Departments of 1 Medical Cell Biology and 2 Diagnostic Radiology, Uppsala University, SE-751 23 Uppsala, Sweden
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ABSTRACT |
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Recent studies of transplanted pancreatic islets have indicated incomplete revascularization. We investigated the pH, in relation to oxygen tension (PO2), in endogenous islets and islets syngeneically transplanted to the renal subcapsular site of nondiabetic and streptozotocin-diabetic recipients. Tissue pH and PO2 were measured using microelectrodes. In the endogenous islets, tissue pH was similar to that in arterial blood. In the transplanted islets, tissue pH was 0.11-0.15 pH units lower. No differences in islet graft pH were seen between nondiabetic and diabetic animals, and none if the islet grafts were investigated 1 day or 1 mo posttransplantation. The PO2 in the endogenous islets was ~35 mmHg. Transplanted islets had a markedly lower tissue PO2 both 1 day and 1 mo after transplantation. A negative correlation between the tissue PO2 and the hydrogen ion concentration was seen in the 1-mo-old islet transplants in diabetic animals. In conclusion, decreased PO2 in transplanted islets is associated with a decreased tissue pH, suggesting a shift toward more anaerobic glucose metabolism after transplantation.
oxygen tension; revascularization; islet graft; metabolism; engraftment
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INTRODUCTION |
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THE RECENT INTRODUCTION of a new treatment regimen, the so-called Edmonton Protocol, has markedly improved the outcome of clinical islet transplantation (3, 29). However, when this protocol is applied, transplantation of a large number of islets (>9,000 islet equivalents/kg body wt) is necessary to achieve insulin independence. In view of the limited availability of human islet tissue, different approaches to optimize the survival and function of the islet grafts are therefore clearly warranted to reduce the number of islets necessary to cure a diabetic individual.
Endogenous pancreatic islets have a complex glomerular-like
angioarchitecture that ensures that no portion of an islet is more than
one cell away from arterial blood (2). Furthermore, the
blood perfusion of the pancreatic islets is markedly higher than that
of the exocrine pancreas and approaches values similar to those of the
renal cortex (5-7
ml · min
1 · g
1)
(4, 16). This unique capillary network and high blood
perfusion secure a high delivery of oxygen and nutrients to the islet
cells and optimize the dispersal of the secreted hormones to the
vasculature. When islets are isolated and cultured before
transplantation, the islet endothelium has been suggested to
dedifferentiate or degenerate (25). In the immediate
posttransplantation period, the islets are therefore supplied with
oxygen and nutrients solely by diffusion from surrounding tissues (see
Ref. 9).
The revascularization process is rapidly initiated, and the islets are revascularized within 7-14 days (20, 26). However, recent experiments on islets transplanted to kidney, liver, or spleen have suggested that this process is incomplete and that an oxygenation of the transplanted tissue similar to that in endogenous islets never occurs (6-8, 19). The metabolic consequences of this for the transplanted islets remain to be determined.
The aim of the present study, therefore, was to measure tissue pH in endogenous pancreatic islets and in islets transplanted under the renal capsule of diabetic and nondiabetic recipients before and after revascularization. We also recorded the oxygen tension (PO2) in these tissues and correlated this with the obtained pH values.
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MATERIALS AND METHODS |
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Animals. The experiments were performed on inbred male Wistar-Furth rats weighing ~325 g and purchased from B&K Universal (Sollentuna, Sweden). The animals had free access to tap water and standard rat chow (R3, Ewos, Södertälje, Sweden) throughout the study. All experiments were approved by the animal ethics committee for Uppsala University.
Islet isolation, culture, and transplantation. Pancreatic islets were prepared by collagenase (Boehringer Mannheim, Mannheim, Germany) digestion, as described elsewhere (1). Groups of ~150 islets were cultured free-floating for 4-7 days in RPMI 1640 medium supplemented with 10% (vol/vol) calf serum (Sigma-Aldrich, St. Louis, MO) (1), and the medium was changed every 2nd day. At transplantation, ~250 islets were packed in a braking pipette and implanted beneath the renal capsule on the dorsal side of the left kidney in pentobarbital-anesthetized (60 mg/kg ip; Apoteket, Umeå, Sweden) syngeneic rats. Some of the recipients were treated with streptozotocin (STZ; 45 mg/kg iv; Sigma-Aldrich) 3-4 days before transplantation and were diabetic (blood glucose concentration >15 mmol/l) at transplantation. The number of transplanted islets was chosen to be insufficient to reverse the hyperglycemia in STZ-diabetic rats. Blood glucose concentrations were determined with test reagent strips (Medisense, Baxter Travenol, Deerfield, IL) from samples obtained from the cut tip of the tail.
Surgical procedures.
The animals were anesthetized with an intraperitoneal injection of
thiobutabarbital (120 mg/kg; Inactin, Research Biochemicals International, Natick, MA), placed on an operating table maintained at
37°C, and tracheostomized. Polyethylene catheters were placed in the
left femoral artery and vein. The arterial catheter was used to monitor
blood pressure (Statham P23dB, Statham Laboratories, Los Angeles, CA),
whereas the catheter in the vein was used for infusion of Ringer
solution (5 ml · kg1 · h
1)
to compensate for loss of body fluid.
PO2 and pH measurements.
PO2 was measured in the endogenous and
transplanted islets with modified Clark-type microelectrodes (Unisense,
Aarhus, Denmark) (6). The microelectrodes were polarized
at 0.8 V, which gives a linear response between the
PO2 and the electrode current. The latter was
measured by a picoamperemeter (University of Aarhus, Aarhus, Denmark).
A two-point calibration of the electrodes was performed in water
saturated with Na2S2O5 or air at
37°C. The electrodes (tip OD 2-6 µm) were inserted into the
tissues with a micromanipulator under a stereomicroscope. The readings
were allowed to stabilize for ~30 s. Stable recordings could then be obtained for long periods (>60 min). In the transplanted islets and
surrounding renal cortex,
10 measurements of
PO2 were performed in each animal. Measurements
were performed at different depths from the tissue surface (250, 500, 750 µm). At least three measurements were performed at each depth.
These locations were chosen on the basis of previous characterization
of similar islet grafts (6). In the pancreas of control
animals, measurements were performed in 3-5 superficial pancreatic
islets and surrounding exocrine parenchyma. Multiple measurements were
usually performed within the same islet; the mean was calculated to
obtain the PO2 value for one islet. The mean of
all measurements in each tissue and animal was calculated and
considered to be one experiment.
Graft insulin content. The islet grafts were dissected free and placed in 1.0 ml of acid ethanol [0.18 M HCl in 95% (vol/vol) ethanol]. The grafts were sonicated to disrupt the islet cells, and the samples were then extracted overnight at 4°C, followed by determination of the insulin contents with an ELISA (rat insulin ELISA, Mercodia, Uppsala, Sweden).
Lactate and pyruvate production in vitro.
Duplicate groups of 20 islets retrieved from 1-mo-old islet grafts (see
previous paragraph) or freshly isolated control islets were
incubated in sealed glass vials at 37°C in 250 µl of Krebs-Ringer bicarbonate buffer with HEPES containing 2 mg/ml albumin and 5.6 mmol/l D-glucose. The medium was for each experiment
saturated with air-5% CO2 (standard culture conditions) or
1% O2-94% N2-5% CO2 before
incubation. The medium was removed after 2 h of incubation and stored at 20°C until analysis. Concentrations of
lactate and pyruvate were measured with a microdialysis analyzer
(CMA/600; CMA/Microdialysis, Stockholm, Sweden), which uses enzymatic
reagents and colorimetric measurements at 546 nm. The incubation medium without islets was used as a blank.
Statistical analysis. All values are given as means ± SE. Multiple comparisons between data were performed by using ANOVA (Statview; Abacus Concepts, Berkeley, CA) and the Bonferroni post hoc test. Correlation analysis was obtained by simple linear regression. For all comparisons, P < 0.05 was considered to be statistically significant. Because the logarithmic pH scale does not allow parametric statistical evaluations, all recorded pH values were converted into hydrogen ion concentrations before the calculation of the means ± SEs. However, to facilitate interpretation of the data, these are presented as the corresponding pH values.
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RESULTS |
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Body weights and blood glucose concentrations.
All normoglycemic donors and recipients weighed ~325 g when the islet
transplantations were performed (Table
1). Animals rendered diabetic by
injection of STZ also weighed ~325 g, but they decreased ~10% in
body weight until the time of islet transplantation 3-4 days
later. After transplantation, normoglycemic animals slowly gained
weight, whereas diabetic animals decreased in weight during the first
posttransplantation week and thereafter leveled off at ~80% of their
pretransplantation weight. All nondiabetic animals had a blood glucose
concentration of 4-6 mmol/l. Administration of STZ made the
animals hyperglycemic (blood glucose concentration >15 mmol/l) within
48 h. All STZ-treated animals remained diabetic when the tissue pH
and PO2 measurements were performed.
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Graft insulin contents. The islet grafts in the diabetic animals contained less insulin than the grafts in the nondiabetic recipients both 1 day and 1 mo after transplantation (Table 1). The insulin content in all islet grafts, i.e., grafts in both nondiabetic and diabetic recipients, decreased between 1 day and 1 mo after implantation.
Arterial blood pressure, Hct, arterial PO2, and pH. The mean arterial blood pressure was ~100 mmHg in all animals (Table 1). The Hct values ranged between 42 and 51% and did not differ between normo- and hyperglycemic animals. Likewise, neither arterial blood PO2 nor arterial blood pH differed between the groups.
Tissue pH and PO2.
In the endogenous pancreatic islets, mean tissue pH was similar to that
in arterial blood (Fig. 1). In the
transplanted islets, tissue pH was markedly lower. Similar pH values
were recorded in islet transplants in nondiabetic and diabetic animals
and when investigated 1 day or 1 mo after transplantation. No
differences in pH were found between different locations in the grafts
(data not shown). Tissue pH in the exocrine pancreas and in the renal cortex adjacent to the implanted islet grafts (Fig.
2) was similar to the pH recordings in
endogenous islets and arterial blood.
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Lactate-to-pyruvate ratios.
When exposed to standard culture conditions (95% air-5%
CO2), lactate-to-pyruvate (lactate/pyruvate) ratios in
incubation medium from islets retrieved from islet grafts were
increased compared with lactate/pyruvate ratios in the incubation
medium of freshly isolated control islets (Fig.
6). The lactate/pyruvate ratios obtained
from the incubation medium of retrieved islets exposed to 95% air-5%
CO2 were instead similar to those obtained from the
incubation medium of freshly isolated control islets exposed to hypoxia
(1% O2). Islets retrieved from islet grafts and exposed to
hypoxia had a markedly increased lactate/pyruvate ratio in the
incubation medium compared with all other groups.
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DISCUSSION |
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We have previously recorded a markedly decreased vascular density, blood flow, and tissue PO2 in transplanted islets irrespective of whether implanted in the kidney, liver, or spleen (6-8, 19). In the present study, we measured tissue pH to assess the metabolic consequences of these changes. We found decreased pH and PO2 in both 1-day-old and 1-mo-old islet transplants compared with endogenous pancreatic islets. Moreover, in diabetic recipients investigated 1 mo posttransplantation, islet graft hydrogen ion concentrations correlated negatively with tissue PO2.
Accumulation of hydrogen ions is known to occur in tissues when a high
glycolytic rate, and thereby lactic acid production, coincides with an
insufficient drainage by convective and/or diffusive transport. Rapidly
growing tumors often display severe tissue acidosis due to their high
metabolic rate, which often cannot be adequately met by the nutrient
blood supply (33). PO2 values, as
low as those recorded in the present and previous studies in transplanted islets, are in tumors often accompanied by a pH below 7.0 (12, 33). In contrast, tissue pH in the transplanted
islets was not decreased by more than 0.11-0.15 pH units. However,
whereas tumor cells have a high rate of lactate production (e.g., see Refs. 24, 33), islet cells, and especially
-cells, have very low lactate dehydrogenase activity (17,
28). Nevertheless, in vitro experiments with islets incubated in
a hypoxic environment have shown increased lactate production
(18). In view of the very low lactate dehydrogenase
activity in the
-cells, the produced lactate is likely to reflect
mainly lactate production from non-
-cells in the grafts. In line
with the present findings of a decreased pH in transplanted islets, we
have in a recent microdialysis study noted 3-4 times higher
lactate/pyruvate ratios in transplanted islets compared with islets
investigated in vitro (5). As shown in the present study,
these changes in metabolism observed in vivo seem to remain also
immediately after retrieval of the transplanted islets. After
incubation at standard culture conditions (95% air-5% CO2), twofold higher lactate/pyruvate ratios were recorded
in the medium of islets retrieved from islet grafts compared with freshly isolated control islets. Exposure of the retrieved islets to
hypoxia (1% O2) caused a further marked increase in
lactate/pyruvate ratios. Although awaiting further study, this suggests
changes in the enzymatic machinery. As evaluated in a previous study
(30), pancreatic islets retrieved from islet grafts also
seem to exhibit other functional disturbances, e.g., deteriorated
glucose-stimulated insulin release.
Concomitant with the decreased tissue pH, a markedly decreased PO2 in all transplanted islets, compared with endogenous islets, was found. In most cases, there was no strict correlation between the PO2 and the pH in the tissues. The PO2 in 1-mo-old islet transplants of normoglycemic recipients was lower than that in the corresponding 1-day-old islet transplants, whereas a similar difference was not observed in tissue pH. Nevertheless, in the 1-mo-old islet transplants in diabetic recipients, there was a negative correlation between the tissue PO2 and hydrogen ion concentration. Interestingly, this experimental group also tended to have the lowest values for tissue PO2 in the transplanted islets. It could be speculated that the rate of nonoxidative glucose metabolism is only proportional to the oxygen supply at this low range. Alternatively, the enzymatic machinery may be altered in transplanted islets when they are exposed to sustained hyperglycemia, as previously observed in remaining islets after an ~90% partial pancreatectomy (15). However, this awaits further study.
PO2 values similar to those recorded in the
islet transplants in the present study have previously been shown to
affect islet function. In TC3 cells, an insulinoma cell line,
PO2 values below 25 mmHg gradually shifted
these cells from aerobic to anaerobic metabolism, with a concomitant
increase in lactate production (23). Reduced insulin
secretion from the
TC3 cells was observed at
PO2 < 7 mmHg. Similarly, glucose-stimulated
insulin secretion from single rat islet cell aggregates (5-10
cells) was affected below a PO2 of 12 mmHg
(10). In vitro studies of pancreatic islets have also
demonstrated a pivotal role of a near normal or slightly alkaline
extracellular pH for glucose-stimulated insulin secretion (13,
22, 31). However, a marked reduction of extracellular pH (pH
7.0) was found mandatory to deteriorate glucose-stimulated insulin
release (31). More modest decreases in extracellular pH,
i.e., ones similar to those recorded in the present study, seemed not
to adversely affect insulin release (22).
The insulin content of the islet transplants was determined to evaluate
islet function in relation to tissue pH and
PO2. In nondiabetic animals, the insulin
content was ~4,000 ng on the day after transplantation and
decreased during the following month to ~2,300 ng. Since these grafts
consisted of 250 islets, this means that each islet contained ~16 ng
of insulin 1 day after transplantation and ~9 ng of insulin 1 mo
after transplantation. In comparison, studies of rat islets in vitro
have demonstrated markedly higher insulin contents (40-60
ng/islet) (27, 32). -Cell death due to nonspecific
inflammation and locally low PO2 in the
immediate posttransplantation period may explain some of the difference
(9). However, low tissue PO2 may
also contribute later on by suppressing insulin production.
In accordance with a vast number of previous studies (e.g., 6, 11, 21), an even further decrease in graft insulin content was observed in the diabetic animals, compared with nondiabetic animals, both 1 day and 1 mo posttransplantation. However, the islets implanted into the diabetic environment continued to produce insulin, as also previously observed (5). Such islets also seem to have a capacity to regain function and normalize their glucose-induced insulin secretion when the recipient is cured by a second islet graft several weeks later (14). A prerequisite for this is an unchanged or increased islet mass, which we have shown repeatedly to be present in the experimental model used (6, 7). We have previously noted a lower tissue PO2 in islet grafts in diabetic animals compared with nondiabetic animals (6-8) and suggested that the detrimental effects of hyperglycemia on graft insulin content may partially be explained by the more pronounced hypoxia to which islet cells are exposed in the diabetic environment. In the present study, however, there was no statistically significant difference in the tissue PO2 of the islet transplants between nondiabetic and diabetic recipients. Moreover, similar pH was recorded in all islet grafts. The lower insulin content in islets exposed to a diabetic environment is therefore unlikely to be explained by a further shift to anaerobic metabolism.
In conclusion, the present study shows that the previously observed decreased tissue PO2 in 1-day-old and 1-mo-old islet transplants compared with endogenous islets is concomitant with a decreased tissue pH. This should be taken to suggest a shift to more anaerobic glucose metabolism after transplantation. The importance of this for islet function merits further investigation.
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ACKNOWLEDGEMENTS |
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This study was supported by grants from the Swedish Medical Research Council (72X-109), the Juvenile Diabetes Research Foundation, the Swedish-American Diabetes Research Program funded by the Juvenile Diabetes Research Foundation, and the Wallenberg Foundation, the Swedish Diabetes Association, the Swedish Society of Medicine, the Novo Nordisk Fund, Svenska Barndiabetesfonden, Anérs Stiftelse, Clas Groschinskys Minne, Magnus Bergvalls Stiftelse, Familjen Ernfors Fond, Goljes Minne, Thurings Stiftelse, Lars Hiertas Minne, and Familjen Ernfors Fond.
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FOOTNOTES |
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Address for reprint requests and other correspondence: P.-O. Carlsson, Dept. of Medical Cell Biology, Biomedical Center, Husargatan 3, Box 571, SE-751 23 Uppsala, Sweden (E-mail: Per-Ola.Carlsson{at}medcellbiol.uu.se).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
First published November 5, 2002;10.1152/ajpendo.00156.2002
Received 12 April 2002; accepted in final form 31 October 2002.
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