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Original Studies |
Department of Internal Medicine and Diabetes and Metabolism, Karl Franzens University Graz (M.E., G.S., A.W., G.A.B., P.W., T.R.P.), A-8036 Graz; the Department of Biophysic, Institute of Electro- and Biomedical Engineering, University of Technology Graz (M.E., L.S., Z.T., P.W.), A-8010 Graz; and the Department of Internal Medicine, Krankenhaus der Barmherzigen Brüder, Teaching Hospital, Karl Franzens University Graz (F.S.), 8020 Graz, Austria
Address all correspondence and requests for reprints to: Thomas Pieber, M.D., Department of Internal Medicine, Diabetes and Metabolism, Karl Franzens University Graz, Auenbruggerplatz 15, A-8036 Graz, Austria. E-mail: thomas.pieber{at}kfunigraz.ac.at
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Abstract |
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Introduction |
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In recent studies a novel technique, called open flow microperfusion (13), was developed for continuous extracorporeal monitoring of sc adipose glucose concentrations during metabolic events such as hyper- or hypoglycemia (14) or lactate concentrations during extensive cycle ergometer exercise (15) using a novel thin film sensor technology. In contrast to microdialysis, in which a sterile barrier prevents direct contact with the interstitial compartment, open flow microperfusion allows direct access to the interstitial compartment of sc adipose tissue and therefore may produce further insight into tissue metabolism. Using open flow microperfusion a perforated double lumen catheter is set into sc adipose tissue and perfused with isotonic ion-free perfusate. Via the perforations of the catheter, the perfusate partially equilibrates with the surrounding tissue fluid. A simple calibration technique (ionic reference technique) allows estimation of the absolute concentrations of the interstitial compartment of sc adipose tissue (13, 14, 15).
The first objective of this study was the validation of the ionic reference technique for the frequent monitoring of absolute lactate concentrations in the interstitial fluid of sc adipose tissue. We measured the sc lactate concentration in the postabsorbtive state using an established calibration protocol (no net flux protocol) (7, 16) and the ionic reference technique.
The second objective was to test whether the method of open flow microperfusion is appropriate for the frequent monitoring of dynamic processes in sc adipose tissue. We performed a hyperinsulinemic euglycemic clamp experiment to confirm the recent findings of a significantly elevated interstitial lactate concentration during hyperinsulinemia.
Our third objective was to investigate the influence of the insulin concentration on the lactate concentration of sc adipose tissue during hyperglycemia. Using a hyperglycemic clamp experiment without somatostatin infusion, we tested whether the sc lactate concentration increases in parallel with the physiological plasma insulin response or is uninfluenced by the increasing insulin concentration.
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Subjects and Methods |
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Sixteen lean healthy young men participated in this study. None
of them used any medication for 2 months before and during the study.
All subjects were informed about possible risks and gave their
volunteered consents. The study was approved by the local ethics
committee of the University of Graz. The subjects were subdivided into
different groups for different study protocols (Table 1
); they were of similar age (mean
± SD, 25.4 ± 3.1 yr) and body mass index (mean
± SD, 23.6 ± 1.9 kg/m-2). All subjects
were investigated at 0800 h after an overnight fast while they
were in the supine position at a room temperature of 21 C. In all
protocols a retrograde cannula was inserted into a dorsal hand vein,
and the hand was placed in a thermoregulated box (55 C) to obtain
arterialized blood samples (17).
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A schematic representation of the sampling device is given in
Fig. 1. The system consists of a
perfusate reservoir, a perforated double lumen catheter, a peristaltic
pump, and vials collecting the perfusate.
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shows a photoprint of the double lumen
catheter. The double lumen catheter was perfused with 5% mannitol in
aqueous solution (protocols II, III, and IV) or with Ringer’s solution
or mannitol (protocol I). A peristaltic pump (Minipuls 3, Gilson,
Villiers-le-Bel, France) was used for applying a negative pressure to
the system, drawing the perfusate out of the reservoir bag and pulling
it through the double lumen catheter as indicated by the
arrows in Fig. 1
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Calculating absolute concentrations in sc adipose tissue (ionic reference technique)
As mentioned in the description of the sampling device, the perfusate partially equilibrates with the surrounding tissue fluid. In previous investigations (14, 15), the conductivity, which is proportional to the sum of the ion concentrations, of the interstitial fluid of sc adipose tissue was assumed to be constant, and the conductivity of the sampled fluid was measured as an indicator of the rate of recovery of interstitial fluid in the perfusate. In the present study the sodium concentration of the perfusate was used to calculate the recovery rate.
The recovery of the sc tissue fluid in the perfusate was calculated as the ratio of the sodium concentration in the sampled fluid to the sodium concentration of the interstitial fluid of sc adipose tissue (140 mmol/L (18, 19)). The interstitial sodium concentration was assumed to be constant during the experiment (14, 20). Absolute lactate concentrations of the sc adipose tissue were calculated as the ratio of the lactate concentration measured in the sampled fluid to the rate of recovery.
Protocol I (no net flux protocol)
Two double lumen catheters were inserted into the abdominal
region of sc adipose tissue of six subjects (Table 1) to perform a no
net flux calibration protocol. One catheter was perfused with 5%
mannitol in aqueous solution (Mayrhofer Pharmazeutika GesmbH, Linz,
Austria) the other catheter was perfused with Ringer’s solution
(Ringer Lösung, Leopold Pharma, Graz, Austria; 147.2 mmol/L Na,
155.7 mmol/L Cl, 4.00 mmol/L K, and 2.25 mmol/L Ca; 309 mosmol/L). The
subjects were fasting throughout the experiment. The no net flux
protocol is based on the principle that the substance of interest is
added to the perfusate in different concentrations, and the point of no
net change of the substance in the sampled fluid compared with the
concentration in the perfusate is calculated by linear regression
analysis. The estimate represents the absolute interstitial fluid
concentration of the substance of interest (7, 16). Within this study,
we added four different concentrations of L-lactate to the
perfusates (0.6, 1.2, 1.8, and 2.4 mmol/L) and included a fifth
perfusion step where no lactate was added to the perfusate. Catheters
were perfused in randomized order in every experiment. For each
concentration a initial equilibration period of 30 min was added.
Protocol II (postabsorbtive state)
In protocol II, five subjects (Table 1) were investigated in the
postabsorbtive state for a period of 6 h. One double lumen
catheter was set into the sc adipose tissue of the right abdominal
region and was perfused with 5% mannitol in aqueous solution. After an
initial equilibration period of 1 h, the experiment was started.
Interstitial fluid samples were obtained every 30 min and were analyzed
for lactate and sodium concentrations.
Protocol III (euglycemic hyperinsulinemic clamp)
Five subjects (Table 1) participated in this 6-h protocol. An iv
cannula for continuous glucose and insulin infusion was set into a
cubital vein opposite the forearm from which arterialized blood samples
were withdrawn. After a basal period of 90 min, a continuous insulin
infusion (40 IU/mL; Actrapid HM, Novo Nordisk A/S,
Bagsvaerd, Denmark) was started for a period of 3 h. Insulin was
infused at a fixed rate (1 mU/kg·min) during the clamp period. The
arterialized plasma glucose concentration was clamped at euglycemic
values (5 mmol/L) by variable glucose infusion (21). After the clamp
period of 3 h, insulin infusion was stopped, and variable glucose
infusion was continued to maintain euglycemia for another 90 min.
Arterialized plasma glucose was measured in duplicate at intervals of 5
min; arterialized plasma samples were withdrawn every 30 min and
analyzed for lactate and insulin concentrations. Subcutaneous tissue
fluid was sampled at intervals of 30 min and analyzed for lactate and
sodium concentrations.
Protocol IV (hyperglycemic clamp)
A hyperglycemic clamp experiment at the physiological insulin
response was performed in six subjects (Table 1). One double lumen
catheter was set into the sc adipose tissue of the right abdominal
region and was perfused with 5% of mannitol in aqueous solution at a
constant flow rate of 2 µL/min. An iv cannula was set into a cubital
vein for continuous glucose infusion (Glucose 20% Leopold, Leopold
Pharma, Graz, Austria) at the forearm contralateral to the arm from
which arterialized blood samples were withdrawn. After a 1-h initial
equilibration period and 2 h of measurement under basal
conditions, the hyperglycemic clamp was started with a bolus infusion
of 20% glucose (300 mg/kg). Thereafter, the plasma glucose
concentration was clamped at 10 mmol/L for a period of 3 h by
continuous variable infusion of 20% glucose (21). Arterialized plasma
glucose was measured in duplicate at intervals of 5 min throughout the
clamp period. Arterialized plasma samples were withdrawn every 30 min
and analyzed for lactate, insulin, and lactate dehydrogenase (LDH)
concentrations. Interstitial fluid samples were obtained every 30 min
and were analyzed for lactate, sodium, and LDH concentrations.
Additionally, for the first hour after catheter insertion, interstitial
fluid was sampled at intervals of 15 min and analyzed for LDH
concentration.
Chemical analysis
Plasma and interstitial lactate and LDH concentrations were determined photometrically using a Cobas Integra Laboratory Analyzer (Cobas Integra, Hoffmann-La Roche, Basel, Switzerland). Using an external lactate standard of 0.8 and 0.2 mmol/L, coefficients of variation of 0.6% and 1.7% (n = 10) were determined. The interstitial sodium concentration was analyzed by a flame photometer (IL 943, Instrumentation Laboratory S.p.A., Milan, Italy). Coefficients of variation of 1.2% and 1.5% for sodium concentrations of 70.0 and 35.0 mmol/L were measured, respectively. Plasma glucose was measured enzymatically using a Beckman Glucose Analyzer II (Beckman Instruments, Fullerton, CA). Plasma insulin was measured using a commercial RIA kit (human insulin-specific RIA kit, Linco Research, Inc., St. Charles, MO).
Statistical analysis
Analysis of the no net flux protocol was performed adopting linear regression analysis of the mean value of each concentration step. Student’s paired t test was used when different time points or different catheters in the same subject were compared, and Student’s independent t test was applied when concentrations between study groups were compared. All statistical analyses and diagrams were performed using Micro Cal Origin (technical graphics and data analysis, Microcal Software, Inc., Northhampton, MA). Unless otherwise indicated, results in the text, figures, and tables are the mean ± SEM.
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Results |
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Mean regression lines for the no net flux protocol are given in
Fig. 3A. The lactate concentrations
estimated for the point of no net flux were 1.36 mmol/L (r = 0.99;
n = 6) and 1.50 mmol/L (r = 0.98; n = 6) for 5% of
mannitol in aqueous solution and Ringer’s solution, respectively.
Individual sc lactate concentrations (mannitol vs.
Ringer’s) were not significantly different (P >
0.05). The simultaneously measured mean arterialized plasma lactate
concentration was significantly lower (0.61 ± 0.03 mmol/L;
P < 0.05) than the estimated absolute sc tissue
lactate concentration.
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). A small, but not significant,
increase (P > 0.05) in the concentration was observed
during the 6-h period (Fig. 3B). The absolute lactate concentration of
protocol II was not significantly different (P > 0.05)
from the absolute sc concentration as estimated by protocol I. The
recovery measured by the ionic reference technique was 56.2 ±
7.9% (mean ± SEM; n = 5; Fig. 6). The
arterialized plasma concentrations of glucose and lactate did not
change from basal levels and were 5.4 ± 0.2 and 0.77 ± 0.07
mmol/L (mean ± SEM), respectively.
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The results of the euglycemic hyperinsulinemic clamp are given in
Fig. 4. During basal conditions the
absolute sc lactate concentration calculated by the ionic reference
technique was 1.14 ± 0.27 mmol/L (mean ± SEM;
n = 5). The concentration was not significantly different
(P > 0.05) from absolute concentrations estimated with
protocols I and II. The sc lactate concentration was significantly
elevated during the clamp (1.8 ± 0.33 mmol/L (mean ±
SEM; P < 0.05) and reached basal values 30
min after the clamp (Fig. 4A). The mean recovery measured by the ionic
reference technique was 43.5 ± 8.2% (mean ±
SEM; Fig. 6). The basal arterialized plasma lactate
concentration was 0.74 ± 0.02 mmol/L (mean ±
SEM). A significant increase (P < 0.05) in
the plasma lactate concentration was observed during the clamp period
(Fig. 4A). The sc lactate concentration was significantly higher than
the arterialized plasma lactate concentration throughout the study
(P < 0.05). The time courses for plasma glucose
(5.01 ± 0.08 mmol/L) and plasma insulin (basal, 54.6 ± 0.36
pmol/L; clamp, 432.6 ± 12.6 pmol/L) concentrations are depicted
in Fig. 4B.
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The results for the hyperglycemic clamp study are presented in
Fig. 5. The basal sc lactate
concentration calculated by the ionic reference technique was 1.28
± 0.10 mmol/L (mean ± SEM; n = 6) and was not
significantly different (P > 0.05) from the absolute
lactate concentration of protocols I, II, and III. Both the sc lactate
concentration (2.15 ± 0.27 mmol/L; P < 0.05) and
the arterialized plasma lactate concentration (basal, 0.76 ± 0.11
mmol/L; clamp, 1.08 ± 0.11 mmol/L; P < 0.05)
were significantly elevated during the hyperglycemic clamp period. The
lactate concentration was significantly higher in sc adipose tissue
than in arterialized plasma throughout the study (P <
0.05). A mean recovery of 38.1 ± 9.7% (mean ±
SEM) between the interstitial fluid and the perfusate fluid
was measured in this study (Fig. 6).
Basal plasma glucose and insulin concentrations in this protocol were
5.15 ± 0.12 and 46.2 ± 4.8 pmol/L (mean ±
SEM). Plasma glucose was clamped at 10.01 ± 0.12
mmol/L (mean ± SEM) for a period of 3 h (Fig. 5B). Arterialized plasma LDH levels were stable throughout the
observation period (72.9 ± 16.7 U/L). LDH levels in the sampled
fluid of sc adipose tissue were high in the first sample after catheter
insertion (69.5 ± 14.6 U/L), but fell to significantly
(P < 0.05) lower levels for the rest of the study
period (25.7 ± 1.5 U/L; Fig. 7).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We have recently shown that combining open flow microperfusion, glucose sensor, and conductivity measurement enables a continuous extracorporal monitoring of sc adipose tissue glucose concentration (13, 14). Moreover, the possibility of on-line monitoring of the sc lactate concentration during basal conditions and extensive cycle ergometer exercise was demonstrated with the same technique (15). However, in these two studies the sampled fluid was analyzed on-line by means of newly developed sensor techniques, and perfusate was not sampled for analysis using well established laboratory analyzers. In the present study we collected the sampled perfusate fluid and used high precision laboratory analyzers (see Analysis and statistics section).
In contrast to microdialysis, open flow microperfusion allows a free exchange of substances between the tissue and the perfusate fluid. The concentration of a substance in fluid sampled by open flow microperfusion depends on various technical parameters such as the flow rate of the perfusate, the area of exchange of the double lumen catheter, the chemical composition of the perfusate, and various physiological characteristics of the tissue, such as temperature, microvascular transport rate, size of the adipocytes, or specific tissue blood flow. Although technical parameters can be kept constant, physiological parameters can only be considered to some extent. Therefore, the recovery varies between the subjects as well as within the subjects as shown previously (13, 14, 15). The ionic reference technique is a newly developed calibration method accounting for these influences on recovery. In protocol I we used a well established calibration protocol (no net flux protocol) (7, 16) for evaluation of the ionic reference technique. The no net flux protocol was performed using two different perfusate solutions to investigate a possible influence of mannitol on equilibration processes in the double lumen catheter. The estimated absolute concentration measured with the more physiological Ringer’s solution was not significantly different from the concentration obtained with 5% mannitol as perfusate (P > 0.05). Therefore, one may conclude that the use of mannitol as an ion-free perfusate, which is necessary for the ionic reference technique, has no significant influence on local equilibration processes relating to lactate measurement.
In protocol II it was shown that the combination of open flow
microperfusion and the ionic reference technique allows a frequent and
stable measurement of the sc lactate concentration in the postprandial
state for a period of at least 6 h. Furthermore, as depicted in
Figs. 4A and 5A, we used the results of protocol II to corroborate the
significant findings of protocols III and IV. The ionic reference
technique is based on the assumption that the sodium concentration in
the interstitial fluid of sc adipose tissue is known and constant. The
ionic strength, the osmolarity, and consequently the sodium
concentration of the interstitial fluid are closely regulated by
antidiuretic hormones and the kidney. Under normal circumstances, the
osmolarity is fairly constant and varies only slightly from day to day
(14, 18, 19, 20). Even pathophysiological influences on the interstitial
ion status result in minor effects on the accuracy of the ionic
reference technique, as discussed in an earlier report of Trajanoski
et al. (14). Therefore, it may be concluded that variations
in the interstitial sodium concentration are negligible and do not
significantly influence the accuracy of the ionic reference
technique.
The mean recoveries of the individual protocols (protocols II, III, and
IV) were stable throughout the experimental study periods. However,
different mean recoveries of the individual protocols were observed, as
indicated in Fig. 6. As mentioned above, the concentration of a
substance in the fluid sampled by open flow microperfusion depends on
various technical parameters as well as on physiological
characteristics of the tissue. These effects and the fact that only
five or six subjects of a large population were investigated in the
protocols of the present study may lead to variations in the recoveries
in the individual protocols. However, independent of the degree of
equilibration (recovery) of a substrate in the perfusate, basal lactate
concentrations of the interstitial fluid of sc adipose tissue estimated
by the ionic reference technique were very similar in all protocols. In
three independent studies (protocols II, III, and IV), the interstitial
lactate concentration calculated by the ionic reference technique was
not significantly different from the lactate concentration estimated by
the no net flux protocol. This indicates that open flow microperfusion
combined with the ionic reference technique is applicable for the
measurement of absolute lactate concentrations in sc adipose
tissue.
Measurement of postprandial lactate concentrations in sc adipose tissue
of healthy humans was performed by various investigators (1, 2, 3, 5, 6, 22). In all studies, the sc lactate concentration was significantly
higher (range, 1.01–2.02 mmol/L) than the lactate concentration in
arterialized plasma. Using open flow microperfusion, we have also
measured a comparable and significantly increased sc lactate
concentration compared with arterialized plasma values. It remains
unknown whether the high sc lactate values represent true physiological
values or are the result of tissue trauma and/or inflammation due to
the insertion of microdialysis or double lumen catheters. Open flow
microperfusion catheters and microdialysis probes are similar in size
and flexibility; therefore, it may be assumed that even the effects of
a probe insertion into the tissue are comparable. Several investigators
attempted to clarify questions of tissue trauma and measured substances
such as adenosine (23), pyruvate (1), LDH (24), ATP (25, 26), and
potassium (27) or the glucose/lactate ratio (28) in the sampled fluid.
Evidence for tissue trauma was found only for approximately the first
hour after insertion of microdialysis catheters. In protocol IV of the
present study we measured the LDH concentration in the sampled tissue
fluid as well as in arterialized plasma, because LDH is known to be
elevated during ischemia and cell destruction (18, 24, 29). In
arterialized plasma, LDH concentrations were constant throughout the
experiment. In the sampled interstitial fluid, LDH levels were
significantly elevated during the first 15 min after catheter insertion
compared with those during the remainder of the experimental period
(Fig. 7). Inflammation is another long acting process after tissue
injury. Signs of inflammation are the liberation of large quantities of
histamine, bradykinin, serotonin, and other substances. These,
especially histamine, increase the local tissue blood flow. Mediators
of inflammation have not yet been measured using open flow
microperfusion. However, no visible sign of inflammation
(e.g. erythema due to a local blood flow increase) occurred
in the different protocols of the present study. Furthermore,
measurement of the sodium concentration in the sampled fluid did not
indicate any sign of instability of the method, as the sodium
concentration was stable throughout the study period in all protocols
(Fig. 6); this might be an indication for a stable tissue blood flow
around the catheter. Therefore, it is concluded that the double lumen
catheter as constructed for the open flow microperfusion technique is
appropriate for human studies, causing only minor and transient damage
to sc adipose tissue.
Coppack et al. (11) used the measurement of arterio-venous differences for the evaluation of adipose tissue metabolism. This method does not give direct access to a specific tissue region, but has the advantage that the investigated tissue region is not traumatically influenced. From their studies Coppack et al. reported that lactate is produced by sc adipose tissue in the postabsorbtive state as well as during hyperinsulinemia. Therefore, there remains little doubt from all experimental protocols that sc adipose tissue is a significant source of lactate production in the postabsorbtive state.
In protocol III the influence of hyperinsulinemia on lactate release of
sc adipose tissue was investigated. Corresponding with previous
microdialysis studies (5, 6, 8) and the measurement of arterio-venous
differences (11), we observed that hyperinsulinemia at euglycemic
values results in a significant increase in lactate in both sc adipose
tissue and arterialized plasma (Fig. 4A). Furthermore, in this study
for the first time the decrease in the sc lactate concentration to
basal levels after the clamp period was monitored.
To investigate the influence of the insulin concentration on the sc
lactate concentration during hyperglycemia, we performed a
hyperglycemic clamp experiment at the physiological insulin response.
We monitored the sc lactate concentration and the arterialized plasma
lactate concentration for a clamp period of 3 h (protocol IV).
Figure 5A depicts a significantly elevated lactate concentration in the
sc adipose tissue 30 min after the start of the clamp compared with the
basal concentration. These results indicate that the combination of
hyperinsulinemia and hyperglycemia results in a significantly elevated
lactate production by sc adipose tissue. The increase in the sc lactate
concentration during the clamp period was similar in protocol III (58%
of the basal level during hyperinsulinemia) and protocol IV (68% of
the basal level during hyperinsulinemia and hyperglycemia); therefore,
it is concluded that the increase in lactate was primarily stimulated
by the insulin concentration, as it was shown in the study of Henry
et al. (8) using the microdialysis technique. During the
hyperglycemic clamp of the present study, the sc lactate concentration
reached an early plateau 30 min after the start of the clamp, which was
not altered by continuously increasing insulin concentrations (Fig. 4).
This finding leads to the assumption that at most a 4-fold increase in
the plasma insulin concentration is necessary to stimulate adipocytes
for maximum lactate release. Further increasing insulin concentrations
has no additional effect on adipocyte stimulation with respect to
lactate formation, as the data indicate. The findings of the present
study suggest that maximal levels of adipose lactate concentrations at
submaximal insulin concentrations might accelerate the effects of
increased fat mass in human obesity. This increased lactate production
driven by moderately elevated insulin levels, as seen in obesity, may
contribute to increased liver gluconeogenesis and, in consequence, lead
to impaired glucose tolerance associated with human obesity (1).
The determination of quantitative amounts of lactate release by the sc adipose tissue depot was not feasible in the present study because the extraction fraction of lactate and the specific tissue blood flow were not measured (30). However, expressing differences in arterialized to interstitial lactate concentrations as qualitative changes in the local lactate production in sc adipose tissue is still valid, as the increase in the interstitial lactate concentration observed during hyperinsulinemia would underestimate the actual lactate production due to a possible tissue-specific blood flow increase. The effects of hyperinsulinemia on adipose tissue blood flow changes remain unclear, as contrary results have been obtained. In various studies using the microdialysis technique it was shown that hyperinsulinemia has no effect on adipose tissue blood flow in vivo (5, 31, 32, 33, 34), whereas Jannson et al. (1) and Henry et al. (8) found an increase in adipose tissue blood flow during hyperinsulinemic conditions using the same technique. In the present study the sodium concentration was used as an endogenous marker and remained constant during the change from basal to hyperinsulinemic conditions of protocols III and IV. This finding might be an additional evidence that hyperinsulinemia has no effect on tissue blood flow around the catheter. However, as the blood flow was not directly measured in the present study, a possible influence of insulin on adipose tissue blood flow cannot be ruled out.
In summary, it was shown that the novel technique of open flow microperfusion combined with the ionic reference technique allows the measurement of absolute lactate concentrations in sc adipose tissue. Furthermore, it could be substantiated that adipocytes in sc adipose tissue are a significant source of lactate release both in the postabsorbtive state as well as during hyperinsulinemic conditions. It is concluded that at the most a 4-fold increase in the plasma insulin concentration is necessary to stimulate adipocytes for maximum lactate release.
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Acknowledgments |
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Received April 2, 1998.
Revised July 20, 1998.
Accepted August 28, 1998.
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References |
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