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Division of Metabolism, Endocrinology, and Nutrition, University of Washington (B.W.P., B.D.F., R.L.P., D.A.D.) and Veterans Affairs Puget Sound Health Care System (R.L.P.), Seattle, Washington 98195; and Division of Endocrinology, University of Cincinnati (T.P.V., D.A.D.), Cincinnati, Ohio 45267
Address all correspondence and requests for reprints to: David D’Alessio, M.D., Division of Endocrinology, University of Cincinnati, ML-0547, Cincinnati, Ohio 45267-0547. E-mail: david.d'alessio{at}uc.edu.
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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After release into the circulation, GLP-1-(7–36)NH2 is metabolized by the enzyme dipeptidyl peptidase IV (DPP-IV), a ubiquitous protease that exists on the endothelium of blood vessels and in a free form in plasma (10, 11, 12). DPP-IV cleaves the two N-terminal amino acids from GLP-1-(7–36)NH2 to form GLP-1-(9–36)NH2, a process that is so rapid that the estimated half-life of GLP-1-(7–36)NH2 in the circulation is only about 1 min (12, 13). Because the clearance of GLP-1-(9–36)NH2 takes longer than the metabolism of GLP-1-(7–36)NH2 by DPP-IV (14), GLP-1-(9–36)NH2 is the most abundant form of GLP-1 in postprandial plasma (11, 15). No biological role for GLP-1-(9–36)NH2 has yet been identified, but several studies using cultured cells suggest that it binds to the GLP-1r, albeit with approximately 100-fold less affinity than GLP-1-(7–36)NH2 (16, 17). Additional in vitro studies have shown that GLP-1-(9–36)NH2 has both agonist and antagonist properties (17, 18, 19) on the GLP-1r. Finally, administration of GLP-1-(9–36)NH2 to dogs and pigs blocks the effects of GLP-1 to inhibit gastric emptying and acid secretion (16, 20). Recently, Deacon and co-workers (14) found that GLP-1-(9–36)NH2 does not stimulate insulin secretion or antagonize the insulinotropic effects of intact GLP-1 in pigs, but does have an independent effect to promote glucose disappearance.
This report describes experiments designed to examine the biological actions of GLP-1-(9–36)NH2 on glucose metabolism in humans. In the first experiment, independent effects of GLP-1-(9–36)NH2 on parameters of iv glucose tolerance were compared with GLP-1-(7–36)NH2 as well as GLP-1-(7–37). The second experiment was designed to test the putative action of GLP-1-(9–36)NH2 as a GLP-1r antagonist by determining its effect on GLP-1-(7–36)NH2-mediated insulin secretion.
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Subjects and Methods |
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Twenty healthy men and women were recruited to participate in the two experiments. The subjects ranged in age from 23–61 yr, were free of any chronic medical conditions, received no medications, and had no history of diabetes or abnormal glucose tolerance. Each subject gave informed consent by signing a form approved by the institutional review boards of University of Washington and University of Cincinnati.
Peptides
GLP-1-(7–36)NH2, GLP-1-(7–37), and GLP-1-(9–36)NH2 were synthesized by solid phase methods at the peptide synthesis core laboratory of the Department of Pharmacology, University of Washington, or the Peptide Synthesis Core laboratory at Baylor University (Houston, TX). Synthetic material was purified to greater than 95% by HPLC, and authenticity was verified by mass spectroscopy and amino acid sequencing. The peptides were aliquoted and stored in lyophilized form and were determined to be sterile and free of pyrogens. Final concentrations of peptide aliquots and infusates were determined by RIA.
Experiment 1: independent effects of GLP-1-(9–36)NH2 on glucose tolerance
Ten subjects (seven men and three women) were admitted to the General Clinical Research Center, University of Washington, on four separate occasions after an overnight fast. Intravenous cannulas were placed in each forearm for the withdrawal of blood and the infusion of hormones and glucose; the arm used for sampling was wrapped in a heating pad to arterialize venous blood. After removal of fasting blood samples, an infusion of GLP-1-(7–37), GLP-1-(7–36)NH2, or GLP-1-(9–36)NH2 at a rate of 0.75 pmol/kg·min was initiated at -30 min and continued for 210 min; a saline infusion of 50 ml/h served as the control study. Each study was separated by at least 1 wk, and the assignment of the peptide and saline infusions was balanced in a predetermined manner so that the order of the studies was varied among the volunteers. Thirty minutes after initiation of the iv infusion of GLP-1 peptides or saline, an iv bolus of glucose (11.4 g/m2) was given over 1 min starting at time zero as the commencement of a frequently sampled iv glucose tolerance test (IVGTT) (21). Twenty minutes later, insulin was infused over 5 min (0.02 U/kg) according to a previously published protocol (22). Blood samples were drawn at -15, -10, 0, 2, 4, 6, 8, 10, 12, 14, 16, 19, 22, 25, 30, 35, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, and 180 min, and plasma was stored at -20 C for measurement of glucose, insulin, glucagon, and GLP-1.
Experiment 2: effect of GLP-1-(9–36)NH2 on GLP-1-mediated insulin secretion
Ten healthy subjects (4 men and 6 women) were admitted to the General Clinical Research Center at Children’s Hospital of Cincinnati on 2 separate occasions. On one occasion the insulin response to glucose was measured with and without GLP-1-(7–36)NH2 to determine the insulinotropic effect of this hormone. On the second occasion, an identical protocol was followed, except that GLP-1-(9–36)NH2 was given before GLP-1-(7–36)NH2 infusion to examine whether the latter hormone acted as an antagonist. Specifically, after an overnight fast 2 iv cannulas were placed as described above, and 4 baseline blood samples were drawn. A solution of 20% glucose was given at rates of 25 mg/kg·min for 2 min, 8 mg/kg·min for 8 min, and 4 mg/kg·min for 10 min, and blood was sampled at 2, 4, 6, 8, 10, 12, 14, 16, 18, and 20 min. After a 90-min equilibrium period, basal blood samples were taken at 110, 115, and 120 min, and infusions of either saline or GLP-1-(9–36)NH2 at 2.5 pmol/kg·min were given from 120–180 min. From 150–180 min, in both the saline and GLP-1-(9–36)NH2 studies, GLP-1-(7–36)NH2 was infused at a dose of 0.25 pmol/kg·min for 30 min. A glucose infusion identical to the earlier one was given from 160–180 min. At 180 min the GLP-1 and glucose infusions were stopped. Blood was collected at 125, 130, 135, 140, 145, 148, 150, 155, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 183, 186, 189, 192, 195, 200, 205, and 210 min into chilled tubes. Blood samples were immediately placed on ice and centrifuged within 1 h, and plasma was stored at -20 C until assayed. The saline and GLP-1-(9–36)NH2 studies were separated by 1–12 wk, and the two protocols were balanced among the 10 volunteers, so that half had saline, and half had GLP-1-(9–36)NH2 as the first study.
Assays
Blood samples were collected in tubes containing heparin for determinations of glucose and insulin, a benzamidine-based antiproteolytic cocktail for glucagon measurement (23), 50 mM EDTA plus 500 kallikrein inhibitory units/ml aprotinin for assay of GLP-1 immunoreactivity (GLP-1-ir), and 0.1 M diprotin A for measurement of intact GLP-1-(7–36)NH2. Plasma glucose was measured using a glucose oxidase method. Insulin concentrations were determined with a previously described RIA (24), and glucagon was measured with a commercial assay (Linco Research, Inc., St. Charles, MO). GLP-1-ir was measured by RIA using antiserum 89390 (provided by Dr. Jens Holst, Panum Institute, Copenhagen, Denmark) using plasma extracted with 70% ethanol. The antiserum was diluted 1:20,000, and 50 µl were added to each assay tube. Synthetic GLP-1-(7–36)NH2 (Peninsula Laboratories, San Carlos, CA) was used for standards and iodinated for use as a tracer, and a double antibody technique was used to separate bound from free peptide. The recovery of standard peptide added to plasma and extracted in ethanol was more than 80%, the intra- and interassay coefficients of variation for this RIA were 6% and 8%, respectively, and the minimum detectable concentration of GLP-1-(7–36)NH2 was 1.17 pM. Figure 1
shows the reactivity of GLP-1-(7–36) NH2, GLP-1-(7–37), and GLP-1-(9–36)NH2 in the GLP-1-ir RIA using antiserum 89390. Based on the lack of displacement of iodinated GLP-1-(7–36)NH2 by GLP-1-(7–37), it appears that the C-terminal arginine amide is required for binding to the antibodies in this serum, as previously reported (2). However, binding of the antiserum to GLP-1-(9–36)NH2 was equivalent to that of GLP-1-(7–36)NH2.
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Calculations and analysis
Fasting concentrations of glucose and hormones were taken as the mean of the four samples drawn at the beginning of each day of study. The glucose disappearance constant (kg) during the IVGTT was computed as the slope of the logarithm of glucose values between 10 and 19 min after glucose infusion, and after the cessation of glucose in experiment 2 as the slope of the logarithm of glucose values between 180 and 210 min. The acute insulin response to glucose (AIRglu) during the IVGTT in experiment 1 was computed as the incremental area above basal in the 10 min after glucose administration, and glucose-stimulated insulin secretion during the glucose infusions in experiment 2 was calculated similarly using values collected over 20 min. The insulin sensitivity index (SI), and glucose effectiveness (SG) were calculated using the minimal model of glucose kinetics (25), and glucose effectiveness at zero insulin (GEZI) was computed as previously described (21). Basal concentrations of glucose and hormones during the infusion of GLP-1-(7–36)NH2, with and without GLP-1-(9–36)NH2, in experiment 2 were taken as the mean of the three or four samples drawn immediately before the administration of iv glucose. The half-life of GLP-1-(9–36)NH2 was calculated from the slope of the natural logarithm of the GLP-1-ir increment above basal from 186–200 min; the mean clearance rate of this peptide was calculated by dividing the actual infusion rate for each subject by the mean GLP-1-ir increment above basal from 145–150 min. The parameters obtained from each subject in the four IVGTTs performed in experiment 1 were compared using repeated measures ANOVA for data that were normally distributed (kg, SI, and AIRglu) and repeated ANOVA for ranks (Friedman test) for data that were not normally distributed (SG and GEZI). Paired t tests were used to compare the parameters obtained for each subject in the paired studies of experiment 2. Data are presented as the mean ± SEM.
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Results |
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Fasting concentrations of GLP-1-ir did not differ in the 10 volunteers on the 4 d of the study (Table 1). Administration of GLP-1-(7–36)NH2 and GLP-1-(9–36)NH2 caused a 4-fold rise in GLP-1-ir to levels of 45–50 pM (Fig. 2A). There was no significant change in GLP-1-ir, measured with the C-terminally directed assay, during the saline or GLP-1-(7–37) infusion. Concentrations of GLP-1-(7–37) measured with an assay specific for this form of the peptide reached steady state levels near 40 pM (Fig. 2B). GLP-1-(7–37) concentrations were significantly lower (P < 0.05) than those of GLP-1-(7–36)NH2 and GLP-1-(9–36)NH2 at -15 and 16 min, but did not differ at other time points.
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). Thirty-minute infusions of GLP-1-(7–36)NH2 and GLP-1-(7–37) given to the fasted subjects caused plasma insulin levels to rise and glucagon and glucose levels to fall significantly (Table 1). In contrast, administration of GLP-1-(9–36)NH2 alone had no effect on blood glucose, insulin, or glucagon concentrations in the fasting state.
The parameters of iv glucose tolerance for each of the four infusions are listed in Table 2. Both GLP-1-(7–36)NH2 and GLP-1-(7–37) increased AIRglu, SG, and GEZI significantly relative to values in the control study, whereas these measures were not augmented by GLP-1-(9–36)NH2. There was no effect of any of the GLP-1 peptides on SI. The rate of glucose disappearance (kg) was approximately 50% greater during the infusion of GLP-1-(7–36)NH2 and GLP-1-(7–37) than it was during the control and GLP-1-(9–36)NH2 studies.
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Experiment 2: effect of GLP-1-(9–36)NH2 on GLP-1-induced insulin secretion
From 0–20 min of the saline and GLP-1-(9–36)NH2 studies, the infusion of glucose increased plasma glycemia from fasting concentrations of 4.92 ± 0.05 and 4.93 ± 0.05 mM to levels of 7.81 ± 0.09 and 7.62 ± 0.07 mM, respectively (Fig. 3A). The second administration of glucose from 160–180 min caused plasma glucose levels to rise from 4.61 ± 0.15 and 4.64 ± 0.06 mM to 7.23 ± 0.08 and 7.27 ± 0.1 mM in the saline and GLP-1-(9–36)NH2 studies, respectively. Thus, the glycemic stimulus for insulin secretion was well matched among the studies.
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). Measurements of intact GLP-1-(7–36)NH2 in the saline study using the ELISA specific for the nonmetabolized peptide demonstrated an increase from basal levels of 3.8 ± 1.4 pM to a steady state concentration of 10.4 ± 2.1 pM (Fig. 4B). As the GLP-1-ir level reflects the sum of GLP-1-(7–36)NH2 and GLP-1-(9–36)NH2 levels, there was an approximately 1.5-fold excess of GLP-1-(9–36)NH2 over GLP-1-(7–36)NH2 during the period of glucose infusion.
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). Concentrations of intact GLP-1 in the GLP-1-(9–36)NH2 study, measured using the specific ELISA, were similar to those observed in the saline study (Fig. 4B), with a fasting level of 3.5 ± 1.2 pM and a steady state concentration of 12.0 ± 1.2 pM. The mean ratio of GLP-1-ir to intact GLP-1 during the glucose infusion in this experiment was about 15:1, indicating an estimated 14-fold excess of GLP-1-(9–36)NH2 over GLP-1-(7–36)NH2. The mean half-life of GLP-1-(9–36)NH2 in plasma was 3.53 ± 0.39 min, and the mean clearance rate was 1.3 ± 0.1 liters/min.
Insulin concentrations during the saline and GLP-1-(9–36)NH2 infusions did not differ significantly (Table 3 and Fig. 3B). Integrated insulin secretion in response to the 20 min infusion of glucose alone was similar in the saline and GLP-1-(9–36) studies (Fig. 5). The integrated insulin responses to glucose and either GLP-1-(7–36)NH2, or GLP-1-(7–36)NH2 plus GLP-1-(9–36)NH2 were significantly greater than with glucose alone in each study, reflecting the insulinotropic effect of GLP-1-(7–36)NH2; however, administration of high concentrations of GLP-1-(9–36)NH2 had no effect on the action of GLP-1-(7–36)NH2 to stimulate insulin release [fold increases of 1.8 ± 0.2 and 1.9 ± 0.2 for the saline and GLP-1-(9–36)NH2 studies, respectively; P = 0.99]. Glucose disappearance after cessation of the glucose and GLP-1 infusions was not different in the saline and GLP-1-(9–36)NH2 studies (1.5 ± 0.1% and 1.6 ± 0.1%/min; P = 0.37).
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Discussion |
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The evidence that GLP-1-(9–36)NH2 acts as a GLP-1r antagonist in vivo comes from two studies in animals in which the GLP-1 metabolite had inhibitory effects on gastric function (16, 20). Based on these data and studies in vitro (18) it had been suggested that GLP-1-(9–36)NH2 could have the same effect on insulin secretion (27). In designing these experiments our intention was to administer GLP-1-(9–36)NH2 in amounts estimated to give supraphysiological concentrations of the peptide to increase the likelihood of detecting any effects. In experiment 1, GLP-1-ir during the GLP-1-(9–36)NH2 infusions exceeded the levels of GLP-1 peptides typically found in the postprandial circulation (
20–40 pM) (26, 28, 29) and so can be considered supraphysiological. Although the lack of any independent effect on insulin secretion or glucose tolerance in this study does not rule out the possibility of effects at higher concentrations, the data do indicate that GLP-1-(9–36)NH2 does not play a physiological role in insulin secretion or glucose disappearance.
In the second experiment GLP-1-(9–36)NH2 was given at rates that were approximately 10-fold greater than the rates of GLP-1-(7–36)NH2 administration to augment any effect of the peptide as a competitive GLP-1r antagonist. It has previously been shown that after the ingestion of glucose, concentrations of GLP-1-(9–36)NH2 are roughly 3–4 times those of GLP-1-(7–36)NH2 (15, 26). Based on the circulating levels of GLP-1-ir during the infusions, we achieved concentrations of GLP-1-(9–36)NH2 that were at least approximately 14-fold higher than those of intact GLP-1 and still found no effect on GLP-1-stimulated insulin secretion. Given a circulating half-life for GLP-1-(7–36)NH2 of about 1 min (1) and the half-life of GLP-1-(9–36)NH2 determined in these studies of about 4 min, it seems very unlikely that a relative excess of metabolite to intact GLP-1 in plasma of greater than 1:10 would occur from the metabolism of GLP-1-(7–36)NH2 either secreted from the gut or given exogenously. Therefore, we believe that the present findings rule out any effect of GLP-1-(9–36)NH2 as a hormonal inhibitor of GLP-1-(7–36)NH2-induced insulin secretion after the secretion or administration of intact GLP-1. Hansen and colleagues (30) recently demonstrated that a considerable proportion of GLP-1-(7–36)NH2 is metabolized in the intestine of pigs even before it reaches the bloodstream. It is conceivable that a significant molar excess of GLP-1-(9–36)NH2 over GLP-1-(7–36)NH2 could occur in the intestine if DPP-IV activity is high and clearance of the metabolite is slower than in the circulation. In this case it would be possible for the metabolite to antagonize GLP-1r located in the gut.
Both the N-terminally intact, insulinotropic, forms of GLP-1 decreased fasting glucagon levels, whereas infusion of GLP-1-(9–36)NH2 did not. Previous studies have reported an effect of GLP-1-(7–36)NH2 to decrease circulating glucagon levels (1), and in fact, the administration of GLP-1r antagonists in the fasting state causes a rise in plasma glucagon (7, 31). Although there is some question about the mechanism by which GLP-1-(7–36)NH2 regulates glucagon release, there is evidence that the GLP-1r is expressed on the pancreatic 
-cell (32, 33). The lack of effect of GLP-1-(9–36)NH2 on fasting glucagon concentrations indicates that this peptide does not have actions specific to the -cell that are comparable to those of unmetabolized GLP-1. None of the GLP-1 peptides had any added effect on the suppression of glucagon concentrations caused by the hyperglycemia after iv glucose administration.
We previously reported that GLP-1-(7–36)NH2 significantly improves iv glucose tolerance in healthy humans, and that this effect is due to increases in both insulin secretion and glucose effectiveness (21, 34). The results of the current study extend our previous findings to GLP-1-(7–37) and are consistent with the report by Orskov and colleagues (3) that GLP-1-(7–36)NH2 and GLP-1-(7–37) are essentially equivalent with respect to their regulation of glucose metabolism. Although the augmentation of glucose effectiveness by GLP-1 has been questioned by other investigators (35), we have now noted this effect consistently in repeated studies (21, 34). As GLP-1-(9–36)NH2 is the most prevalent form of the peptide in the postprandial circulation, and because it has been previously reported that amidated, but not unamidated, GLP-1 peptides have a potent independent effect on glycogen synthesis in vitro (36), we were interested to determine whether GLP-1-(9–36)NH2 might account for some of the insulin-independent effects of GLP-1. However, in neither experiment 1, in which GLP-1-(9–36)NH2 was tested alone, nor in experiment 2, in which it was given with GLP-1-(7–36)NH2, did we see any effect of this peptide on insulin-dependent or insulin-independent glucose disposition.
Our findings in humans are compatible with many of the results reported by Deacon et al. in their study of pigs (14). The half-life and plasma clearance rate of GLP-1-(9–36)NH2 are remarkably similar in pigs and humans. Furthermore, there was no direct effect of GLP-1-(9–36)NH2 on insulin secretion in either study nor an effect of the metabolite to antagonize the insulinotropic action of GLP-1-(7–36)NH2. However, in pigs there was an apparent effect of GLP-1-(9–36)NH2 to promote glucose disappearance that was not seen in humans. It is plausible that the discrepant results between our study and that by Deacon and colleagues are a function of species difference. Pigs have a greatly accelerated rate of glucose disposal relative to humans. Thus, it may be that alternative mechanisms and regulation are involved in carbohydrate assimilation in these animals (14).
One concern in applying GLP-1 as a diabetes treatment is the rapid conversion of the intact hormone to GLP-1-(9–36)NH2, and the potential effects of the metabolite on the actions of GLP-1-(7–36)NH2. Several studies have now demonstrated that inhibiting DPP-IV, and blunting the generation of GLP-1-(9–36)NH2 improves glucose metabolism in animals and humans (37). Based on the results of the studies presented here we think that the most likely explanation for the utility of DPP-IV inhibitors is the prolongation of GLP-1 action, as we found no evidence of deleterious effects of GLP-1-(9–36)NH2 on insulin secretion and glucose tolerance. The possibility that GLP-1-(9–36)NH2 could augment glucose lowering, either alone or in combination with GLP-1-(7–36)NH2 (14), has also been proposed. Our results suggest that this does not happen in healthy men and women and raise doubts about any physiological role for GLP-1-(9–36)NH2 in the disposition of circulating glucose in humans. Although it is possible that GLP-1-(9–36)NH2 could have completely different effects in diabetic patients than it does in the nondiabetic subjects who volunteered for our studies, this seems unlikely to us. Thus, although it is possible that GLP-1-(9–36)NH2 produced after pharmacological administration of GLP-1-(7–36)NH2 may have actions unrelated to glucose metabolism, even relatively high levels of the metabolite should not interfere with the antidiabetic properties of intact GLP-1.
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Acknowledgments |
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Footnotes |
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This work was supported by a Clinical Research Award from the American Diabetes Association and Grants R01-DK-54263 and M01-RR-08084.
Abbreviations: AIRglu, Acute insulin response to glucose; DPP-IV, Dipeptidyl peptidase IV; GEZI, glucose effectiveness at zero insulin; GLP-1, glucagon-like peptide 1; GLP-1r, GLP-1 receptor; -ir, immunoreactivity; IVGTT, iv glucose tolerance test; kg, glucose disappearance constant; SG, glucose effectiveness; SI, insulin sensitivity index.
Received September 23, 2002.
Accepted January 8, 2003.
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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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), and GLP-1-(9–36)NH2 (
). The assay was performed as described in Subjects and Methods.
) in experiment 1. A, GLP-1-ir was determined by RIA using antiserum 89330, reacting with the amidated C terminus of GLP-1-(7–36)NH2. B, GLP-1-ir determined by RIA using an antiserum specific for the unamidated C terminus of GLP-1-(7–37).
) and in response to glucose with GLP-1-(7–36)NH2 or glucose with GLP-1-(7–36)NH2 plus GLP-1-(9–36)NH2 (