be used in a broader context to assess physiologic relationships among acute insulin secretory responses, insulin secretory reserve, and ß-cell mass. In the cross-sectional studies, the parallel declines in AIRgluc and AIRarg as FPG levels rose may seem intuitively predictable, but previously reported studies have suggested otherwise. Preservation of acute insulin secretory responses to intravenous nonglucose secretagogues when the response to intravenous glucose is absent is well established from studies in type 2 diabetic patients using isoproterenol, secretin, and arginine as intravenous agonists (1,19,20). Yet, disagreement exists in the literature regarding the sensitivity with which responses to glucose and arginine reflect diminution of ß-cell mass. Ward et al. (4) compared these two agonists in partially pancreatectomized dogs and concluded that the ß-cell loss was underestimated by the acute insulin response to glucose. In that study, after partial pancreatectomy the responses to arginine, but not to glucose, declined dramatically when the dogs were normoglycemic and even more so during hyperglycemia induced by an intravenous glucose infusion. In contrast, McCulloch et al. (5) reported just the opposite from studies of streptozotocin-induced ß-cell loss in baboons, i.e., a proportionately greater reduction in insulin responses to glucose compared with arginine with mild ß-cell loss. At more severe levels of ß-cell loss due to streptozotocin, i.e., when there was only 4050% of the original ß-cell mass detectable histologically, insulin responses to glucose were completely lost, whereas responses to arginine were clearly present. The present cross-sectional studies in humans, in which AIRgluc reflected the degree of hyperglycemia in both segmental and whole PTX recipients just as sensitively as AIRarg, agree more, although not entirely, with the findings of McCulloch et al. (5) as well as with published data from studies (1) of patients with type 2 diabetic patients. This is clearly demonstrable by the comparison of data from segmental versus whole PTX recipients because both AIRgluc and AIRarg were similarly reduced in the segmental PTX group. The latter comparisons also support the validity of AIRargmax as a measure of insulin secretory reserve because the recipients of the 50% segments had
50% less AIRargmax than the recipients of whole pancreata. Although a recent study (6) of GPAIS in minipigs given streptozocin has been published, comparisons with the data reported herein are not possible because AIRarg was not reported in that publication.
A judgment as to whether or not these observations are necessarily in conflict with previous reports (4,5) requires several considerations. First, major species differences are involved, i.e., baboon versus dog versus humans with type 1 diabetes. Second, the animal studies involved surgery to remove 65% of the pancreas in one case and streptozotocin to kill ß-cells in the other. While surgical excision is clearly a precise approach to diminishing ß-cell mass, the use of streptozotocin is not necessarily as precise. Even though histology and immunochemistry are valuable approaches to assessing residual ß-cell mass, they cannot assess the functional integrity of the surviving ß-cells, some of which may have undergone functional damage but not death during exposure to the drug. Third, decline in the magnitude of acute insulin responses to glucose over time in PTX recipients may reflect events other than declining ß-cell mass. Other variables include the decreasing doses of prednisone that patients use over time. This would be accompanied by lesser degrees of insulin resistance and therefore less secretory demand on and smaller insulin responses from the allografted organs ß-cells. This situation is similar to that observed in previously obese individuals who have lost weight, have become more insulin sensitive, and have smaller glucose-stimulated insulin responses. Another variable is the use of cyclosporine in PTX recipients, an immunosuppressive drug that is well documented to decrease insulin content of the islet as well as inhibit glucose-stimulated insulin responses (2124). However, a previous study by Teuscher et al. (3) demonstrated that this drug also decreases insulin secretory reserve in humans, so it seems unlikely to be an explanation for the results in the present study in which AIRargmax was unchanged. Perhaps the most reasonable position to take is that the previously reported dog and baboon studies are sufficiently different from the current human studies that the markedly different results do not necessarily contradict one another. This position is reinforced by the fact that the dog and baboon studies are in disagreement with each other because in one case AIRarg changed little when AIRgluc decreased greatly and in the other AIRarg changed greatly when AIRgluc changed little.
In conclusion, these studies establish that in successful recipients of segmental and whole PTXs, the physiologic reciprocal relationship between AIRgluc and FPG is maintained; that AIRarg and AIRgluc decline in parallel as FPG increases; that AIRarg is present in instances where AIRgluc has disappeared; that segmental PTX recipients have roughly 50% of the magnitudes of AIRgluc, AIRarg, and AIRargmax observed in whole PTX recipients; that the simpler measurements of AIRgluc and AIRarg can both be used reliably to estimate insulin secretory reserve in PTX, and presumably islet transplant, recipients; and that successful PTX recipients studied long term and longitudinally, who maintain euglycemia without exogenous insulin treatment, experience time-dependent declines in ß-cell responsivity as reflected by AIRgluc. At the clinical level, the most important indicator of success for transplant recipients is their ability to maintain stable levels of fasting glucose, intravenous glucose tolerance, and HbA1c over many years despite the use of immunosuppressive drugs known to diminish insulin sensitivity and ß-cell function. While it seems fairly remarkable that some patients can maintain normoglycemia under these therapeutic conditions for >20 years, the answer to the question of whether the decrease in the magnitude of AIRgluc in the longitudinal studies is a harbinger of eventual organ failure and a return to hyperglycemia will have to await continued follow-up and further metabolic studies.
 |
ACKNOWLEDGMENTS
|
---|
This work was supported by National Institutes of Health Grant no. RO1 DK 39994 and by the National Institutes of Health General Clinical Research Centers at the University of Washington and the University of Minnesota.
The author gratefully acknowledges the superb assistance provided by the research staffs of the University of Minnesota and University of Washington General Clinical Research Centers as well as the excellent technical assistance of Elizabeth Oseid and valuable manuscript preparation assistance of Mike Toney.
Address correspondence and reprint requests to R. Paul Robertson, Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122. E-mail: rpr{at}pnri.org
Received for publication July 31, 2003
and accepted in revised form December 18, 2003
ACRarg, acute C-peptide response to arginine; ACRargmax, acute C-peptide response to GPAIS; ACRgluc, acute C-peptide response to glucose; AIRarg, acute insulin response to intravenous arginine; AIRgluc, acute insulin response to intravenous glucose; FPG, fasting plasma glucose; GPAIS, glucose potentiation of arginine-induced insulin secretion; PTX, pancreas transplant
 |
REFERENCES
|
---|
- Ward WK, Bolgiano DC, McKnight B, Halter JB, Porte D Jr: Diminished B cell secretory capacity in patients with noninsulin-dependent diabetes mellitus.
J Clin Invest74
:1318
1328,1984[Medline]
- Seaquist ER, Robertson RP: Effects of hemipancreatectomy on pancreatic alpha and beta cell function in healthy human donors.
J Clin Invest89
:1761
1766,1992[Medline]
- Teuscher AU, Seaquist ER, Robertson RP: Diminished insulin secretory reserve in diabetic pancreas transplant and nondiabetic kidney transplant recipients.
Diabetes43
:593
598,1994[Abstract]
- Ward WK, Wallum BJ, Beard JC, Taborsky GJ Jr, Porte D Jr: Reduction of glycemic potentiation: sensitive indicator of ß-cell loss in partially pancreatectomized dogs.
Diabetes37
:723
729,1988[Abstract]
- McCulloch DK, Koerker DJ, Kahn SE, Bonner-Weir S, Palmer JP: Correlations of in vivo ß-cell function tests with ß-cell mass and pancreatic insulin content in streptozocin-administered baboons.
Diabetes40
:673
679,1991[Abstract]
- Larsen MO, Rolin B, Wilken M, Carr RD, Gotfredsen CF: Measurements of insulin secretory capacity and glucose tolerance to predict pancreatic ß-cell mass in vivo in the nicotinamide/streptozotocin Gottingen minipig, a model of moderate insulin deficiency and diabetes.
Diabetes52
:118
123,2003[Abstract/Free Full Text]
- Gruessner AC, Sutherland DE: Analysis of United States (US) and non-US pancreas transplants reported to the United network for organ sharing (UNOS) and the International pancreas transplant registry (IPTR) as of October 2001.
Clin Transpl41
72,2001
- Robertson RP, Sutherland DE, Lanz KJ: Normoglycemia and preserved insulin secretory reserve in diabetic patients 1018 years after pancreas transplantation.
Diabetes48
:1737
1740,1999[Abstract]
- Robertson RP, Diem P, Sutherland DE: Time-related, cross-sectional and prospective follow-up of pancreatic endocrine function after pancreas allograft transplantation in type 1 (insulin-dependent) diabetic patients.
Diabetologia34 (Suppl. 1)
:S57
S60,1991[Medline]
- Robertson RP, Sutherland DE, Kendall DM, Teuscher AU, Gruessner RW, Gruessner A: Metabolic characterization of long-term successful pancreas transplants in type I diabetes.
J Investig Med44
:549
555,1996[Medline]
- Morgan CR, Lazarow A: Immunoassay of insulin: two antibody system: plasma insulin levels of normal, subdiabetic, and diabetic rats.
Diabetes12
:115
126,1963
- Diem P, Abid M, Redmon JB, Sutherland DE, Robertson RP: Systemic venous drainage of pancreas allografts as independent cause of hyperinsulinemia in type I diabetic recipients.
Diabetes39
:534
540,1990[Abstract]
- Brunzell JD, Robertson RP, Lerner RL, Hazzard WR, Ensinck JW, Bierman EL, Porte D Jr: Relationships between fasting plasma glucose levels and insulin secretion during intravenous glucose tolerance tests.
J Clin Endocrinol Metab42
:222
229,1976[Abstract]
- Redmon JB, Teuscher AU, Robertson RP: Hypoglycemia after pancreas transplantation.
Diabetes Care21
:1944
1950,1998[Abstract]
- Tran MP, Larsen JL, Duckworth WC, Ruby EI, Miller SA, Frisbie K, Taylor RJ, Stratta RJ: Anti-insulin antibodies are a cause of hypoglycemia following pancreas transplantation.
Diabetes Care17
:988
993,1994[Abstract]
- Cottrell DA, Henry ML, ODorisio TM, Tesi RJ, Ferguson RM, Osei K: Hypoglycemia after successful pancreas transplantation in type I diabetic patients.
Diabetes Care14
:1111
1113,1991[Medline]
- Barrou Z, Seaquist ER, Robertson RP: Pancreas transplantation in diabetic humans normalizes hepatic glucose production during hypoglycemia.
Diabetes43
:661
666,1994[Abstract]
- Kendall DM, Rooney DP, Smets YF, Salazar Bolding L, Robertson RP: Pancreas transplantation restores epinephrine response and symptom recognition during hypoglycemia in patients with long-standing type I diabetes and autonomic neuropathy.
Diabetes46
:249
257,1997[Abstract]
- Robertson RP, Porte D Jr: The glucose receptor: a defective mechanism in diabetes mellitus distinct from the beta adrenergic receptor.
J Clin Invest52
:870
876,1973
- Lerner RL: Augmented insulin responses to glucose after secretin priming in diabetic subjects.
J Clin Endocrinol Metab48
:462
466,1979[Medline]
- Nielsen JH, Mandrup-Poulsen T, Nerup J: Direct effects of cyclosporin A on human pancreatic ß-cells.
Diabetes35
:1049
1052,1986[Abstract]
- Hahn HJ, Laube F, Lucke S, Kloting I, Kohnert KD, Warzock R: Toxic effects of cyclosporine on the endocrine pancreas of Wistar rats.
Transplantation41
:44
47,1986[Medline]
- Gillison SL, Bartlett ST, Curry DL: Inhibition by cyclosporine of insulin secretion: a beta cell-specific alteration of islet tissue function.
Transplantation52
:890
895,1991[Medline]
- Paty BW, Harmon JS, Marsh CL, Robertson RP: Inhibitory effects of immunosuppressive drugs on insulin secretion from HIT-T15 cells and Wistar rat islets.
Transplantation73
:353
357,2002[Medline]