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Department of Medicine I, St. Josef Hospital, Ruhr University (J.J.M., B.G., S.S., O.G., W.E.S., M.A.N.), 44791 Bochum, Germany; Department of Medical Physiology, The Panum Institute, University of Copenhagen (J.J.H.), 2200 Copenhagen, Denmark; and Diabeteszentrum (M.A.N.), 37431 Bad Lauterberg, Germany
Address all correspondence and requests for reprints to: Dr. Juris J. Meier, Medizinische Klinik I, St. Josef Hospital, Klinikum der Ruhr Universität Bochum, Gudrunstrasse 56, 44791 Bochum, Germany. E-mail: Juris.Meier{at}ruhr-uni-bochum.de.
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Abstract |
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Plasma glucose concentrations were equally normalized with all GLP-1 doses (P < 0.001). Insulin and C-peptide concentrations dose-dependently rose during GLP-1 infusion in the fasting state (P < 0.05), but were dose-dependently reduced by GLP-1 after meal ingestion (P = 0.0031 and 0.0074, respectively). Glucagon secretion was suppressed with GLP-1. Gastric emptying was decelerated by GLP-1 in a dose-dependent fashion (P < 0.001).
Despite a dose-dependent stimulation of insulin secretion, glucose normalization can be achieved even with 0.4 pmol GLP-1/kg·min. Due to the dose-dependent inhibition of gastric emptying, lower GLP-1 doses than previously used may be as suitable for glucose control in patients with type 2 diabetes.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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In addition to its metabolic effects, GLP-1 strongly decelerates gastric emptying (13, 14, 15, 16), thereby slowing the entry of nutrients into the circulation and reducing appetite and food intake (5, 17). However, a deceleration of gastric motility may potentially lead to nausea or vomiting after meal ingestion (18). Considering that disturbed gastrointestinal motility is present in at least a subgroup of patients with type 2 diabetes (19), one might speculate that further inhibition of gastric emptying by GLP-1 might not be beneficial in such patients.
In most previous studies using iv administration of GLP-1 in patients with type 2 diabetes, an infusion rate of 1.2 pmol/kg body weight·min or more has been chosen (1, 9, 14, 20, 21). There are only a few studies that compared smaller doses of GLP-1 (15, 22), but the relationship between the glucose-lowering effects and the deceleration of gastric emptying with different GLP-1 doses has not yet been studied in patients with type 2 diabetes. Therefore, it was the aim of this study to compare the effects of different infusion rates of GLP-1 (0.4, 0.8, and 1.2 pmol/kg·min) and placebo on glucose homeostasis in the fasting state as well as in the postprandial state and to quantify its effects on gastric emptying after a solid meal in patients with type 2 diabetes. Preliminary results have been communicated in abstract form (23).
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Patients and Methods |
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The study protocol was approved by the ethics committee of the Ruhr University of Bochum before the study. Written informed consent was obtained from all participants.
Patients
Twelve patients with type 2 diabetes (five men and seven women) participated in the study. The mean age was 57 ± 9 yr (mean ± SD), the body mass index was 30.2 ± 5.0 kg/m2, the waist to hip ratio was 0.95 ± 0.11, and the diabetes duration was 4 ± 1 yr. Ten patients were treated with diet alone, one person received sulfonylurea (glibenclamide), and one was treated with metformin. The mean hemoglobin A1c was 6.8 ± 1.3% (normal range, 4.8–6.0%), the total cholesterol concentration was 5.1 ± 1.06 mmol/liter (normal range, 0–5.2 mg/dl), the triglyceride concentration was 1.38 ± 0.44 mmol/liter (normal range, 0–2.3 mg/dl), and the fasting glucose concentration was 8.88 ± 2.72 mmol/liter (normal fasting range, <7.0 mg/dl). None of the patients received any drug with a known modulating effect on gastric emptying.
From all participants, blood was drawn in the fasting state for measurements of standard hematological and clinical chemistry parameters. Spot urine was sampled for the determination of albumin, protein, and creatinine by standard methods. Patients with anemia (hemoglobin, <12 g/dl), an elevation in liver enzymes (alanine amino transferase, aspartate amino transferase, alkaline phosphatase, and 
-glutamyl transferase) to higher activities than double the respective normal value, or elevated creatinine concentrations (>1.5 mg/dl) were excluded.
Study design
All participants were studied on five occasions. 1) At a screening visit, blood was drawn in the fasting state for laboratory parameters and a clinical examination was performed. If subjects met the inclusion criteria, they were recruited for the following tests. 2) On two separate occasions glucose metabolism was evaluated during a 360-min infusion of GLP-1 or placebo in the fasting state. 3) On 2 additional d glucose metabolism and gastric emptying after a solid meal were evaluated during a 300-min infusion of GLP-1 or placebo. The test meal was served 60 min after starting the GLP-1/placebo infusion. At least 1 d had to pass between the tests. All antidiabetic treatment was withdrawn 1 d before the experiments. Each participant was studied with two different doses of GLP-1, according to the following randomization protocol: 1) placebo and 0.4 pmol/kg·min, 2) placebo and 0.8 pmol/kg·min, 3) placebo and 1.2 pmol/kg·min, 4) 0.4 and 0.8 pmol/kg·min, 5) 0.4 and 1.2 pmol/kg·min, and 5) 0.8 and 1.2 pmol/kg·min. Therefore, six patients were studied with each dose.
Experimental procedures
The tests were performed in the morning after an overnight fast in the supine position throughout the experiments with the upper body lifted by 30°. Two forearm veins were punctured with a Teflon cannula (Moskito 123, 18 gauge, Vygon, Aachen, Germany) and kept patent using 0.9% NaCl (for blood sampling and for glucose and GLP-1 administration, respectively). Both ear lobes were made hyperemic using Finalgon (Nonivamid, 4 mg/g; Nicoboxil, 25 mg/g).
After drawing basal blood specimen at -30 and 0 min, at 0 min an infusion of GLP-1 or placebo (1% human serum albumin in 0.9% NaCl) was started and maintained for 360 min (20 ml/h; Perfusor Secura, Braun Melsungen, Germany). Capillary and venous blood samples were collected in 30-min intervals.
The experiments were started after drawing basal blood samples (-30 and 0 min) with the infusion of GLP-1 or placebo at 0 min. After 60 min, a standard test meal (one egg, two slices of white bread, 5 g margarine, and 150 ml water; 250 kcal) containing 100 mg [13C]sodium-octanoic acid, was served, and breath samples were collected in 10-min intervals. Venous and capillary blood samples were collected at 30-min intervals.
Blood specimen
Venous blood was drawn into chilled tubes containing EDTA and aprotinin (Trasylol; 20,000 kallikrein inhibitor units/ml, 200 µl/10 ml blood; Bayer Corp., Leverkusen, Germany) and kept on ice. A sample (
100 µl) was stored in sodium fluoride (Microvette CB 300, Sarstedt, Numbrecht, Germany) for the immediate measurement of glucose. After centrifugation at 4 C, plasma for hormone analyses was kept frozen at -28 C.
Peptides
Synthetic human GLP-1 was a gift from Restoragen, Inc (Lincoln, NE). The lot number (pharmaceutical grade) was 0340298. The peptide was dissolved in 0.9% NaCl/1% human serum albumin (salt poor; Behring, Marburg, Germany), filtered through 0.2 µm nitrocellulose filters (Sartorius, Gottingen, Germany) and stored frozen at -28 C. HPLC profiles (provided by the manufacturer) showed that the preparation was more than 99% pure (single peak coeluting with appropriate standards). Samples were analyzed for bacterial growth (standard culture techniques) and for pyrogens (laboratory of Dr. Balfanz, Munster, Germany). No bacterial contamination was detected. The endotoxin concentration in samples from the GLP-1 stock solution was 0.08 IU/ml.
Determination of gastric emptying
[13C]Sodium-octanoate [100 mg; CH3-(CH2)6-13COONa, Euriso-top, Saint-Aubin, France; chemical purity, 99.7%; isotopic purity, 99.1%] was mixed into scrambled eggs to label the solid component of the test meal. Because the liquid served with the meal did not contain nutrients, substrates, or any 13C-labeled material, the gastric emptying rates reported are those for the solid component of the meal. At intervals of 10 min, breath specimens were sampled into gas-tight plastic bags holding approximately 50 ml. Within 24 h, the 13CO2 content of these samples was determined using nondispersive infrared spectrometry (Wagner Analysentechnik, Bremen, Germany). The results were both expressed as 
value per million (
) and over baseline (DOB = s - 0). Definition of the value: s = (RS/RPDB - 1) x 1000 [], with Rs = 13C/12C isotope ratio in CO2 in breath, and RPDB = 0.0112372 = isotope ratio in reference (PDB, PeeDeeBelmnite, SC; O = isotope ratio at baseline).
To measure the proportion of the substrate given by mouth that is metabolized the results were expressed as a percentage dose of 13C recovered (PDR) over time for each time interval from which the cumulative PDR (cPDR) for each time interval was calculated, according to Ghoos et al. (24). The CO2 production rate was assumed to be 300 mmol/m2 body surface area·h.
The evaluation of the octanoate breath test for gastric emptying was performed by nonlinear regression analysis (PRISM, version 2, GraphPad Software, Inc., San Diego, CA) of the 13CO2 excretion curves (PDR) to the formula: PDR (t) = atbe-ct (Eq I), which has been derived from the 
2 distribution in statistics. The expression ln a, which is the gastric emptying coefficient, is a reliable parameter to describe the rate at which the stomach empties (24).
The percentage of 13CO2 cumulative values was fit using a model given by: cPDR (t) = M (1 - e-kt)ß (Eq II), where y is cPDR at time t in hours, and m, k, and ß are regression estimated constants, with M the total amount of 13CO2 expired when time is infinite. The gastric emptying half-time (t1/2; calculated in the placebo group only) was calculated by taking PDR (t) equal to M/2 in the PDR equation, which is expressed as: t1/2 = (-1/k) ln (1 - 2-1/ß) (Eq III) (25). Gastric emptying was expressed as a percentage of the initial gastric content (M = 100%) by computing the difference from this initial value at each time point: gastric content (t) = ((M - cPDR(t))/M) x 100% (Eq IV).
Laboratory determinations
Glucose was measured as previously described (26) using a glucose oxidase method with a Glucose Analyzer 2 (Beckman, Munich, Germany).
Insulin was measured using an insulin microparticle enzyme immunoassay (IMx Insulin, Abbott Laboratories, Wiesbaden, Germany). Intraassay coefficients of variation were approximately 4%.
C-Peptide was measured using C-peptide antibody-coated microtiter wells (C-peptide MTPL enzyme immunoassay) from DRG Instruments GmbH (Marburg, Germany). Intraassay coefficients of variation were approximately 6%. Human insulin and C-peptide were used as standards.
Immunoreactive glucagon was measured using porcine antibody 4305 in ethanol-extracted plasma, as previously described (27). The detection limit was less than 1 pmol/liter. Intraassay coefficients of variation were 6.7%, and interassay coefficients of variation were 16%.
GLP-1 immunoreactivity was determined in ethanol-extracted plasma after freeze-drying and resuspension in assay buffer, as previously described (28), using the antiserum 89390. This assay measures the sum of intact GLP-1 and the primary metabolite, GLP-1-(9–39) amide, which is formed in the circulation. Therefore, measured concentrations accurately reflect the amount of GLP-1 infused. Intraassay coefficients of variance were approximately 8%. The detection limit was less than 5 pmol/liter.
Calculations
For integrated incremental responses of glucose, insulin, and C-peptide, the positive or negative area under the curve was calculated (baseline subtracted). For calculating integrated incremental concentrations separately during the preprandial and postprandial states in the meal study, the experimental period was divided into two periods (period 1, 0–60 min; period 2, 60–300 min). The mean basal concentrations of glucose, insulin, and C-peptide at –60 and 0 min were used as baseline for calculating incremental response in both experimental periods.
Statistical analysis
Results are reported as the mean ± SEM. All statistical calculations were carried out using repeated measures ANOVA using Statistica version 5.0 (Statsoft Europe, Hamburg, Germany). This analysis provides P values for differences between groups/experiments (A), differences over time (B), and the interaction of group/experiment with time. If a significant interaction of treatment and time was documented (P < 0.05), values at single time points were compared by one-way ANOVA and Duncan’s post hoc test. A two-sided P < 0.05 was taken to indicate significant differences.
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Results |
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Steady state plasma levels of GLP-1 were 1 ± 1, 48 ± 7, 96 ± 17, and 146 ± 17 pmol/liter during the infusion of placebo and 0.4, 0.8, and 1.2 GLP-1/kg·min, respectively (P < 0.001; Fig. 1 A
). Fasting glucose concentrations were significantly lowered during the infusion of all GLP-1 doses compared with those during placebo infusion (P < 0.001; Fig. 2A). The decline in glucose concentrations was almost equal in all groups of patients treated with GLP-1, reaching the normal fasting range (<110 mg/dl) within 120 min (Fig. 2A). With the iv administration of GLP-1, insulin and C-peptide concentrations rose significantly in a dose-dependent fashion, but they remained almost unchanged in the placebo group (P < 0.001; Fig. 2, B and C). Glucagon concentrations were significantly lowered during the study period (P < 0.001; Fig. 1B), but without a significant difference between the placebo group and the GLP-1 groups (P = 0.89). The interaction of GLP-1 dose and glucagon concentration time courses was also not significant (P = 0.73). If, however, glucose was included as a covariate, changes in glucagon with time (P = 0.0006) and the interaction (P < 0.0001) were significant.
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The test meal only slightly increased GLP-1 plasma concentrations in the placebo group from a basal level of about 4 to 6 pmol/liter 60 min after meal ingestion (P = 0.53; Fig. 1
). Steady state plasma concentrations of GLP-1 were 54 ± 7, 100 ± 12, and 130 ± 17 pmol/liter with the infusions of 0.4, 0.8, and 1.2 GLP-1/kg·min, respectively (P < 0.001; Fig. 1C). After the ingestion of the test meal, the glucose concentration rose to a peak of 244 ± 18 mg/dl in the placebo group and remained in the hyperglycemic range during the entire study period (Fig. 3A). In contrast, only with the 0.4 pmol GLP-1/kg·min dose was a slight increase in glucose concentrations observed after the test meal, whereas with the higher GLP-1 doses glucose levels declined after meal ingestion (P < 0.001).
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, B and C). During the preprandial administration of GLP-1 from 0–60 min, integrated incremental insulin and C-peptide concentrations increased in a dose-dependent fashion, whereas they remained almost unchanged in the placebo group (P < 0.001 and P = 0.085 for insulin and C-peptide, respectively; Fig. 3, E and F). In contrast, during the postprandial period, insulin and C-peptide secretion was highest in the placebo group, whereas it was dose-dependently lowered by GLP-1 (P = 0.0031 and P = 0.0074 for insulin and C-peptide, respectively; Fig. 3, H and I).
Glucagon secretion was suppressed during the infusion of GLP-1, but remained almost unchanged in the placebo group (P = 0.012; Fig. 1D). There were overlapping values because of different baseline concentrations.
Gastric emptying
During the iv administration of placebo in the patients with type 2 diabetes, the half-time of gastric emptying after the solid meal was 164 ± 8 min. During GLP-1 administration, gastric emptying was decelerated in a dose-dependent fashion (Fig. 4). Accordingly, 240 min after meal ingestion, 26 ± 3%, 39 ± 6%, 56 ± 9%, and 74 ± 9% of the initial gastric content remained inside the stomach during the administration of placebo and 0.4, 0.8, and 1.2 pmol GLP-1/kg·min, respectively (P < 0.001; Fig. 4A). Gastric emptying coefficients were significantly reduced with increasing doses of GLP-1 (P < 0.001; Fig. 4B). The deceleration of gastric emptying by GLP-1 was pronounced; half-times of gastric emptying were not reached within the study period of 240 min. Comparing the individual results, gastric emptying coefficients were lowered with the higher GLP-1 dose in each patient (details not shown).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Type 2 diabetes is characterized by a progressive loss of first phase insulin secretion and a compensatory increased second phase secretion (29, 30). Delayed insulin secretion after meal ingestion causes reduced suppression of hepatic glucose output as well as glucagon secretion, leading to postprandial hyperglycemia (31). As a GLP-1 infusion started 1 h before meal ingestion markedly raised preprandial insulin concentrations, postprandial glycemic excursions could be effectively reduced.
The reduction of postprandial insulin secretion with increasing GLP-1 doses in the present study is most likely due to the lower glucose concentrations at the time of meal ingestion reached by the GLP-1 pretreatment. Accordingly, calculation of the insulinogenic index revealed similar amounts of insulin secreted relatively to the glucose concentrations in all GLP-1-treated groups after the meal (P = 0.14; details not shown).
Similar to previous studies, there was a trend toward a lowering of glucagon secretion during GLP-1 infusion, but only in the meal study was statistical significance reached without including glucose concentrations as a covariate. This makes sense, because glucose concentrations have an immediate effect on pancreatic glucagon secretion (32) that is taken into account by this statistical approach.
Although endogenous secretion of GLP-1 is stimulated by meal ingestion, there was only a slight increase in the GLP-1 plasma concentration after ingestion of the test meal in the placebo group. This is most likely due to the low caloric content of the meal (250 kcal), which had little effect on endogenous GLP-1 secretion.
The GLP-1 effects on fasting and postprandial glucose concentrations were similar with all doses tested, but gastric emptying was delayed in a dose-dependent fashion. This finding highlights the glucose dependency of the metabolic GLP-1 actions that guarantees glucose normalization without causing hypoglycemia (1). The inhibition of gastric emptying, however, appears to primarily depend on the amount of GLP-1 administered. In the present study the deceleration of gastric emptying by GLP-1 was prominent; only 25% of the initial content of the stomach had emptied after 4 h in the patients receiving 1.2 pmol GLP-1/kg·min, whereas almost 75% had emptied in the placebo group.
It is worth mentioning that although one might expect delayed gastric transit to result in nausea or vomiting, the deceleration of gastric emptying in the present study did not cause any symptoms consciously reported by the patients. Nausea and vomiting have previously been reported after the administration of high GLP-1 doses in some (15, 18), but not all, studies (8, 21, 22). This is in line with the absence of gastrointestinal symptoms in patients with diabetes who have a proven deceleration of gastric emptying (gastroparesis) (19, 33, 34).
Gastric emptying has been decelerated in approximately 30–50% of patients with type 2 diabetes, but it can also be accelerated, due to autonomic neuropathy (19, 35). It might therefore be reasonable to assess gastric emptying before initiating GLP-1 treatment to avoid the induction of gastroparesis in these patients, especially as delayed gastric emptying and GLP-1 treatment may also alter the pharmacokinetic properties of other medications.
As the broad clinical application of GLP-1 is limited by its in vivo half-life of 2–3 min (36), various attempts have been undertaken to overcome its unfavorable pharmakokinetic properties. Currently, different analogs of GLP-1, resistant to in vivo degradation by dipeptidyl peptidase IV (7, 37), as well as inhibitors of dipeptidyl peptidase IV are tested in clinical trials (6, 38), but none of these agents has proven the same antidiabetic potency as an iv infusion of native GLP-1. Therefore, it appears to be worth reconsidering the iv administration of native GLP-1, at least in some temporarily limited situations. Such situations might include acute myocardial infarction, ischemic stroke, and major surgery, as the development of hyperglycemia limits the patients’ prognosis under these conditions (39, 40, 41). In contrast, intensive insulin treatment aimed at glucose normalization has been shown to reverse the detrimental effects of hyperglycemia in those patients (11, 39). However, insulin treatment requires tight glucose control and poses a risk of inducing hypoglycemia. An antidiabetic treatment with GLP-1 may offer a practicable alternative for glucose control in these patients (12).
In conclusion, during the iv administration of different GLP-1 doses, fasting and postprandial glucose concentrations can equally be normalized. When administered before meal ingestion, GLP-1 raises preprandial insulin concentrations and reduces postprandial hyperglycemia. Gastric emptying is dose-dependently decelerated by GLP-1 with an almost complete arrest of emptying 4 h after meal ingestion during the infusion of 1.2 pmol/kg·min. Therefore, to avoid gastrointestinal side effects, lower doses than previously used appear to be suitable for the iv administration of GLP-1 in patients with type 2 diabetes.
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Acknowledgments |
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Footnotes |
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Abbreviations: GLP-1, Glucagon-like peptide 1; PDR, percentage dose of 13C recovered.
Received January 10, 2003.
Accepted March 6, 2003.
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T. J. Little, A. N. Pilichiewicz, A. Russo, L. Phillips, K. L. Jones, M. A. Nauck, J. Wishart, M. Horowitz, and C. Feinle-Bisset Effects of Intravenous Glucagon-Like Peptide-1 on Gastric Emptying and Intragastric Distribution in Healthy Subjects: Relationships with Postprandial Glycemic and Insulinemic Responses J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1916 - 1923. [Abstract] [Full Text] [PDF]
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 G. M. Bray Exenatide Am. J. Health Syst. Pharm., March 1, 2006; 63(5): 411 - 418. [Abstract] [Full Text] [PDF]
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J. J. Meier, G. Kemmeries, J. J. Holst, and M. A. Nauck Erythromycin Antagonizes the Deceleration of Gastric Emptying by Glucagon-Like Peptide 1 and Unmasks Its Insulinotropic Effect in Healthy Subjects Diabetes, July 1, 2005; 54(7): 2212 - 2218. [Abstract] [Full Text] [PDF]
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P. K. Chelikani, A. C. Haver, and R. D. Reidelberger Intravenous infusion of glucagon-like peptide-1 potently inhibits food intake, sham feeding, and gastric emptying in rats Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2005; 288(6): R1695 - R1706. [Abstract] [Full Text] [PDF]
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 G Uckaya, P Delagrange, A Chavanieu, G Grassy, M-F Berthault, A Ktorza, E Cerasi, G Leibowitz, and N Kaiser Improvement of metabolic state in an animal model of nutrition-dependent type 2 diabetes following treatment with S 23521, a new glucagon-like peptide 1 (GLP-1) analogue J. Endocrinol., March 1, 2005; 184(3): 505 - 513. [Abstract] [Full Text] [PDF]
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M. A. Nauck, B. Baller, and J. J. Meier Gastric Inhibitory Polypeptide and Glucagon-Like Peptide-1 in the Pathogenesis of Type 2 Diabetes Diabetes, December 1, 2004; 53(suppl_3): S190 - S196. [Abstract] [Full Text] [PDF]
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J. J. Meier, B. Gallwitz, B. Kask, C. F. Deacon, J. J. Holst, W. E. Schmidt, and M. A. Nauck Stimulation of Insulin Secretion by Intravenous Bolus Injection and Continuous Infusion of Gastric Inhibitory Polypeptide in Patients With Type 2 Diabetes and Healthy Control Subjects Diabetes, December 1, 2004; 53(suppl_3): S220 - S224. [Abstract] [Full Text] [PDF]
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J. J. Meier, O. Goetze, J. Anstipp, D. Hagemann, J. J. Holst, W. E. Schmidt, B. Gallwitz, and M. A. Nauck Gastric inhibitory polypeptide does not inhibit gastric emptying in humans Am J Physiol Endocrinol Metab, April 1, 2004; 286(4): E621 - E625. [Abstract] [Full Text] [PDF]
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