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Medizinische Universitäts-Klinik (M.A.N., M.M.H., K.B., R.R., W.H.S.), Knappschafts-Krankenhaus Bochum, Klinikum der Ruhr-Universität Bochum, D-44892 Bochum, Germany; Department of Medical Physiology (J.J.H.), Panum Institute, University of Copenhagen, DK-2200 Copenhagen N, Denmark; Department of Clinical Chemistry (M.S.N.), Central Laboratory, University Hospital Freiburg, D-79106 Freiburg, Germany; and Division of Endocrinology (M.H.), Department of Medicine, Georg-August-Universität, D-37075 Göttingen, Germany
Address all correspondence and requests for reprints to: Dr. Michael Nauck, Diabeteszentrum Bad Lauterberg, Kirchberg 21, D-37431 Bad Lauterberg, Germany. E-mail: . M.Nauck{at}diabeteszentrum.de
Abstract
Glucagon-like peptide 1 (GLP-1) and analogues are being evaluated as a new therapeutic principle for the treatment of type 2 diabetes. GLP-1 suppresses glucagon secretion, which could lead to disturbances of hypoglycemia counterregulation. This has, however, not been tested.
Nine healthy volunteers with normal oral glucose tolerance received infusions of regular insulin (1 mU·kg-1·min-1) over 360 min on two occasions in the fasting state. Capillary glucose concentrations were clamped at plateaus of 4.3, 3.7, 3.0, and 2.3 mmol/liter for 90 min each (stepwise hypoglycemic clamp); on one occasion, GLP-1 (1.2 pmol·kg-1·min-1) was administered iv (steady-state concentration, 
125 pmol/liter); on the other occasion, NaCl was administered as placebo. Glucagon, cortisol, GH (immunoassays), and catecholamines (radioenzymatic assay) were determined, autonomous and neuroglucopenic symptoms were assessed, and cognitive function was tested at each plateau. Insulin secretion rates were estimated by deconvolution (two-compartment model of C-peptide kinetics).
At insulin concentrations of approximately 45 mU/liter, glucose infusion rates were similar with and without GLP-1 (P = 0.26). Only during the euglycemic plateau (4.3 mmol/liter), GLP-1 suppressed glucagon concentrations (4.1 ± 0.4 vs. 6.5 ± 0.7 pmol/liter; P = 0.012); at all hypoglycemic plateaus, glucagon increased similarly with GLP-1 or placebo, to maximum values greater than 20 pmol/liter (P = 0.97). The other counterregulatory hormones and autonomic or neuroglucopenic symptom scores increased, and cognitive functions decreased with decreasing glucose concentrations, but there were no significant differences comparing experiments with GLP-1 or placebo, except for a significant reduction of GH responses during hypoglycemia with GLP-1 (P = 0.04). GLP-1 stimulated insulin secretion only at plasma glucose concentrations of at least 4.3 mmol/liter.
In conclusion, the suppression of glucagon by GLP-1 does occur at euglycemia, but not at hypoglycemic plasma glucose concentrations (
3.7 mmol/liter). GLP-1 does not impair overall hypoglycemia counterregulation except for a reduction in GH responses, which is in line with other findings demonstrating pituitary actions of GLP-1. Below plasma glucose concentrations of 4.3 mmol/liter, the insulinotropic action of GLP-1 is negligible.
INSULIN SECRETION AFTER meals is stimulated not only by the rise in glycemia after glucose absorption but also by the secretion and insulinotropic action of gut hormones with incretin activity (1, 2). The main candidates for the incretin role are gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) (3, 4, 5). Together, they account for approximately half of the insulin increment after oral glucose (4). GLP-1 has received special attention, because an iv infusion of this gut hormone is able to lower plasma glucose in type 2 diabetic patients into the normal range (6, 7). Based on this finding, the concept has emerged that GLP-1 or analogues may have a definite therapeutic potential (8, 9, 10), based on the ability of GLP-1 to stimulate insulin secretion (3, 4, 11, 12), suppress glucagon concentrations (13, 14), and decelerate gastric emptying (15, 16).
Given the facts that the reduction in glucagon concentrations (17) is an important component of the antidiabetogenic actions of GLP-1 (18) and that glucagon plays an essential role in the defense against hypoglycemia (19, 20, 21), impaired counterregulatory responses might occur during treatment with GLP-1 itself or GLP-1 analogues. Therefore, we saw the necessity to exclude a potential interaction of GLP-1 with counterregulatory hormone responses and the activity of hypoglycemia counterregulation in general. Along this line, we wanted to study the influence of exogenous GLP-1 in a pharmacological dose (as is necessary to normalize plasma glucose in type 2 diabetic patients) (6, 7), in comparison to placebo, on the secretion of glucagon, cortisol, catecholamines, and GH as well as on symptoms of hypoglycemia and cognitive functions during hyperinsulinemic, stepped hypoglycemic clamp experiments (22) in healthy volunteers. This experimental approach also makes it possible to judge the glucose-dependence of the insulinotropic action of GLP-1. Preliminary data have been published in abstract form (23).
Subjects and Methods
Study protocol
The study protocol was approved by the ethics committee of the medical faculty of the Ruhr-University (Bochum, Germany) on Dec. 4, 1995 (registration no. 715) before the study. Written informed consent was obtained from all participants.
Subjects
Nine healthy male volunteers were studied. They were 28 ± 5 yr old, 186 ± 7 cm tall, and weighed 85 ± 8 kg (body mass index, 24.5 ± 1.1 kg/m2). All had a normal oral glucose tolerance according to World Health Organization criteria (75 g glucose in 300 ml; fasting glucose, 5.1 ± 0.8; 120-min value, 5.7 ± 0.5 mmol/liter). None had a family history of diabetes mellitus or a personal history of gastrointestinal disorders. Blood cell counts, serum transaminases, creatinine values (0.8–1.1 mg/dl), triglyceride (65–123 mg/dl), cholesterol (112–226 mg/dl) and HDL-cholesterol concentrations (51–71 mg/dl) were in the normal range.
Study design
All participants were studied in random order on two occasions: 1) hyperinsulinemic, stepwise hypoglycemic clamp experiment (22, 24) with glucose plateaus of 4.3, 3.7, 3.0, and 2.3 mmol/liter with exogenous GLP-1 at an iv infusion rate of 1.2 pmol·kg-1·min-1 from 0–360 min; or 2) 0.9% NaCl plus 1% (vol/vol) human serum albumin as placebo.
Peptides
Synthetic GLP-1 [7–36 amide] was purchased from Saxon Biochemicals GmbH (Hannover, Germany). The lot number of GLP-1 [7–36 amide] (pharmaceutical grade) was PGAS 242, FGLP7369301 A; net peptide content, 88%. The peptide was dissolved in 0.9% NaCl/1% human serum albumin (HSA Behring, salzarm, Marburg, Germany, lot no. 012931), filtered through 0.2 µm nitrocellulose filters (Sartorius, Göttingen, Germany), and stored frozen at -28 C as previously described. 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 (LAL coatest, lot no. 326-35; sensitivity 0.125 EU/ml, Chromogenix, Mölndal, Sweden). No bacterial contamination or measurable endotoxin concentrations were detected.
Experimental Procedures
The tests were performed in the morning after an overnight fast. The volunteers were in a supine position throughout the experiments, with the upper body lifted by approximately 30 degrees. 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 GLP-1/placebo administration). Both ear lobes were made hyperemic using Finalgon.
After drawing basal blood specimens, at 0 min an iv infusion (rate, 5 ml/h; Perfusor secura, Braun Melsungen, Germany) of regular insulin (Actrapid, Novo-Nordisk, Copenhagen, Denmark; diluted in 0.9% NaCl with 1% human serum albumin) was begun and maintained at an infusion rate of 1 mU·kg-1·min-1. Preliminary results had indicated that it was not necessary to increase the insulin infusion rate to reach the last glycemic plateau [as described in published studies (22, 24)]. At 5-min intervals, plasma glucose was determined in approximately 100 µl capillary samples drawn from an ear lobe to assure close to arterial plasma glucose concentrations. When necessary, an iv infusion of glucose (20% in water; Braun Melsungen, Germany) was begun and maintained at a rate that resulted in the desired plasma glucose concentration. During each 90-min plateau, plasma glucose was allowed to fall slowly to the desired range during the initial 30 min and was maintained at the target concentration for the remaining 60 min. The glucose infusion rates and time points of changing it were recorded to allow a calculation of the total amount of glucose infused to maintain glucose levels in the desired range.
An iv infusion of GLP-1 [7–36 amide], 1.2 pmol·kg-1·min-1, or placebo (0.9% NaCl containing 1% human serum albumin) was started at 0 min and continued for 360 min. This infusion rate was based on previous studies and was selected to raise plasma GLP-1 concentrations into the pharmacological range (approximately 3- to 4-fold higher concentrations in comparison to those measured after oral glucose) (16, 25). This infusion rate would normalize plasma glucose in hyperglycemic patients with type 2 diabetes (6, 26).
Cognitive function tests
Cognitive function tests were performed as described by Mitrakou et al. (22, 24) with equipment from PSYTEST Psychologische Testsysteme (Herzogenrath, Germany) (27). Vigilance was tested by asking that a button be pushed whenever certain acoustic signals and letters where successively presented to the volunteers. Both speed and precision were evaluated. Phasic alertness was tested by testing the response to a visual cue after an acoustic warning signal raised the level of expectation. The number connection test measured the time to connect numbers 1–90 on standardized paper forms. The word repetition test required subjects to memorize 10 different words presented at the beginning of each glycemic plateau for 45 min, when the number of correctly remembered words was counted. The Stroop color-word-interference test required the correct description of words naming colors, of colored lines, and of colors of letters (e.g. green) presented in a different color (color-word incongruence) (28). All parameters were assessed once in the basal state (fasting conditions, euglycemia, no insulin infusion) and once during each of the clamped glycemic plateaus.
Hypoglycemic symptoms
Autonomic (anxiety, palpitation, irritability, sweating, tremor) and neuroglucopenic (numbness, hunger, difficulty with thinking, impaired vision, fainting) symptoms of hypoglycemia were rated on a visual analog scale ranging from 0–10 during each of the glycemic plateaus. The total score was derived by summing up individual ratings (five items each).
Blood specimens
Blood for all determinations except for plasma glucose (which was taken from a capillary source, see above) was drawn from an indwelling venous cannula into chilled tubes containing EDTA and aprotinin (Trasylol; 20,000 kIU/ml, 180 µl/9 ml blood; Bayer Corp. AG, Leverkusen, Germany) and kept on ice. A sample (100 µl) was stored in NaF (Microvette CB 300; Sarstedt, Nümbrecht, Germany) for the immediate measurement of glucose. After centrifugation at 4 C, plasma for hormone analyses was kept frozen at -28 C.
Laboratory determinations
Glucose was measured using a glucose oxidase method with a Glucose Analyser 2 (Beckman Coulter, Inc. Instruments, Munich, Germany). Insulin was measured using an insulin microparticle enzyme immunoassay, IMx Insulin, (Abbott Laboratories, Wiesbaden, Germany). Intra-assay coefficients of variation were approximately 4%. C-peptide was measured using C-peptide-antibody-coated microtitre wells (C-peptide MTPL EIA, DRG Instruments GmbH, Marburg, Germany). Intra-assay coefficients of variation were approximately 6%. Human insulin and C-peptide were used as standards.
Immunoreactive GLP-1 was determined in ethanol-extracted plasma as previously described (29, 30), using antiserum 89 390 (final dilution, 1:150,000) for the measurement of GLP-1 [7–36 amide] and synthetic GLP-1 [7–36 amide] for tracer preparation and as standard (29, 30). Recovery of GLP-1 [7–36 amide] standards after alcohol extraction was 75 ± 8%. The experimental detection limit (2 SD over samples not containing GLP-1 [7–36 amide]) was less than 5 pmol/liter. Antiserum 89 390 binds to the amidated carboxy terminus of GLP-1 [7–36 amide] (30). Intra-assay coefficients of variation were approximately 8%.
Cortisol was measured by a fluorescence-polarization-immunoassay on a TDx analyser (Abbott Laboratories) using a commercially available reagent kit.
GH was determined by a commercial immunoradiometric assay (Biochem Immunosystems Italia S.P.A., Casalecchio di Reno, Italy) using a mouse monoclonal antibody and human GH as standard. Coefficients of variation were 2% (intra-assay) and 3% (interassay).
Catecholamines were determined by a radioenzymatic method. Epinephrine and norepinephrine were radioactively methylated by catechol-O-methyl transferase from rat liver, and the catecholamine derivatives were separated by TLC (31).
Calculations and statistical analysis
Results are reported as mean ± SEM.
Insulin secretion rates were calculated by deconvolution analysis using an open two-compartment model (32, 33) and population-based transition coefficients (34) as described by Hovorka and Jones (35) The software (ISEC, version 2) was kindly supplied by Dr. R. Hovorka, Center for Measurement and Information in Medicine, Department of System Science, City University, and Department of Medicine, United Medical and Dental Schools, St. Thomas Hospital (London, UK).
All statistical calculations were carried out using repeated-measures ANOVA and NCSS Version 5.01 (Jerry Hintze, Kaysville, Utah). If a significant interaction of treatment and time was documented (P < 0.05), this was taken as indicating significant effects, and in a secondary analysis, values at single time points were compared by t test (paired analyses) to locate periods with significant differences. A two-sided P value < 0.05 was taken to indicate significant differences.
Results
During the infusion of GLP-1, steady-state plasma GLP-1 levels of 126 ± 9 pmol/liter were measured; with placebo, basal concentrations of 13 ± 2 pmol/liter were maintained (Fig. 1
).
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).
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), with rather narrow variations as indicated by the coefficients of variation of 5–8% for each plateau.
The amount of glucose that needed to be infused to maintain the level of glycemia predetermined for the course of the experiments is shown in Fig. 2C. There was a decreasing glucose infusion rate with lower levels of glycemia (P < 0.0001 with time). The total amount of glucose infused did not differ for the experiments with GLP-1 or placebo.
Plasma glucagon concentrations (Fig. 3A) decreased slightly during the 4.3 mmol/liter plateau with GLP-1 (30 min, P = 0.012 by t test), but increased with progressive hypoglycemia (P < 0.0001) more than 3-fold over basal concentrations. Overall, there was no significant difference regarding the experiment (P = 0.67) or concerning the interaction of experiment and time (P = 0.97).
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).
GH concentrations increased with time (P < 0.0001). The increment was most prominent during the 3.0 and 2.3 mmol/liter glucose plateaus (Fig. 3C) and was significantly reduced with GLP-1 (interaction of experiment and time: P = 0.037). However, t tests did not locate specific time points with a significantly different GH concentration (minimum P value, 0.089 at 240 min).
Epinephrine increased with time (P < 0.0001), but there were no differences attributable to GLP-1. Norepinephrine showed a trend toward a rise with decreasing glucose but did not significantly increase with time (P = 0.51), and there were no differences attributable to GLP-1 (Fig. 3, C and D).
Hypoglycemic symptoms increased with progressing degrees of hypoglycemia (P < 0.0001) for both autonomic (from 0.3 ± 0.2 in the basal state to 5.3 ± 1.8 at the lowest glycemic plateau on a scale from 0–10) and neuroglucopenic symptoms (from 0.0 ± 0.0 to 2.5 ± 1.6, respectively; data not shown). No differences were noted that pointed to a changed symptom recognition under the influence of exogenous GLP-1 (P = 0.99 for autonomic and P = 0.97 for neuroglucopenic symptoms).
Cognitive tests (Table 1) demonstrated significant deterioration in function with progressing degrees of hypoglycemia (time), especially when speed was considered (vigilance, P = 0.0004; attention, P = 0.012; number connection, P = 0.0015; word repetition, P < 0.0001; Stroop tests, 0.0001–0.002). However, there were no significant differences between experiments with GLP-1 and placebo (Table 1).
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). Immediately after the iv administration of GLP-1 started, C-peptide concentrations rose sharply, to a peak increment of 1.13 ± 0.14 nmol/liter at 30 min. Afterward, C-peptide concentrations fell, but remained significantly higher than measured with placebo until 270 min, during the 3.0 mmol/liter plateau.
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), and after the peak of 4.9 ± 0.6 pmol·kg-1·min-1 at 15 min, secretion rates decreased more rapidly. No significant differences remained to placebo conditions after 105 min, i.e. during or after the 4.3 mmol/liter plateau, except for one occasional value (0.19 ± 0.02 pmol·kg-1·min-1 with GLP-1 vs. 0.15 ± 0.03 pmol·kg-1·min-1 with placebo) at 225 min (3.0 mmol/liter glucose plateau) (Fig. 4B). Discussion
The main finding of the present study is that glucagon responses to hypoglycemia were not changed by exogenous GLP-1 (Fig. 3). This was so although GLP-1 has been shown to reduce glucagon in the isolated perfused pancreas (13, 14) and in healthy volunteers (3, 36, 37) as well as type 2 diabetic patients (6, 7, 17). Our results might appear to contradict the notion that GLP-1 generally lowers glucagon concentrations. But a reduction in glucagon has been demonstrated only under certain conditions that always included plasma glucose concentrations at least in the normal fasting range; in healthy volunteers the fall in glucagon concentrations in response to GLP-1 infused in the basal state (fasting conditions) was small and transient (3, 36, 37), and in hyperglycemic type 2 diabetic patients (clamp experiments), the glucagonostatic action of exogenous GLP-1 lasted as long as hyperglycemia was maintained (17). Also in type 1 diabetic patients, in whom only a small reduction in glucose concentrations was reached in response to exogenous GLP-1 (18), the suppression of glucagon lasted for more than 4 h. In experiments performed with type 2 diabetic patients, glucagon concentrations were suppressed by GLP-1 until plasma glucose fell and normal basal glucose readings were approached or maintained (6, 7). The present study, however, is the first one to extend these findings into the hypoglycemic range of glucose concentrations and to measure other counterregulatory hormones, which might compensate for potential differences in glucagon concentrations. It appears that in normal subjects (3, 37) and in type 2 diabetic patients (6, 7), similar glucose thresholds exist for the disruption of glucagonostatic activities of GLP-1, which are equivalent to a normal fasting glucose concentration.
The transient suppression of glucagon concentrations by GLP-1 during the initial glucose plateau (4.3 mmol/liter; Fig. 3) may be viewed as being of surprisingly low extent, when compared with previous reports (3, 36, 37), but the most likely explanation is that already this glucose level was lower than truly basal levels (Fig. 2). This reduction in glycemic levels by 0.6–0.8 mmol/liter may already have limited the glucagonostatic activity of GLP-1.
The reduction in GH responses during deeper stages of hypoglycemia (Fig. 3) was a surprise and is in contrast to the undisturbed counterregulatory secretion of glucagon, cortisol, and catecholamines (Fig. 3). The mechanism is unclear, but there have been previous reports about GLP-1 modifying pituitary and hypothalamic functions (38, 39). However, in contrast to the present findings, stimulatory actions rather than an inhibition had been reported (38, 39). The presence of GLP-1 receptors on somatotropic (this study), thyreotropic (38) pituitary cells, and GnRH-producing hypothalamic cells (39) therefore appears likely. In line with previous studies indicating a rather nonacute action of GH only in the course of prolonged hypoglycemic episodes (40), the reduction in GH responses did not impair overall counterregulatory activity as indicated by similar glucose infusion rates with and without GLP-1 (Fig. 2). In case of an overall reduced counterregulatory activity, one would have expected a greater need for exogenous glucose to maintain the predetermined levels of glycemia.
At the 3.0 mmol/liter glucose plateau, epinephrine concentrations appeared to rise more with GLP-1 than with placebo (Fig. 3D). This, however, was not a uniform finding. Only two of nine subjects responded in that manner, and the overall difference was not significant. Norepinephrine plasma levels tended to increase with decreasing plasma glucose, but this was not significant (P = 51; repeated-measures ANOVA for changes with time). This apparently contradicts results presented by Minaker et al. (41), who described a rise in plasma norepinephrine with euglycemic hyperinsulinemia. The failure to detect a significant rise in norepinephrine may be the consequence of the small number of subjects studied. Certainly, our results do not suggest a difference in response to GLP-1 (Fig. 3E).
Although GLP-1 is produced in certain areas of the brain and, at least in rats, some brain regions appear to be accessible even for circulating GLP-1 (42), brain function as determined by a battery of cognitive function tests (Table 1) was not influenced by exogenous GLP-1. This does not exclude influences on other specific functions, especially those related to the regulation of satiety (43, 44) and water intake (45).
The differences in GH secretion proved that biologically active GLP-1 was circulating during our experiments. This was also evident from the transient stimulation of insulin secretion (C-peptide) that was observed especially during the initial phase of the study, i.e. at near basal glucose concentrations (Fig. 4). The present results support the view of a glucose threshold for insulinotropic activities of GLP-1 in vivo in healthy human subjects; C-peptide concentrations (Fig. 4A) and insulin secretion rates (Fig. 4B) increase when a GLP-1 infusion is started at euglycemic glucose concentrations (basal conditions) like in previous studies (36, 37, 46, 47), but this insulinotropic activity is limited to the initial period of the hyperinsulinemic, stepwise hypoglycemic clamp experiments, i.e. to conditions characterized by glucose concentrations of at least 4.3 mmol/liter. The time course was different when looking at C-peptide concentrations (Fig. 4A) in comparison to insulin secretion rates (Fig. 4B), but this difference was expected; C-peptide has a plasma half-life of approximately 20 min (32, 33), and changes in insulin secretion may occur much more rapidly than can be detected by alterations in C-peptide levels. Deconvolution analysis is an established method to estimate insulin secretion rates in vivo (33, 34) and has been evaluated thoroughly. Therefore, the insulin secretion rates calculated from C-peptide time courses probably are a reliable estimate of pancreatic insulin release. The time course suggests insulinotropic activities of the pharmacological concentration of GLP-1 (125 pmol/liter) at a plasma glucose concentration of approximately 5 mmol/liter (basal conditions) and, to a certain extent at 4.3 mmol/liter, but not at any glucose plateau lower than 4.3 mmol/liter. The transient effect at the 4.3 mmol/liter plateau can be explained by either an intrinsic time course typical for the insulinotropic activity of GLP-1 or changes in plasma glucose occurring during this period. In previous studies employing the continued administration of GLP-1 in human subjects during periods characterized by permissive glucose concentrations (i.e. hyperglycemia), insulin and C-peptide concentrations increased or were maintained for at least 1 h (17, 48). This does not suggest an intrinsically transient effect on insulin secretion. On the other hand, during the first glucose plateau in the present experiments, there was a slight fall in glucose concentrations from initially 5.0 ± 0.1 mmol/liter to 4.2 ± 0.1 mmol/liter (GLP-1) or from 4.9 ± 0.1 mmol/liter to 4.3 ± 0.1 (placebo), when the intended level of 4.3 mol/liter was approached over approximately 30 min (Fig. 2A). The fall in insulin secretion rates (Fig. 4B) paralleled this reduction in glucose concentrations (Fig. 2A). All parameters representing insulin secretory activity (basal insulin, C-peptide, and insulin secretion rates) tended to be higher or were significantly elevated on the occasion of the experiments with exogenous GLP-1 (Figs. 2 and 4). The differences were much smaller than those brought about by exogenous GLP-1. This has to be considered a chance finding with little, if any, influence on the overall interpretation of the present study.
Because of this strict glucose-dependence of insulinotropic actions, and in line with cell biological experiments characterizing GLP-1 actions on insulin secretion in relation to ambient glucose concentrations (49, 50, 51), GLP-1 alone probably cannot cause hypoglycemia. In fact, hypoglycemia in response to exogenous GLP-1 has only been observed under artificial conditions, i.e. the concomitant administration of GLP-1 and iv glucose (52, 53). In fasting subjects (6, 10) or in combination with oral nutrient intake (16, 25), there is no potential of GLP-1 to cause hypoglycemia. This is in contrast to pharmacological properties of other insulin secretagogues like sulfonylureas and meglitinides (54, 55) and may point to a specific advantage of GLP-1 as a therapeutic agent.
In conclusion, exogenous GLP-1 led to a transient reduction in plasma glucagon at euglycemia but did not prevent normal increases after exposure to insulin-induced hypoglycemia in healthy volunteers. Surprisingly, GH increments were less prominent with GLP-1. Overall counterregulation as determined by glucose infusion requirements, however, did not indicate compromised recovery from hypoglycemia at pharmacological concentrations of GLP-1. The stimulation of insulin secretion by exogenous GLP-1 was limited to basal state and the 4.3 mmol/liter glycemic plateaus, indicating the strict glucose dependence of the insulinotropic action of GLP-1.
Acknowledgments
The excellent technical assistance of S. Richter, T. Gottschling, K. Faust, L. Bagger, and L. Albæk is gratefully acknowledged. We thank Mrs. L. Faber for secretarial assistance.
Footnotes
This work was supported by the Deutsche Forschungsgemeinschaft, Grant Na 203/6.
Abbreviations: GIP, Gastric inhibitory polypeptide; GLP-1, glucagon-like peptide 1.
Received August 22, 2001.
Accepted November 14, 2001.
References
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 J. J. Holst The Physiology of Glucagon-like Peptide 1 Physiol Rev, October 1, 2007; 87(4): 1409 - 1439. [Abstract] [Full Text] [PDF]
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K. Thomaseth, A. Pavan, G. Pacini, and B. Ahren Glucagon-like peptide-1 accelerates the onset of insulin action on glucose disappearance in mice Am J Physiol Endocrinol Metab, June 1, 2007; 292(6): E1808 - E1814. [Abstract] [Full Text] [PDF]
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 B. E. Dunning and J. E. Gerich The Role of {alpha}-Cell Dysregulation in Fasting and Postprandial Hyperglycemia in Type 2 Diabetes and Therapeutic Implications Endocr. Rev., May 1, 2007; 28(3): 253 - 283. [Abstract] [Full Text] [PDF]
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B. Balas, M. R. Baig, C. Watson, B. E. Dunning, M. Ligueros-Saylan, Y. Wang, Y.-L. He, C. Darland, J. J. Holst, C. F. Deacon, et al. The Dipeptidyl Peptidase IV Inhibitor Vildagliptin Suppresses Endogenous Glucose Production and Enhances Islet Function after Single-Dose Administration in Type 2 Diabetic Patients J. Clin. Endocrinol. Metab., April 1, 2007; 92(4): 1249 - 1255. [Abstract] [Full Text] [PDF]
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J. de Heer and J. J. Holst Sulfonylurea Compounds Uncouple the Glucose Dependence of the Insulinotropic Effect of Glucagon-Like Peptide 1 Diabetes, February 1, 2007; 56(2): 438 - 443. [Abstract] [Full Text] [PDF]
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J. J. Meier, A. E. Butler, R. Galasso, and P. C. Butler Hyperinsulinemic Hypoglycemia After Gastric Bypass Surgery Is Not Accompanied by Islet Hyperplasia or Increased {beta}-Cell Turnover Diabetes Care, July 1, 2006; 29(7): 1554 - 1559. [Abstract] [Full Text] [PDF]
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J. J. Meier, A. Gethmann, M. A. Nauck, O. Gotze, F. Schmitz, C. F. Deacon, B. Gallwitz, W. E. Schmidt, and J. J. Holst The glucagon-like peptide-1 metabolite GLP-1-(9-36) amide reduces postprandial glycemia independently of gastric emptying and insulin secretion in humans Am J Physiol Endocrinol Metab, June 1, 2006; 290(6): E1118 - E1123. [Abstract] [Full Text] [PDF]
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 D. F. Kruger, C. L. Martin, and C. E. Sadler New insights into glucose regulation. The Diabetes Educator, March 1, 2006; 32(2): 221 - 228. [Abstract] [Full Text] [PDF]
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R. Basu, R. Singh, A. Basu, C.M. Johnson, and R. A. Rizza Effect of Nutrient Ingestion on Total-Body and Splanchnic Cortisol Production in Humans Diabetes, March 1, 2006; 55(3): 667 - 674. [Abstract] [Full Text] [PDF]
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F. Fehse, M. Trautmann, J. J. Holst, A. E. Halseth, N. Nanayakkara, L. L. Nielsen, M. S. Fineman, D. D. Kim, and M. A. Nauck Exenatide Augments First- and Second-Phase Insulin Secretion in Response to Intravenous Glucose in Subjects with Type 2 Diabetes J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 5991 - 5997. [Abstract] [Full Text] [PDF]
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A. K. Bose, M. M. Mocanu, R. D. Carr, C. L. Brand, and D. M. Yellon Glucagon-like Peptide 1 Can Directly Protect the Heart Against Ischemia/Reperfusion Injury Diabetes, January 1, 2005; 54(1): 146 - 151. [Abstract] [Full Text] [PDF]
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C. F. Deacon Therapeutic Strategies Based on Glucagon-Like Peptide 1 Diabetes, September 1, 2004; 53(9): 2181 - 2189. [Abstract] [Full Text] [PDF]
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K. B. Degn, B. Brock, C. B. Juhl, C. B. Djurhuus, J. Grubert, D. Kim, J. Han, K. Taylor, M. Fineman, and O. Schmitz Effect of Intravenous Infusion of Exenatide (Synthetic Exendin-4) on Glucose-Dependent Insulin Secretion and Counterregulation During Hypoglycemia Diabetes, September 1, 2004; 53(9): 2397 - 2403. [Abstract] [Full Text] [PDF]
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 S. L. Aronoff, K. Berkowitz, B. Shreiner, and L. Want Glucose Metabolism and Regulation: Beyond Insulin and Glucagon Diabetes Spectr, July 1, 2004; 17(3): 183 - 190. [Abstract] [Full Text] [PDF]
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S. Madsbad, O. Schmitz, J. Ranstam, G. Jakobsen, and D. R. Matthews Improved Glycemic Control With No Weight Increase in Patients With Type 2 Diabetes After Once-Daily Treatment With the Long-Acting Glucagon-Like Peptide 1 Analog Liraglutide (NN2211): A 12-week, double-blind, randomized, controlled trial Diabetes Care, June 1, 2004; 27(6): 1335 - 1342. [Abstract] [Full Text] [PDF]
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 X. Wu, J. Gao, J. Yan, C. Owyang, and Y. Li Hypothalamus-Brain Stem Circuitry Responsible for Vagal Efferent Signaling to the Pancreas Evoked By Hypoglycemia in Rat J Neurophysiol, April 1, 2004; 91(4): 1734 - 1747. [Abstract] [Full Text] [PDF]
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D. J. Drucker Enhancing Incretin Action for the Treatment of Type 2 Diabetes Diabetes Care, October 1, 2003; 26(10): 2929 - 2940. [Abstract] [Full Text] [PDF]
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J. J. Meier, B. Gallwitz, S. Salmen, O. Goetze, J. J. Holst, W. E. Schmidt, and M. A. Nauck Normalization of Glucose Concentrations and Deceleration of Gastric Emptying after Solid Meals during Intravenous Glucagon-Like Peptide 1 in Patients with Type 2 Diabetes J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2719 - 2725. [Abstract] [Full Text] [PDF]
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