Department of 1 Endocrinology and Metabolism M, and 2 Medicine V (Hepatology and Gastroenterology), Aarhus University Hospital, 8000 Aarhus C, Denmark; 3 Department of Medicine and National Science Foundation Center for Biological Timing, University of Virginia, Charlottesville, Virginia 22908; and 4 Department of Hepatology, Freiburg University Hospital, Freiburg, Germany
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ABSTRACT |
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Insulin is secreted as a series of
punctuated secretory bursts superimposed on variable basal insulin
release. The contribution of these secretory bursts to overall insulin
secretion has been estimated on the basis of peripheral vein sampling
in humans to encompass 75% of overall insulin release. A similar
contribution of the pulsatile mode of release was inferred in a canine
model by use of portal vein sampling. The primary regulation of insulin secretion is through perturbation of the mass and frequency of these
secretory bursts. The mode of delivery of insulin into the circulation
seems important for insulin action; therefore, physiological conditions
that alter the pattern of insulin release may affect insulin action
through this mechanism. Transhepatic intraportal shunt in humans may
provide access to portal vein samples, thus potentially improving the
sensitivity of detecting and quantitating the frequency, mass, and
amplitude of secretory bursts along with basal release and the
regularity of these variables. To establish the insulin-secretory
mechanism in nondiabetic humans by the use of portal vein sampling, we
here assessed the mass, frequency, amplitude, and overall contribution
of pulsatile insulin secretion by deconvolution analysis of portal vein
insulin profiles. We find that, in nondiabetic humans fasted overnight,
the portal vein insulin concentration oscillates at a periodicity of
4.1 ± 0.2 min/pulse and with secretory peak amplitudes averaging
660% of basal (interpulse) release. The frequency was confirmed by spectral and autocorrelation analyses. The punctuated insulin-secretory bursts partially overlap and are responsible for the majority (70 ± 4%) of insulin release. After ingestion of a mixed meal, the
insulin release was increased through amplification of the secretory
burst mass (507 ± 104 vs. 1,343 ± 211 pmol · l
1 · min
1,
P < 0.001), whereas frequency (4.4 ± 0.2 vs.
4.3 ± 0.2, P = 0.86) and basal secretion (62 ± 14 vs. 91 ± 22 pmol · l
1 · min
1,
P = 0.33) were unaffected. One subject with diabetes
and cirrhosis had a similar insulin-secretory pattern, whereas a
subject with insulin-dependent diabetes mellitus and minimal insulin
release had preserved pulsatile release. A single subject was entrained to show agreement between entrained frequency and portal vein insulin
oscillations. We conclude that insulin release in the human portal vein
occurs at a mean periodicity of 4.4 ± 0.2 min with a high
signal-to-noise ratio (pulse amplitude 660% of basal). The impact of
noise on the detected high frequency cannot be excluded.
C-peptide; oscillations; cirrhosis; secretion; diabetes
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INTRODUCTION |
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INSULIN IS SECRETED in a pulsatile
manner (4), resulting in high-frequency insulin
concentration oscillations in the peripheral circulation. These
high-frequency oscillations are apparently caused by interislet
coordinate insulin-secretory bursts at a periodicity of 5-15
min/pulse (4, 7, 21). The contribution of these
insulin-secretory bursts to overall insulin secretion has been
quantified in a canine model by direct sampling across the pancreas
(21) and in a human model by employing high-frequency sampling of peripheral venous blood, a highly specific insulin assay,
and validated deconvolution analysis (20). In both
species, the overall contribution of pulsatile insulin secretion to
total insulin release is 70-75%. Furthermore, the mechanisms
underlying changes in overall insulin secretion after stimulation
(18, 19) and inhibition (16, 20) are exerted
principally via modulations in the pulsatile component of insulin
secretion, with changes in the mass and/or frequency of
insulin-secretory bursts. It therefore appears that the pulsatile
pattern is physiologically integrated to overall
-cell
secretory performance, as underscored by impaired pulsatility in
non-insulin-dependent diabetes mellitus (NIDDM) (6) and
glucose-intolerant first-degree relatives of NIDDM patients
(11) and by a defective release process in
glucose-tolerant first-degree relatives of NIDDM patients
(24). Conversely, more effective actions of insulin on
muscle (9), adipose (23), and liver
(5) tissues have been reported when the hormone is delivered in a pulsatile vs. constant manner.
Most of our present knowledge on pulsatile insulin secretion in the human is based on analysis of concentration changes in the peripheral circulation (4, 6, 7, 11, 21, 24) and to some extent on portal vein sampling in animal models (18-20), in human patients with cirrhosis (27), and recently as reported in Ref. 25. Application of portal vein sampling in humans would offer insights into the pattern of insulin delivery to the liver in humans, allow estimates of true insulin release patterns under optimal sampling conditions, and permit comparisons with previously published literature on in vivo pulsatile insulin secretion. One drawback would be noise from variable catheter placement and streaming, both of which may introduce false signals. Portal vein sampling through transjugular intrahepatic portosystemic shunt (TIPS) is possible in patients with cirrhosis or portal vein thrombosis. Because liver failure is associated with diabetes, in this context, the model may provide insight into the insulin-secretory role in this specific metabolic disease. In contrast, in isolated portal vein occlusion, pancreatically healthy subjects may be investigated.
The present studies were designed to accomplish sampling from the portal vein in humans and provide insulin concentration time series for detailed analysis of secretory patterns in nondiabetic individuals. The potential role of using TIPS for pancreatic hormonal release studies could thus be explored in these circumstances and in a single subject with type 1 diabetes but preserved (trivial) insulin release.
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METHODS |
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Subjects and Design
The protocol was approved by the Ethics Committee of Freiburg University Hospital and was performed in accordance with the Helsinki Declaration. Ten volunteers were studied. The study was designed to allow multiple analyses of basal and mixed-meal-stimulated insulin release processes in a rather heterogeneous group of participants who needed transhepatic portal vein catheterization as part of TIPS treatment. The subjects did not receive any other medication than local anesthesia and their usual medicine on the day of the study. The treatments with steroids or
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Protocols
After an overnight fast, the participants were brought to the Clinical Research Unit, University of Freiburg. The TIPS catheterization procedure has previously been described in detail (27). After puncture of the internal jugular vein and introduction of an 11-F sheath, a catheter was advanced into the right or middle hepatic vein. A puncture needle (modified Ross needle, Collx, Mönchengladbach, Germany) was inserted through the catheter, and the puncture of an intrahepatic branch of the portal system was performed under fluoroscopy and ultrasound guidance. After successful puncture, the catheter was placed in the mainstream of the extrahepatic portal vein to allow repeated blood sampling. In the patients with portal vein thrombosis, the catheter was placed at the confluence of the splenic and mesenteric veins. After blood sampling from the portal catheter and central venous sheath, the TIPS procedure was accomplished by implantation of a metallic stent into the parenchymal tract of the liver (27). In patients with portal vein thrombosis, TIPS and thrombolysis were performed the day before the study day.After catheter placement, 30 min were allowed as a resting period before sampling protocols were initiated. Sampling was performed for 40 min from portal vein (F; n = 9) and peripheral vein catheters (P; n = 2) simultaneously in the basal state (protocol 1). After the basal period, the patients ingested a standardized mixed meal, and 40 min after meal ingestion, a second sampling period of 40 min (M; n = 9) was performed (protocol 2). One subject (subject 10) was studied during pulse induction, a recently introduced method whereby glucose was infused into a peripheral vein at a rate of 6 mg/kg for 1 min every 10 min. This method has been shown to allow the pulsatile insulin release to be controlled by predetermined intervals. Samples were collected simultaneously from the portal and peripheral circulation.
Samples were collected from the portal vein catheter and from a
peripheral catheter placed in the femoral vein. Blood sampled at 1-min
intervals was processed for later measurement of insulin concentrations; in addition, blood was collected at 10-min intervals for measurements of C-peptide and glucose concentrations. To ensure the
patency of the portal vein sampling catheter, blood was collected by
slow and continuous withdrawal. The femoral vein catheter was flushed
with saline after each sample collection, and catheter dead space plus
0.8 ml was withdrawn before the next collection. All samples were
stored at 20°C until analysis for concentration measurements.
Assays
Glucose. Plasma glucose concentrations were measured by the glucose oxidation method (Beckman Instruments, Palo Alto, CA).
Insulin. Serum insulin concentrations were measured in triplicate by a two-site immunospecific insulin ELISA, as previously described (1). In brief, the assay uses two monoclonal murine antibodies (Novo Nordisk, Bagsvaerd, Denmark) specific for insulin. The detection range of this insulin ELISA is 5-600 pM. At low (20 pM), medium (150 pM), medium-high (200 pM), and high (350 pM) plasma insulin concentrations, the interassay coefficients of variation (among triplicates) were 5.2, 3.7, 4.0, and 4.5%. Corresponding intra-assay variations were 3.0, 2.3, 2.1, and 2.0%. There is no cross-reactivity with C-peptide, insulin-like growth factor (IGF)-I, IGF-II, glucagon proinsulin, and split (32,33) and des (31,32)-proinsulin. The antibodies cross-react 30 and 63% with split (65,66)-proinsulin and des (64,65)-proinsulin, respectively (1).
C-peptide. C-peptide measurements were performed using a commercially available kit (K6218, DAKO Diagnostics, Cambridgeshire, UK). The assay is a two-site ELISA based on two monoclonal antibodies and employs the same principles referred to in Insulin. Each sample was assayed in duplicate, and the intra- and interassay (among triplicates) coefficients of variation were 2.2 and 3.3%, respectively. The detection limit was 35 pM.
Data Analysis
Detection and quantification of pulsatile insulin secretion by deconvolution analysis. The plasma insulin concentration time series were analyzed by deconvolution for purpose of detection and quantification of insulin-secretory bursts. Deconvolution of venous insulin concentration data was performed with a multiparameter technique (29), which requires the following assumptions. The venous plasma insulin concentrations measured in samples collected at 1-min intervals are assumed to result from five determinable and correlated parameters: 1) a finite number of discrete insulin-secretory bursts occurring at specific times and having 2) individual amplitudes (maximal rate of secretion attained within a burst), 3) a common half-duration (duration of and algebraically Gaussian secretory pulse at half-maximal amplitude), which is superimposed on 4) a basal time-invariant insulin-secretory rate, and 5) a biexponential insulin disappearance model. In the systemic circulation, disappearance consisted of assumed half-lives of 2.8 and 5.0 min and a slow component fraction of 0.28, as previously measured (21), whereas in the portal vein, disappearance consisted of assumed half-lives of 0.2 and 3.0 min and a fractional slow component of 0.065 based on repetitive analysis using a wide range of kinetic values and choosing the model with best agreement to the observed data (lowest sum of squared residuals). The kinetic values are in agreement with literature reports (21), although different values would be expected due to TIPS and liver diseases. Shunting of insulin, recirculation, and esophageal varices all contribute in varying degrees to the (already large) uncertainty in the estimated kinetic values. The assumed kinetic parameters would ideally be determined by bolus insulin injection upstream of the sampling catheter, but this would not be possible for ethical reasons. Therefore, the kinetic parameters are not measured directly and may be inaccurate, although a similar procedure for estimating insulin kinetics in a canine model with infusion and sampling catheters showed a good ability to quantitate parameters from fitting to endogenously released insulin. Assuming the foregoing nominal insulin disappearance values, we estimated the number, locations, amplitudes, and half-duration of insulin-secretory bursts, as well as a simultaneous zero or nonnegative basal insulin-secretory rate, for each data set by nonlinear least squares fitting of the multiparameter convolution integral to each insulin time series. A modified Gauss-Newton quadratically convergent iterative technique was employed with an inverse (sample variance) weighting function. Parameters were estimated until their values and the total fitted variance both varied by less than 1 part in 100,000. Asymmetric highly correlated variance spaces were calculated for each parameter by the Monte Carlo support plane procedure. Secretory rates are expressed as mass units of insulin (pmol) released per unit of distribution volume (liters) per unit of time (min). The mass of hormone secreted per burst (time integral of the calculated secretory burst) was thus computed as picomoles of insulin released per liter of corresponding distribution volume. Because the calculated values represent posthepatic insulin appearance for peripherally deconvoluted secretory rates, total insulin secretion was calculated using C-peptide concentrations (28). When the deconvolution analysis was performed, basal secretion was adjusted to allow accommodation of most interpulse troughs. Likewise, the secretory burst half-duration was adjusted to fit individual obvious secretory bursts, consisting of series of data points building up to a peak and down to a trough. All data analysis was performed in a blinded manner.
Periodicity analysis. The frequency of the insulin pulses may be estimated by spectral analysis or autocorrelation analysis, which evaluate the concentration time series for regular periodicities. Autocorrelation analysis examines the replicability of patterns by moving a template across the time series and estimates the correlation among data points at increasing time lags. Spectral analysis tests the comparability of the data with a sinusoidal variability and gives a spectral density peak as a measure of the signal at a given periodicity. Both methods are well established in mathematics and biology and have been used in the studies herein on insulin pulsatility.
Regularity Statistics
The pulsatile insulin release pattern may also be characterized in further detail to examine the reproducibility of the subordinate patterns in the data set. A validated mathematical approach is the application of approximate entropy (ApEn) (15, 24). ApEn is a recently introduced regularity statistics tool that measures the logarithmic likelihood that runs of patterns reproduce on the next incremental comparison. The method has proved useful in analysis of pulsatile insulin secretion (10, 24) for discriminating between pathophysiology and health. The method is robust to noise and to absolute differences in data.Statistics
All data in the text and figures are given as means ± SE. Student's two-tailed paired t-test was used to examine statistical significance. ![]() |
RESULTS |
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Concentrations
The portal vein insulin concentrations showed large oscillations (~80-600%) both before and during meal ingestion (Fig. 1). In contrast, the peripheral vein concentrations oscillated by ~30%, thus revealing a 3- to 20-fold reduction in the insulin pulsatile signal (Fig. 2). Despite the reduced amplitude, the peripheral insulin pulses could still be detected as concentration changes (Fig. 2). From Fig. 1, it appears visually that the liver is exposed to large-amplitude insulin oscillations that occur at an interval of ~5 min/pulse and with mean changes of 100-600%. In subject 10, portal vein concentrations were controlled by the glucose infusion, indicating that the observed variability in portal vein insulin concentrations truly represents coordinate insulin release rather than noise (Fig. 2).
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Secretion
Nondiabetic subjects: basal state.
Insulin secretion was assessed (n = 8) by deconvolution
analysis of serial portal vein serum insulin concentration measurements and revealed the presence of discrete, punctuated insulin-secretory bursts that were superimposed on basal insulin secretion in all studies. For the nondiabetic subjects (n = 7), analysis
revealed, consistent with inspection of raw portal vein insulin
concentration data, that the concentration changes arise from high
frequency (i.e., low periodicity, 4.4 ± 0.2 min/pulse), large
amplitude (213 ± 53 pmol · l1 · min
1)
insulin-secretory bursts, with little basal insulin secretion (65 ± 14 pmol · l
1 · min
1).
Consequently, the overall contribution of pulsatile insulin secretion
was calculated as 70 ± 4%. On the basis of peripheral vein
deconvolution in two subjects, a similar observation of frequency (5.0 min/pulse) and relative pulsatile contribution to overall insulin
release of ~70% was made. The nature of the individual insulin-secretory burst in all cases was compatible with a Gaussian distribution and half-duration of 2.3 ± 0.2 min. Analysis
of simultaneously measured peripheral and portal vein insulin
concentrations yielded good agreement between calculated secretory
patterns at these two sampling sites. The changes in insulin secretion
were reflected in C-peptide concentrations: peripheral vein (1,019 ± 277 vs. 1,682 ± 750 pM) and portal vein (1,175 ± 290 vs.
2,686 ± 278 pM) concentrations increased as expected after meal ingestion.
Postprandial insulin secretion.
In the postprandial state, the insulin-secretory pattern was preserved
(n = 7; Fig. 1). The mechanism of increasing the
insulin secretion was by amplification of the insulin-secretory
burst mass (507 ± 104 vs. 1,343 ± 211 pmol · l1 · min
1,
P < 0.001), whereas frequency (4.4 ± 0.2 vs.
4.3 ± 0.2, P = 0.86) and basal secretion (62 ± 14 vs. 91 ± 22 pmol · l
1 · min
1,
P = 0.33) were not significantly affected, although the
latter might have been significant had a larger number of subjects been studied.
Regularity Statistics
The application of autocorrelation and spectral analyses resulted in significant periodicities in some, but not all, of the subjects. The results are shown in Table 2. The lack of significant periodicities is likely due to short sampling durations. The design was limited because of the underlying diseases of the participants and was originally chosen to allow for deconvolution, where sampling duration is of lesser importance. As is seen, spectral analysis showed significant peaks in seven of eight subjects in the non-glucose-induced studies, revealing a mean periodicity of 4.50 ± 0.63 min/oscillation. Autocorrelation tended to show periodicities in five of eight subjects, with a mean periodicity of 4.90 ± 1.00, although these were not significant in any subject. During glucose induction, there was a significant spectral density peak at 10-min intervals, as would be expected.
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Pulsatile Insulin Secretion in Type 1 Diabetes Mellitus?
The subject with insulin-dependent diabetes mellitus (IDDM) had some variation in portal vein insulin concentrations. This variation was very modest; nonetheless, inspection of raw data indicated that the variation was not random (Fig. 3). Analysis by ApEn for data regularity could not detect any significant pattern compared with randomly shuffled data, and there was not a significant frequency by autocorrelation analysis of first-differenced data. However, for both statistical approaches, a P value of 0.1-0.15 indicated that the lack of significance could potentially be secondary to the short data series (40 data points), which for both approaches is a small sample size for analysis. In contrast, deconvolution analysis, with use of 95% confidence intervals for all amplitudes considered jointly, suggested significant secretory burst activity. The C-peptide concentrations were, in almost all cases, below the detection limit (35 pM). The only detectable concentration occurred after meal ingestion and in the portal vein. By use of the concentrations read by the ELISA reader there was an increase in the portal vein vs. peripheral vein C-peptide concentrations (mean of 5 measurements, 13 vs. 7 pM) and a portal vein increase after meal ingestion (mean of 5 measurements, 13 vs. 32 pM), thus indicating the occurrence of minimal insulin release in response to meal ingestion. The absorbance detected by the ELISA reader showed the same changes.
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Insulin Secretion in Type 2 Diabetes and Cirrhosis
One patient with diabetes and cirrhosis was studied. The subject did not receive antidiabetic drugs. Comparison of the deconvoluted secretory pattern in this subject with that of the nondiabetic subjects revealed an apparently similar pulsatile secretory pattern (Fig. 4). The burst periodicity and mass were (4.8 min/pulse and 563 pmol · l
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DISCUSSION |
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We have employed transhepatic intraportal high-frequency blood sampling in humans to measure prehepatic insulin concentration time series in a highly sensitive and specific insulin ELISA. Data were subjected to deconvolution analysis to define secretory burst activity. These analyses reveal that the release of insulin consists of serial secretory burst-like events and is regulated by amplification of the secretory burst mass upon mixed-meal ingestion. In one subject with NIDDM and cirrhosis, a similar pattern was observed, whereas the insulin concentration data in one subject with type 1 diabetes suggested a minimally preserved release of low-amplitude secretory bursts.
Because the nature of insulin secretion is pulsatile (4)
and the contribution by secretory bursts per se may be the major mechanism regulating release in fasting (20, 21),
inhibited (16, 20), and stimulated (19, 22)
states, we sought to characterize in vivo insulin secretion in humans
by use of the portal vein sampling procedure combined with a
deconvolution technique. Similar sampling protocols have previously
been employed in humans (27) with the use of discrete
pulse detection algorithms to identify significant oscillations in
insulin concentrations and, recently (25), with the use of
methods similar to those herein and reporting similar changes upon
stimulation with hyperglycemia. Also, portal vein sampling has
been used in one other species and combined with deconvolution
techniques to allow quantitative measurements of insulin secretion
(21). The techniques used confirm previous inferences on
the importance of the pulsatile mode of release in overall insulin
release. The present detailed analysis of the shape, frequency, and
relative amplitude of insulin-secretory episodes in the human portal
vein shows that the vast majority of insulin is secreted as
high-frequency (~4.4 min/pulse), high-amplitude (~660% of basal
secretion) pulses with a brief half-duration of ~2.3 min and with
little interpulse secretion (referred to as basal secretion).
Therefore, the insulin release patterns to which the liver is exposed
are very dynamic and resemble an on/off delivery pattern. In a large
number of in vivo (9, 12-14, 23) and in vitro
(5) studies, this on/off signal pattern is important for
insulin action. In addition to the enhanced actions on target tissues,
the pulsatile pattern of insulin signaling via secretory bursts and
secretory pauses may be important for optimal -cell function, since
this dynamic process may allow short-term "pancreatic rest/recovery" without the depolarization, increase of intracellular calcium, and ionic changes in the
-cells known to occur during a
secretory burst (3, 8). Portal vein sampling has also been
used recently (25) under basal and hyperglycemic
conditions. The reported frequency of ~5 min/pulse is similar to the
present periodicity, and similarly, hyperglycemia did not alter the
frequency. The present study included a diabetic subject with cirrhosis
as the likely cause and a subject in whom control of the pulsatile insulin release was attempted by punctuated glucose infusions, confirming that between-pulse secretory activity is minimal, if present
at all. We acknowledge that noise may be dependent on catheter
placement and that differences in frequency reported herein and
previously (19) may depend on optimal sampling conditions. The
problem with detection of false-positive pulses is clearly demonstrated
in patient 10 (Fig. 2), in whom one false positive, nonentrained pulse was detected. However, this patient also
demonstrates that portal vein concentrations are at times similar to
peripheral vein concentrations, picked up as minimal basal secretion by
portal vein deconvolution, whereas peripheral vein deconvolution
detected some basal release.
The present study using portal vein catheterization revealed that
overall insulin secretion after meal ingestion is modulated by changes
in secretory burst amplitude (and, hence, mass), whereas no significant
changes in frequency were observed in the subjects studied, which
supports previous reports (2). The amplification of the
secretory burst mass indicates that an increased amount of insulin is
released per -cell within each secretory event and/or that more
-cells are contributing to the secretory burst; i.e., that
recruitment occurs. Our observations also imply that the hepatic
insulin exposure patterns change with nutrient supply, which may be of
importance for hepatic handling of nutrients.
Portal vein insulin concentration profiles and C-peptide concentrations in the IDDM patient suggested trivial insulin release but preserved pulsatile insulin secretion despite a very limited insulin-secretory capacity. Although these data did not reveal significant oscillatory patterns by autocorrelation analysis and ApEn, this could be an artifact resulting from the short sampling duration. Deconvolution analysis to detect any concerted secretory activity by use of defined detection criteria showed modest but significant insulin-secretory activity. If this observation is confirmed, it will indicate preserved interislet coordinating mechanisms in IDDM; that is, coordinating mechanism(s) do not arise from an insulin/target-organ/insulin feedback loop, because the very small changes in portal vein insulin concentrations are unlikely to have an impact on target organs. Therefore, this finding will support the hypothesis of an intrapancreatic neuronal pacemaker (17, 26).
The present study also included one subject with NIDDM and cirrhosis. In this subject, insulin release was not detectably different from that in the nondiabetic subjects. The cause of diabetes in this subject is unknown, but the presence of "normal" pulsatile insulin release suggests that the cause was cirrhosis rather than type 2 diabetes, because pulsatile insulin secretion is impaired in the latter. This would imply that the pulsatile release may be preserved in some secondary diabetes despite chronic hyperglycemia and the concomitant metabolic abnormalities.
The benefits of portal vein sampling in humans are, to some extent, vitiated by the primary diseases that make these subjects suitable for TIPS. Indeed, the patients studied herein had different primary diseases causing stress and, likely, variable insulin resistance. Nonetheless, the derived insulin-secretory profiles mimic both those reported in a healthy canine model with the use of portal vein sampling and in healthy humans evaluated via peripherally sampled blood, indicating that the model is not severely impaired by the primary diseases. To address specific questions, the portal vein sampling model may be the most accurate in affording detailed insights into insulin-secretory activity. Also, the present study shows that the model is very suitable for studies in liver disease, where prehepatic hormonal delivery is likely of great importance for hepatic performance. Further investigations using TIPS may prove useful to further elucidate metabolic derangement(s) in cirrhosis and other primary liver diseases. The obvious drawback is potential noise, causing detection of false pulses leading to a too-high estimate of frequency. The data herein suggest that this does play some role.
We conclude that human portal vein blood sampling corroborates previously reported insulin-secretory pattern(s) based on peripheral sampling and that the pulsatile mode is dominant (70 ± 4% of total insulin release) in the fasting and postprandial states. We suggest that the TIPS portal vein sampling model may be suitable for addressing specific questions on the dynamics of insulin release. Furthermore, data from one subject with IDDM suggest preserved insulin pulsatility despite a lack of insulin-to-glucose feedback mechanisms and very low secretory capacity. Finally, a cirrhotic-diabetic patient exhibited insulin secretion that evidently was not different from that in nondiabetic subjects.
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ACKNOWLEDGEMENTS |
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The work for this study was conducted at Department of Medicine V (Hepatology and Gastroentorology), Aarhus University Hospital.
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FOOTNOTES |
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Address for reprint requests and other correspondence: N. Pørksen, Dept. of Medicine M (Endocrinology and Metabolism), Aarhus Univ. Hospital, 8000 Aarhus C, Denmark. (E-mail: porksen{at}dadlnet.dk).
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.
10.1152/ajpendo.00516.2000
Received 6 November 2000; accepted in final form 4 October 2001.
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