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Diabetes and Metabolism Section (J.M.E., D.E.), Laboratory of Clinical Investigation, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224; and Geriatric Research Laboratory (A.R.C., D.E.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Dariush Elahi, Ph.D., Massachusetts General Hospital, Geriatric Research Laboratory, GRBSB-015, 55 Fruit Street, Boston, Massachusetts 02114. E-mail: . elahi.dariush{at}mgh.harvard.edu
Abstract
Exendin-4 is a potent and long-acting agonist of the glucagon-like peptide-1 (GLP-1) receptor. GLP-1 is an insulinotropic gut peptide and is being evaluated for the regulation of plasma glucose in type 2 diabetes. The purpose of the present study was to ascertain whether exendin-4 is insulinotropic and whether it has long-lived biological effects in nondiabetic and type 2 diabetic subjects. Because incretins are glucose dependent with respect to their insulin-releasing capacity, we used the hyperglycemic glucose clamp technique to begin to address these issues in two separate protocols. In one protocol, we infused exendin-4 (0.15 pmol·kg-1·min-1) in seven nondiabetic and seven type 2 diabetic subjects during the second hour of a 5-h hyperglycemic clamp in which fasting plasma glucose was raised by 5.4 mmol/liter. The second protocol was identical to the first except that plasma glucose was allowed to fall to the fasting levels during the fourth hour and again raised by 5.4 mmol/liter during the fifth hour in four nondiabetic and four diabetic subjects. With the initiation of exendin-4 infusion at 60 min, plasma insulin response was potentiated 4- to 5-fold in both groups. Despite termination of exendin-4 at the end of the second hour, the insulin levels remained elevated for several hours and hyperglycemia was maintained. All volunteers ate a meal 5.5 h after inducing hyperglycemia. Postprandial plasma glucose, insulin, and GLP-1 did not rise in any subject, possibly because of delayed gastric emptying by exendin-4 even though its infusion had been terminated 4 h previously. We concluded that exendin-4 is a potent and long-lasting insulinotropic agent in nondiabetic and diabetic subjects.
GLUCAGON-LIKE PEPTIDE-1 (GLP-1), a gastrointestinal hormone secreted by the L cells of the intestine, regulates blood glucose primarily via stimulation of glucose-dependent insulin release. It has been viewed and is being evaluated as a potential treatment for type 2 diabetes because it lowers blood glucose levels when given in pharmacological concentrations (1, 2, 3). The major drawback to its clinical use is its short biological half-life necessitating continuous administration iv or by frequent sc injection. Exendin-4 is a 39 amino acid agonist of the GLP-1 receptor, present in the saliva of the Gila monster (Heloderma suspectum). We have shown in diabetic rodent models that it is 10 times more potent as an insulinotropic agent than is GLP-1. Of greater clinical relevance is its longer duration of action in vivo (4, 5). The purpose of the present study was to ascertain the extent of the insulinotropic effect of exendin-4 in humans, in both the nondiabetic and type 2 diabetic state. We were especially interested in type 2 diabetic subjects because all incretins are not insulinotropic in this disease. Finally, knowing that in rodents exendin-4 has a much longer biological effect than does GLP-1 (4, 5) we attempted to document the duration of its insulinotropic effect. Because incretins are glucose dependent with regard to their insulin-releasing capacity, we used two hyperglycemic glucose clamp protocols for 5 h to examine these issues. In the first study, hyperglycemia was established and maintained for the entire 5 h. In the second study to examine the glucose dependency of the peptide in addition to its duration of action, we allowed the plasma glucose to fall to fasting levels during the fourth hour and again reestablished hyperglycemia during the fifth hour. We show that in humans, exendin-4 is indeed a very potent insulinotropic agent with a long half-life.
Subjects and Methods
Experimental subjects
We employed two hyperglycemic clamp designs. In the first, seven nondiabetic individuals (three males, four females; five Caucasians, two African Americans) were enrolled. They ranged in age from 24 to 56 yr (mean ± SE = 43.6 ± 4.0) and in body mass index (BMI) from 20.2 to 36.4 kg·m2 (27.8 ± 2.0). Seven non-insulin-treated type 2 diabetic individuals (five males, 2 females; two Caucasian, four African-Americans, and one Hispanic) also volunteered. They ranged in age from 45 to 74 yr (60.5 ± 3.8) and in BMI from 32.7 to 46.8 kg·m2 (34.6 ± 2.0). In the second design, four nondiabetic Caucasian volunteers (two males, two females), age range 26–50 yr (41 ± 5.3), BMI 22.2 to 26.6 kg·m2 (25 ± 1.0) and four non-insulin-treated type 2 diabetic volunteers (two males, two females; three Caucasians, one African-American), age range 40–69 yr (42 ± 6.4), BMI 28.9–40.1 kg·m2 (38 ± 2.5) volunteered. In design one, four of the seven type 2 volunteers were being treated with sulfonylureas (S) and in design two, one was taking S and one was taking both S and metformin (M). All other type 2 volunteers were not taking hypoglycemic agents. Hemoglobin A1C levels were obtained in only four volunteers (N = 10.6, S = 8.9, 9.1, M = 8.6). All methods and procedures were approved by the Johns Hopkins Bayview Medical Center Institutional Review Board (along with an investigator initiated IND from the FDA). All volunteers provided written informed consent.
Materials and methods
Experimental design.
We asked all subjects to consume a weight-maintaining diet without carbohydrate restriction, maintain their usual level of physical activity, and withhold diabetic medication for 3 d before testing. We performed all clamps after an overnight fast, at 0730 h as described previously (6). After determination of the stable fasting state, at time 0, in both clamp designs, we initiated a hyperglycemic clamp, whereby the fasting plasma glucose levels were raised by 5.4 mmol/liter (Fig. 1
). In the first design, this level was held stable for 5 h, and in the second design, the plasma glucose level was allowed to fall to basal levels at the end of the third hour and maintained there until the beginning of the fifth hour. At that time we again raised plasma glucose level by 5.4 mmol/liter and held it stable for the next hour. In both designs we infused synthetic full-length exendin-4 (AC2993: Amylin Pharmaceuticals, Inc., San Diego, CA) for 1 h (60–120 min) in a primed continuous manner. The infusion rate was changed at 2-min intervals during the first 10 min from 0.59 to 0.25, 0.23, 0.22, and 0.20, and at 10 min and for the remainder of the hour to 0.15 pmol·kg-1·min-1. We chose this design because we had previously given GLP-1 with a similar infusion method, except the concentration infused was 10-fold higher (7) because we wanted to compare the responses. Exendin-4 was supplied as a 1-ml pyrogen-free, sterile formulation (72 nmol/liter) in acetate buffer (pH 4.5) with mannitol. Just before administration the peptide was diluted in a 50-ml solution of normal saline containing 2 ml of each subject’s blood.
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Analytical techniques. We collected blood samples in heparinized syringes. An aliquot of plasma glucose was immediately assayed by the glucose oxidase method, and the remaining blood samples were processed and stored as previously described (8). All determinations were performed in duplicate except for nonessential fatty acids (NEFA). Plasma insulin, C-peptide, GLP-1, glucagon, and NEFA were also determined as previously described (8, 9). NEFA was measured by an enzymatic colorimetric method (Wako Chemicals USA, Inc., Richmond, VA).
Statistical analysis. Glucose utilization (M) was calculated at 30-min intervals from 0 to 300 min, from the 30-min interval glucose infusion rates, corrected for changes in glucose content in the glucose space of the body and for urinary glucose losses during the test. Glucose utilization, assessed with M, may be underestimated because we did not measure hepatic glucose production. Although this is highly unlikely following exendin-4 administration because of the marked hyperinsulinemia in the normal subjects, the same cannot be unequivocally stated for the diabetic subjects. Metabolic clearance rate of glucose (MCR, ml·kg-1·min-1), the volume of plasma from which glucose is completely and irreversibly removed per unit time was calculated as M divided by the plasma concentration of glucose for the specific time interval. We used the trapezoidal rule to calculate the integrated responses over 30-min intervals. The integrated responses were divided by its time interval resulting in mean concentrations or values. Means of the individual values were calculated for MCR, glucose, NEFA, and hormones.
All data were analyzed using SAS version 6.12 (SAS Institute, Inc., Cary, NC). Standard methods were used to compute means and SEM. The hormone and substrate concentration curves for each type of study were compared for the periods before and after exendin-4 infusion with paired t test. P values below 0.05 were regarded as indicating statistical significance. Results are presented as mean ± SEM.
Results
The nondiabetic group of subjects had a significantly lower BMI, compared with the diabetic group of subjects (P < 0.01). In design one, plasma glucose levels were increased and maintained stable in both groups for 5 h (
5.3 mmol/liter, Fig. 2 and 3). In design two, plasma glucose levels were also stable from 0 to 180 and from 240 to 300 min.
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and 3, inset, third panel). With the start of exendin-4 infusion at 60 min, insulin responses were potentiated in both groups and in both designs. In design one, the potentiated insulin response was maintained for the duration of the hyperglycemic clamp, despite termination of exendin-4 at 120 min. The anticipated 90- to 120-min insulin concentration, had exendin-4 not been given, can be computed in these volunteers from the 30- to 60-min insulin responses as previously described (6) and is represented as solid lines in the third panels of Fig. 2 and 3. The actual 90–120 min concentrations are significantly increased in both groups and in both designs (P < 0.01). In design two, after stopping the glucose infusion at 180 min, plasma insulin levels fell in both groups. With reestablishment of hyperglycemia, a much-potentiated first-phase insulin response (240–250 min), compared with that observed initially (0–10 min), was clearly evident in the nondiabetic volunteers (P < 0.01). An increase in second-phase insulin response was also evident during the reestablishment of hyperglycemia. However, insulin levels were not as high as during the 60- to 180-min period (Fig. 2). The insulin response in the diabetic group also increased, but a first-phase insulin response was not evident and again the level did not reach those observed during the 60- to 180-min period (Fig. 3). C-peptide levels generally followed the pattern of the insulin response in both groups and in both study designs (Fig. 2 and 3, bottom panels).
NEFA are exquisitely sensitive to insulin and were seen to rapidly drop as hyperinsulinemia develops in both nondiabetic and diabetic groups (Fig. 4 and 5). In the diabetic subjects in both designs, there was a small escape of suppression of NEFA during the 240- to 330-min period, which probably reflects the small fall in the plasma insulin levels during this time. Basal glucagon levels were significantly elevated in the diabetic group, compared with the nondiabetic group (Fig. 5, P = 0.008) and fell with the commencement of the hyperglycemic clamp in both groups. There was a continuation of the decline during the exendin-4 infusion after which plasma glucagon levels reached a plateau in design one. In design two, with the concomitant fall of hyperglycemia and insulin levels, plasma glucagon levels increased (180–240 min). This was most evident in the diabetic group (P = 0.048, compared with 120–180 min). When hyperglycemia was reestablished during the fifth hour, glucagon levels fell again. Glucagon levels are seen to rise again with termination of the clamp.
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In the second design, we terminated glucose infusion at 180 min in both groups and had to restart glucose infusions within 10 min in the nondiabetic group or within 20 min in the diabetic group to prevent hypoglycemia because of the persisting effect of hyperinsulinemic state. Furthermore, at 240 min, to reestablish hyperglycemia, a significantly larger priming dose (150–200%) of glucose was required, compared with the initial dose in both groups. In each design, glucose infusion was terminated at 300 min. In the nondiabetic group, in both designs, the glucose infusion was restarted within 10 min to prevent hypoglycemia.
We computed peripheral glucose uptake (M) in both designs in both groups. Because fasting plasma glucose levels were significantly higher in the diabetic group, we calculated MCR of glucose. In design one, after exendin-4 administration, MCR in both groups increased about 4-fold. The increase in MCR after exendin-4 is statistically significant within each group as well as between each group in all 30-min comparisons (P 
0.02 to 0.0001). In design two, MCR in both groups before and after exendin-4 administration were similar to that of design one. With the fall in plasma glucose level and reestablishment of hyperglycemia, MCR did not change significantly in either group.
The postprandial elevation in plasma glucose typically observed when subjects are fed was absent in the present experiments. No changes in plasma GLP-1 (data not shown), insulin, NEFA, or glucagon levels were seen for the duration of the observed postprandial period (Fig. 6 and 7).
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We demonstrated that exendin-4, an agonist at the GLP-1 receptor, is a potent insulinotropic agent in nondiabetic and type 2 diabetic patients. Plasma insulin levels achieved in response to iv infusion of 0.15 pmol·kg-1·min-1 were comparable with that achieved with 1.5 pmol·kg-1·min-1 GLP-1 (7). In addition to its greater potency, the duration of the biological effects of exendin-4 far exceeded that of GLP-1. This is clear in the prolonged elevation of plasma insulin levels following termination of exendin-4 infusion, which is on the order of hours, as opposed to minutes in the case of GLP-1 (7, 8). This is the case even in subjects with type 2 diabetes whose plasma insulin levels were double fasting levels 5–6 h after exendin-4 infusion was terminated.
To examine glucose dependency of exendin-4, we modified the clamp protocol. In four nondiabetic and four type 2 diabetic patients after 3 h of hyperglycemia, we allowed plasma glucose levels to fall for 1 h. Plasma insulin levels fell in both groups during this period and with reestablishment of hyperglycemia, first-phase insulin levels were approximately 10-fold higher than the first-phase response achieved at the start of hyperglycemic clamp in the nondiabetic volunteers. Thus, it appears that on reestablishment of hyperglycemia, exendin-4, with our presumption of its prolonged half-life, potentiates first-phase insulin response; however, it is also possible that at least part of this potentiation could be owing to the priming effect the previously sustained 3-h hyperglycemia.
Plasma glucagon and nonesterified fatty acid levels started to fall precipitously with establishment of hyperglycemia and the resultant hyperinsulinemia, and the fall continued during the exendin-4 administration. This is most evident in the diabetic group in which the fasting levels of both glucagon and NEFA were higher. Thus, despite significantly elevated plasma insulin levels, glucagon, and NEFA remain relatively elevated in the diabetic subjects. This leads us to hypothesize that there is an insulin-independent component of glucagon and perhaps NEFA regulation, which is altered in type 2 diabetes and is not influenced by endogenous insulin secretion.
Under normal conditions plasma insulin levels rise during the postprandial period in response to release of the incretins, GIP and GLP-1, and absorption of the products of digestion. We measured GLP-1 concentrations during this period in 14 subjects and could not demonstrate an increase, suggesting that food was probably not reaching the duodenum or ileum. This is consistent with the known effect of GLP-1 on inhibition of gastric emptying, and presumably exendin-4 is doing likewise (10). However, this observation needs to be studied with appropriate measurement of gastric emptying. Insulin levels were approximately double fasting levels in both nondiabetic and diabetic subjects following ingestion of food, indicating that insulinotropic action persisted. The postprandial hyperinsulinemia is not just a delay in clearance of insulin or a return of insulin from interstitial fluid into the plasma space because C-peptide levels are still several-fold higher than the basal C-peptide level.
Following our studies in rodents (4), we have demonstrated in humans, potent, prolonged insulinotropic actions of exendin-4. To our knowledge, exendin-4 is a unique product of the Gila monster, which has no human counterpart. Current literature shows that exendin-4 acts as an agonist of the GLP-1 receptor (11). It binds the cloned human GLP-1 receptor with high affinity, and it is displaced from the binding sites by GLP-1 and the GLP-1 receptor antagonist, exendin-(9–39) (11). Exposure of fibroblasts transfected with the human GLP-1 receptor to exendin-4 lead to a 12-fold increase in cAMP, which again was prevented by exendin-(9–39), demonstrating that exendin-4 is an agonist of the receptor. Exendin-4 has also been shown to increase cAMP generation in rat islets (4). Therefore, our assumption is that exendin-4, when given to humans, is stimulating insulin secretion through the GLP-1 receptor.
In conclusion, we have demonstrated that exendin-4 is a very potent insulinotropic agent in humans when administered iv. It is being explored as a candidate therapy for type 2 diabetes.
Acknowledgments
We express our appreciation to the volunteers who participated in this study. We thank the staff of the Clinical Research Center at Johns Hopkins Bayview Medical Center. We thank Gail Chin for excellent technical support and Brenda I. Vega for her assistance with the preparation of this manuscript. We thank Amylin Pharmaceuticals, Inc. for the generous donation of exendin-4 (AC2993).
Footnotes
This work was supported in part by the Intramural Research Program of NIA, Juvenile Diabetes Foundation International through the JDF Center for Islet Transplantation at Harvard Medical School, and General Clinical Research Center Grant M01RR02719 at Johns Hopkins Bayview Medical Center.
Abbreviations: BMI, Body mass index; GLP-1, glucagon-like peptide-1; M, metformin; MCR, metabolic clearance rate of glucose; NEFA, nonessential fatty acids; S, sulfonylureas.
Received May 22, 2001.
Accepted December 7, 2001.
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