1 The Clinical Research Unit for Gastrointestinal Endocrinology, Department of Internal Medicine, Philipps University, 35033 Marburg, Germany; 2 Department of Internal Medicine, Washington University, St. Louis, Missouri 63110; and 3 Department of Gastroenterology, Inselspital, University of Bern, CH-3010 Bern, Switzerland
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ABSTRACT |
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The present study was undertaken to
establish in normal volunteers the alterations in -cell
responsiveness to glucose associated with a constant infusion of
glucagon-like peptide-1 (GLP-1) or a pretreatment infusion for 60 min.
A high-dose graded glucose infusion protocol was used to explore the
dose-response relationship between glucose and insulin secretion.
Studies were performed in 10 normal volunteers, and insulin secretion
rates (ISR) were calculated by deconvolution of peripheral C-peptide
levels by use of a two-compartmental model that utilized mean kinetic
parameters. During the saline study, from 5 to 15 mM glucose, the
relationship between glucose and ISR was linear. Constant GLP-1
infusion (0.4 pmol · kg
1 · min
1) shifted
the dose-response curve to the left, with an increase in the slope of
this curve from 5 to 9 mM glucose from 71.0 ± 12.4 pmol · min
1 · mM
1
during the saline study to 241.7 ± 36.6 pmol · min
1 · mM
1 during
the constant GLP-1 infusion (P < 0.0001). GLP-1
consistently stimulated a >200% increase in ISR at each 1 mM glucose
interval, maintaining plasma glucose at <10 mM (P < 0.0007). Pretreatment with GLP-1 for 60 min resulted in no significant
priming of the
-cell response to glucose (P = 0.2).
Insulin clearance rates were similar in all three studies at
corresponding insulin levels. These studies demonstrate that
physiological levels of GLP-1 stimulate glucose-induced insulin
secretion in a linear manner, with a consistent increase in ISR at each
1 mM glucose interval, and that they have no independent effect on
insulin clearance and no priming effect on subsequent insulin secretory
response to glucose.
insulin secretion; connecting peptide; priming; -cell
sensitivity
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INTRODUCTION |
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IN NORMAL SUBJECTS, insulin secretion is far more enhanced in response to an oral than an intravenous glucose load, resulting in similar plasma glucose concentrations (9, 30). This hyperinsulinemia occurring after oral glucose results from a combination of increased insulin secretion and diminished insulin clearance (29). The enhanced insulin response is mediated by the gastrointestinal hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), which act as physiological incretins in humans. GLP-1 is a natural enteric peptide that results from posttranslational processing of the glucagon precursor proglucagon in the intestinal L-cells (6). It is secreted in response to a mixed meal and has been shown to potently stimulate glucose-induced insulin secretion in animals (1, 2, 19, 21) and in humans (15, 20, 23, 28). It thereby plays a physiological role in the control of postprandial glucose levels (8). However, the precise in vivo alterations in the glucose-insulin secretion dose-response relationships in response to GLP-1 in healthy human subjects and its effects on insulin clearance have not been described.
In addition to its effect as an incretin, in vitro studies have
proposed that GLP-1 regulates -cell function by maintaining at least
a portion of the
-cell population in a glucose-competent state by
making resistant islets glucose sensitive (17, 18). Pretreatment of isolated islets (18) or the isolated
perfused pancreas (11) with GLP-1 in vitro has been shown
to enhance the insulin secretory response to a subsequent stimulation
with glucose or other secretagogues.
The present study was therefore undertaken to establish the in vivo
glucose dependency of the action of GLP-1 in normal healthy volunteers
and the effect of GLP-1 on insulin clearance, and to establish whether
a priming effect of GLP-1 on subsequent insulin secretory response to
glucose exists. The protocol first involved characterizing the
dose-response relationship between glucose and insulin secretion rates
(ISR) during a high-dose graded glucose infusion and then examined the
alterations that occurred after pretreatment with GLP-1 or with a
constant infusion of GLP-1, resulting in postprandial physiological
levels. The advantage of this protocol is that it yields ISR at each 1 mM glucose interval, and therefore ISR can be compared at corresponding
glucose levels in the same individuals by use of factors that may alter
the sensitivity of the pancreatic -cells to glucose. This protocol
also allows changes in insulin clearance to be defined.
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MATERIALS AND METHODS |
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Subjects
Studies were performed in 10 healthy male Caucasian volunteers aged 22-27 yr (mean ± SE, 25.2 ± 0.6). Subjects were within 10% of ideal body weight (body mass index, 23.5 ± 0.5 kg/m2). None of the participants had a personal or family history of diabetes. Subjects had no other medical illnesses and were not receiving any medications. All subjects were placed on a weight maintenance diet consisting ofExperimental Protocol
Each subject was studied on three occasions separated by intervals ofHigh-Dose Graded Intravenous Glucose Infusion Protocol
This protocol was designed to explore the dose-response relationship between glucose and ISR and to study the effects of GLP-1 on this relationship. The protocol is similar to that previously validated (4, 5) but utilizes higher glucose infusion rates. Baseline samples were drawn every 10 min for 30 min to define baseline glucose, insulin, C-peptide, and glucagon. A stepped-up infusion of glucose (20% dextrose) was then started at +30 min at a rate of 1 mg · kgSynthetic human GLP-1-(7-36) amide was synthesized by
Saxon Biochemicals (Hannover, Germany), with a peptide content of
88.08% and a peptide purity of >99%. The infusion rate of the
peptide was calculated from the net peptide content (88%) rather than the total weight. GLP-1-(7-36) amide was dissolved in
1% human serum albumin (Bayer, guaranteed to be free of hepatitis-B
surface antigen and human immunodeficiency virus antibodies), filtered through 0.2-µm nitrocellulose filters, and then stored at 70°C in
individual glass ampules under sterile conditions until the day of the
experiment. HPLC after sterile filtration showed a single peak for
GLP-1-(7-36) amide. Samples were tested for pyrogens, bacteria, and endotoxins.
Assays
Plasma glucose levels were measured by the Yellow Springs Instrument glucose oxidase technique (Schlag, Bergisch-Gladbach, Germany). The coefficient of variation of this method is <2%. Plasma insulin was measured by the Abbott IMx Microparticle Enzyme Immunoassay, which shows cross-reactivity with proinsulin of <0.005%. The average intra-assay coefficient of variation was 5%. Plasma C-peptide was measured as previously described (10). The lower limit of sensitivity of the assay is 20 pmol/l, and the intra-assay coefficient of variation averaged 6%. Glucagon was measured by using a commercially available radioimmunoassay kit (Biermann, Bad Nauheim, Germany), and the intra-assay coefficient of variation averaged 8%. IR-GLP-1 was measured using the specific polyclonal antibody GA 1178 (Affinity Research, Nottingham, UK) (16). It has 100% reactivity with GLP-1-(1-36) amide and the truncated GLP-1-(7-36) amide. Immunoreactive GLP-1-like material was extracted from plasma samples on C18 cartridges with use of acetonitrile for elution of the samples. The detection limit of the assay was 2 fmol/tube. The antiserum did not cross-react with GIP, pancreatic glucagon, glicentin, oxyntomodulin, or GLP-2. Intra- and interassay coefficients of variation were 3.4 and 10.4%, respectively.Data Analysis
Determination of ISR. Standard kinetic parameters for C-peptide clearance adjusted for age, sex, and body surface area were used (32) to derive, in each 10-min interval between blood sampling, the ISR from the plasma C-peptide concentrations by deconvolution, as previously described (7, 26).
Relationship between glucose and ISR, and glucose and insulin.
Baseline glucose, insulin, C-peptide, and ISR were calculated as means
of the values in the 30,
20,
10, and 0 min samples. ISR, insulin,
and glucose concentrations used in the analysis represented the average
of the values between 10 and 40 min during each glucose infusion
period. Mean ISR and mean insulin for each glucose infusion period were
then plotted against the corresponding mean glucose level to define the
dose-response relationship between glucose and these variables. Mean
ISR and mean insulin were determined for 1 mM glucose concentration
intervals by calculating the area under the curve for each interval
with the trapezoidal rule. This area was then divided by 1 mM to obtain
the correct units. The local absolute slope of the glucose-ISR
dose-response curve at a given glucose interval was defined as the
increment in ISR from that interval to the next, divided by the glucose
interval. This definition yields the units of picomoles per minute
times concentration in mM. Insulin clearance was calculated by dividing
the mean ISR by the mean plasma insulin at each period of glucose
infusion (30) adjusted for body surface area. Mean insulin
clearance at each glucose infusion rate was plotted against the
corresponding mean insulin level to compare insulin clearance at
corresponding insulin levels.
Statistical Analysis
All results are expressed as means ± SE. Data analysis was performed using the Statistical Analysis System (SAS version 6 edition for personal computers; SAS Institute, Cary, NC). The significance of intraindividual differences induced by GLP-1 infusion was determined using paired t-tests. Two-way analysis of variance for repeated measures was used to assess whether there were significant differences between study conditions in glucose, ISR, insulin, and insulin clearance. Differences were considered to be significant at P < 0.05. ![]() |
RESULTS |
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Mean Glucose, Insulin, and Glucagon Levels During the 60-Min Pretreatment Infusion of GLP-1
Mean glucose, insulin, and glucagon profiles are shown in Fig. 1. Plasma glucose levels were reduced from 4.59 ± 0.12 mM at
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Plasma GLP-1 Levels
Mean GLP-1 levels during the constant GLP-1 infusion from 30 to 240 min were 16.3 ± 1.6 vs. 1.1 ± 0.2 pmol/l during saline infusion vs. 1.2 ± 0.2 pmol/l after pretreatment with GLP-1; P < 0.0002. Pretreatment with GLP-1 yielded levels of 16.4 ± 0.9 pmol/l fromResponses in Glucose, Insulin, and ISR during a High-Dose Graded Intravenous Glucose Infusion with Saline, after 60-Min Pretreatment with GLP-1 and During Constant Infusion with GLP-1
Mean glucose and ISR profiles are shown in Fig. 2. Mean levels of plasma glucose, insulin, and ISR for each period of glucose infusion are shown in Table 1. To allow the ISRs at the same plasma glucose levels to be compared during the three studies, the average amount of insulin secreted at each glucose infusion rate was plotted against the corresponding glucose level. The resulting glucose-ISR dose-response relationships are shown in Fig. 3. The curve obtained during saline infusion is linear in the glucose range from 5 to 15 mM. Pretreatment with GLP-1 resulted in no alteration of the dose-response curve. Constant GLP-1 infusion shifted the dose-response curve upward and to the left. The mean slope of the glucose-ISR dose-response curve from 5 to 9 mM glucose in the respective studies was 71.0 ± 12.4 vs. 82.2 ± 11.5 vs. 241.7 ± 36.6 pmol · min
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Average insulin levels from 5 to 9 mM glucose were increased from
72.9 ± 7.4 to 77.1 ± 7.8 to 511.7 ± 121.7 pmol/l;
P < 0.0002, representing an increase of 539 ± 80% compared with the saline study. The increase in insulin was
greater than the increase in ISR, implying that there was a change in
the clearance rate of insulin during the constant GLP-1 infusion.
Calculation of insulin clearance rates (Fig.
4) revealed that insulin clearance
significantly decreased during the saline study at glucose infusion
rates of 16 and 24 mg · kg1 · min
1
(P < 0.001) and was significantly further reduced
during the last three periods of glucose infusion during the constant
GLP-1 infusion (P < 0.0005). Interestingly, when
insulin clearance was compared at corresponding insulin levels, there
was no significant difference between the studies. For saline vs.
constant GLP-1 infusion, clearance at insulin levels from 0 to 250 pmol/l was 1.64 ± 0.14 vs. 1.82 ± 0.11 l · min
1 · m
2;
P = 0.15, at insulin levels of 250-500 pmol/l,
1.14 ± 0.05 vs. 1.06 ± 0.05 l · min
1 · m
2;
P = 0.3, and from 500 to 750 pmol/l, 0.87 ± 0.05 vs. 0.90 ± 0.05 l · min
1 · m
2;
P = 0.7.
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DISCUSSION |
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The present study was undertaken to explore the
dose-response relationships between glucose and insulin secretion in
normal human volunteers during a high-dose glucose infusion and to
study the alterations resulting from constant GLP-1 infusion and
pretreatment with GLP-1. We infused GLP-1 at a dose of 0.4 pmol · kg1 · min
1, as this
dose yields plasma levels in the upper range of postprandial physiological levels, which have previously been shown to potently increase the insulin response to intravenous glucose (3,
20). The high-dose graded glucose infusion resulted in changes
in plasma glucose from 5 to 15 mM. Use of the two-compartmental
mathematical model with standard kinetic parameters for C-peptide
enabled ISR to be derived from peripheral C-peptide concentrations by
deconvolution and thereby enabled changes in insulin clearance to be
detected. The ability of the
-cell to respond to glucose over a wide
glucose range was examined in the same individual in response to
factors known to alter the sensitivity of the pancreatic
-cells to glucose.
The high-dose graded glucose infusion resulted in a dose-response curve
that was linear in the glucose concentration range from 5 to 15 mM,
with no evidence of tapering off of insulin secretion as higher glucose
concentrations are achieved. Short-term constant GLP-1 infusion
resulted in a shift of the dose-response curve to the left, with an
increase in slope from of 71.0 ± 12.4 to 241.7 ± 36.6 pmol · min1 · mM
1 from 5 to
9 mM glucose. At each 1 mM glucose interval, there was consistently a
>200% increase in ISR, with no evidence of
-cell exhaustion.
In vitro studies have shown that GLP-1 has a priming effect on the
-cell response to glucose (11, 18) and constitutes biphasic insulin release in human fetal pancreatic
-cells
(24). These priming effects of GLP-1 may reflect the
prolonged action of cytosolic second messengers and/or slow
dissociation of GLP-1 from its receptor, or they may be due to
increased GLUT-2 expression and glucokinase mRNA (33). In
our study, pretreatment with GLP-1 resulted in no shift of the glucose
insulin secretion dose-response curve. These results suggest that
GLP-1-induced priming of
-cells, demonstrated in in vitro studies
(11, 18), cannot be detected in humans, at least at
physiological levels. It is well known that glucose sensitivity of
individual
-cells is diminished compared with
-cells of whole
intact islets. Examination of single cells may well yield different
results from those obtained in a human, where glucose competence may
already exist, if it is envisioned as a metabolic state in which the
glucose signaling system is fully primed and ready to go. In a previous
study (27), no priming effects of GLP-1 were seen in type
2 diabetic subjects in whom fasting glucose levels were normalized
during an overnight infusion of GLP-1 (1.2 pmol · kg
1 · min
1) but
returned to diabetic levels within 30 min of discontinuing the GLP-1
infusion. In line with these findings, "glucose competence" has
been shown to be preserved in mouse pancreatic
-cells after disruption of the GLP-1 receptor gene (13).
The results presented here demonstrate that, when insulin levels are
matched, GLP-1 did not have an independent effect on insulin clearance
beyond simply stimulating ISR to a greater level. Insulin clearance
saturates as the plasma insulin concentration increases (12,
22). Stimulation of endogenous insulin secretion is associated
with a reduction in insulin clearance at peripheral insulin
concentrations in the high physiological range of 60-70 µU/ml
(366-488 pmol/l) (25, 29, 31). This corresponds to the reduction in insulin clearance seen here during and after the 8 mg · kg1 · min
1 infusion
period. Reduced insulin clearance is presumably due to alterations in
insulin receptor number and/or affinity, in view of the importance of
the insulin receptor in mediating insulin clearance (14).
In conclusion, this study demonstrated the in vivo glucose dependency of the action of postprandial physiological levels of GLP-1 in healthy subjects over the glucose range of 5-10 mM. ISR were consistently increased at each 1 mM glucose interval. GLP-1 had no independent effect on insulin clearance beyond stimulating ISR to a greater level, and there was no priming effect of GLP-1 on subsequent insulin secretory response to glucose. These results enhance our knowledge of the regulation of insulin secretion by GLP-1 in humans.
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ACKNOWLEDGEMENTS |
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We thank Paul Rue, Sabine Jennemann, and Elisabeth Bothe for their excellent technical support.
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FOOTNOTES |
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This study was supported by a grant from the P. E. Kempkes Foundation to M. M. Byrne.
Address for reprint requests and other correspondence: M. M Byrne, Clinical Research Unit for Gastrointestinal Endocrinology, Dept. of Internal Medicine, Philipps Univ., 35033 Marburg, Germany (E-mail: byrnem{at}mailer.uni-marburg.de).
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.
Received 18 October 2000; accepted in final form 21 March 2001.
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