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Original Article |
Diabetes Section, Laboratory of Clinical Investigation (J.M.E.), National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224; Department of Medicine (G.S.M.), University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada; Laboratory of Molecular Endocrinology (J.F.H.), Howard Hughes Medical Institute, Boston, Massachusetts 02114; and Department of Medicine (J.F.H., 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, Gray/Bigelow Sub-Basement 0015, 55 Fruit Street, Boston, Massachusetts 02114. E-mail: . delahi{at}partners.org
Abstract
The insulinotropic hormone, glucagon-like peptide-1 (GLP-1), is being examined as a potential new agent for treatment in type 2 diabetic patients. Whereas the insulinotropic properties of this peptide are well established, another property of the hormone, an insulinomimetic effect per se, is controversial. In the normal glucose-tolerant lean state, it is difficult to demonstrate an insulinomimetic effect. The current study was conducted to examine whether GLP-1 has insulinomimetic effect in the obese state. Ten obese volunteers (body mass index, 34.6 ± 0.8 kg/m2), whose ages were 32.5 ± 3.0 yr, participated in two euglycemic clamp studies (n = 20 clamps) for 120 min. Five of the volunteers were females. The initial clamp was performed with a primed (0–10)-constant (10–60) infusion of GLP-1 at a final rate of 1.5 pmol · kg-1 · min-1. At 60 min, the GLP-1 infusion was terminated, and euglycemic was maintained from 60–120 min. After the GLP-1 study, each individual’s plasma insulin level was measured. A second study was performed that was identical to the first, with the infusion of regular insulin in place of GLP-1. Insulin infusion rates were regulated in each individual to simulate plasma insulin levels produced during the GLP-1 infusion. The rate of disappearance of glucose was calculated for each subject. Fasting plasma insulin levels were similar between studies. In response to the GLP-1 infusion, with maintenance of plasma glucose level clamped at fasting level, significant increases in plasma insulin occurred in all subjects (P < 0.001). The insulin levels during the insulin infusion study were similar to that induced by GLP-1. The rate of disappearance of glucose (insulin-mediated glucose uptake) progressively increased in response to both the GLP-1 and insulin infusion. However, the rate of disappearance of glucose during the GLP-1 study was significantly higher (P = 0.033) than during the insulin study. We conclude that in insulin-resistant states, GLP-1 has insulinomimetic properties per se.
GLUCAGON-LIKE PEPTIDE-1 (GLP-1) is an insulinotropic hormone released from the entero-endocrine cells of the gut. It augments insulin secretion in response to meals and lowers blood glucose levels in both type 1 and type 2 diabetic subjects (1, 2) when given in pharmacological concentrations. It has been proposed that a component of the glucose-lowering effects of GLP-1 occurs via insulin-independent mechanisms, so called insulinomimetic actions (3, 4). However, the interpretations of the studies have been controversial. An earlier study that we conducted to examine whether glucagon-like peptide (GLP-1) has insulinomimetic effects during euglycemia in young lean male [age, 25 ± 1.4 yr; body mass index (BMI), 24.0 ± 0.7 kg/m2] volunteers did not demonstrate any added effects of GLP-1 on glucose homeostasis beyond that of its insulin-secreting properties (5). In that particular study we performed two, 2-h euglycemic protocol using clamp methodology. During the first hour, we administered GLP-1 in a primed continuous infusion of GLP-1 at a final rate of 1.5 pmol · kg-1 · min-1 from 10–60 min, and during the second hour, euglycemia was maintained without infusion of GLP-1. After the GLP-1 study, each subject’s insulin was measured and a second clamp study was performed more than a month later. In the second clamp, insulin was infused during the 0–60 min period to exactly mimic the peripheral insulin levels of each individual from the first clamp study when GLP-1 was infused. During the second hour, once again, euglycemia was maintained without infusion of insulin. We measured glucose uptake and disposal rates during both clamps using tracer methodology. No difference in glucose uptake or disposal rates was appreciated. Some other studies using different methodologies (6, 7, 8) are in agreement with our findings. However, our previous study (5) was performed under conditions in which the subjects had normal glucose tolerance. Therefore it is possible that the putative insulinomimetic effects of GLP-1 are masked when insulin-mediated glucose uptake is normal.
More recently, we have shown in elderly subjects with type 2 diabetes that GLP-1 increased both insulin-mediated, and, with the use of somatostatin, noninsulin-mediated glucose uptake (9, 10). The present study was undertaken, with exactly the same design as in the study of lean males (5), to evaluate the insulin-like effects of GLP-1 on glucose utilization in obese subjects. We postulated that, because obesity is associated with insulin resistance, the insulinomimetic effects of GLP-1 will not be masked.
Materials and Methods
Experimental subjects
Five females and five males participated in the study. There were three Caucasian and two African-Americans of each gender. The mean age of the subjects was 32.5 ± 3.0 yr. All subjects were nonsmokers, free of underlying disease and not taking any medications. Subjects were screened by medical history, physical examination, routine biochemical assessment of blood and urine samples, and a 75-g glucose tolerance test. All subjects had a normal glucose tolerance as defined by the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (11). A BMI of more than 30 kg/m2 was required as an inclusion criteria. The mean BMI of the subjects was 34.6 ± 0.8 kg/m2. The Intramural Research Branch of the National Institute on Aging (NIA) and the Institutional Review Board of Johns Hopkins Bayview Medical Center approved all methods and procedures. All subjects provided written, informed consent before participation in the study.
All subjects were asked to consume a weight-maintaining diet without carbohydrate restriction and to maintain their usual level of physical activity. Each subject was admitted to the General Clinical Research Center for two separate studies, which were conducted at least 4 wk apart. All testing was performed after an overnight fast and begun at 0730 h. Euglycemia was maintained during both studies using glucose clamp methodology.
During the first clamp study (study 1), GLP-1 levels were rapidly raised and then maintained stable with a falling primed (0–10 min, with a change at 2-min intervals) constant (10–50 min, 1.5 pmol·kg-1 · min-1) infusion, as we have described previously (5). We used synthesized GLP-1 (Boston Molecules, Woburn, MA), which had a peptide content of 79%. The peptide was more than 99% pure and gave a single peak on high performance liquid chromatography. The peptide was lyophilized in vials under sterile conditions for single use and was certified to be both pyrogen free and sterile. Net peptide content was used for all calculations.
After the GLP-1 study, each individual’s plasma insulin level was measured. A second study (study 2) was performed that was identical to the first, with an infusion of regular insulin (Humulin, Eli Lilly Co., Indianapolis, IN) in place of GLP-1. We were able to design an insulin infusion pattern in each individual to simulate plasma insulin levels produced during the GLP-1 infusion. At 60 min, the GLP-1 or the insulin infusions were terminated and all parameters were maintained for another 60 min.
In each study, glucose production and utilization rates were determined by means of the primed constant rate infusion technique with tritiated glucose (12). A priming dose of 8.5 kilobecquerals/kg sterile and pyrogen-free [3H] glucose (NEN Life Science Products, Boston, MA) was administered at -120 min, followed by a constant intravenous infusion of 85 becquerels-1 · kg-1 · min-1 for the duration of the experiment. Four arterialized blood samples (13) were taken from a dorsal hand vein enclosed in a box heated to 68–70 C at 10-min intervals starting at -30 min to assess basal metabolic parameters. At 0 min, employing the euglycemic clamp technique (14), and using 20% glucose solution (Travenol, Deerfield, IL), glucose levels were maintained at the fasting levels for the duration of both studies (120 min). The actual concentration of the glucose solution measured 1.02 ± 0.003 mol/liter, only 92% of its stated concentration. The glucose solution was spiked with tritiated glucose to maintain a constant glucose-specific activity as previously described (15).
Analytical technique
Blood samples were collected with heparinized syringes. Plasma glucose was immediately assayed by the glucose oxidase method (Beckman Glucose Analyzer II, Beckman Instruments, Fullerton, CA). The remaining blood samples were placed into prechilled test tubes containing kallikrein-trypsin inhibitor (Trasylol, Miles, NY), ethylenediamine tetraacetate, and Diprotin A, 0.1 µmol/ml blood, (a protease inhibitor which prevents the action of dipeptidyl peptidase lV, manufactured by Bachem, Torrence, CA) as previously described (5). The blood was centrifuged and the plasma subsequently aliquoted and stored at -80 C until analyzed. Samples were collected every 5 min for plasma glucose determination and every 10 min for subsequent measurements of insulin, C-peptide, glucagon, GLP-1 (total and active), Nonesterified fatty acids (NEFA), and the specific activity of glucose. All previous methodologies have been previously described (1, 5, 16, 17).
Statistical analyses
The rates of appearance (Ra) and rates of disappearance (Rd) of glucose were calculated according to the nonsteady state equations of Steele (12), as modified for use with spiked glucose (15). The volume of distribution of glucose was assumed to be 210 ml/kg (18). Endogenous glucose production was estimated as the difference between the calculated total appearance rate and the exogenous glucose infusion for the appropriate time interval during the clamp (19).
The mean concentrations of glucose, all the hormones, and the Rd and Ra were calculated for each time point for both clamp studies. The trapezoidal rule was used to calculate the integrated responses over 30-min intervals for each subject. The integrated response was divided by its time interval (30 min), resulting in a mean concentration or value. Means of the individual values were calculated for all parameters assayed. The differences between studies were evaluated with paired t test and repeated measures ANOVA (20) and P values less than 0.05 were regarded as significant. Mix-model analysis for repeated measures design was used to analyze hormone and glucose turnover rates. All statistical tests were two-tailed. Except where otherwise stated, results are presented as mean ±SEM.
Results
Plasma glucose levels and the glucose infusion rates necessary to maintain euglycemia during both the GLP-1 and insulin studies are illustrated in Fig. 1
. Fasting glucose levels (5.3 ± 0.1 mmol/liter) were identical in both studies, and during both subsequent clamp studies, stable plasma levels were maintained (Fig. 1A), also at 5.3 ± 0.1 mmol/liter. Glucose infusion rates during the GLP-1 and insulin studies were 9.8 ± 0.9 and 7.8 ± 0.9 mmol · kg-1 · min-1 (Fig. 1B).
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). The 30–60 min total and active GLP-1 plasma levels were 190 ± 13 and 53 ± 9.0 pmol/liter. Following termination of the GLP-1 infusion at 60 min both total and active GLP-1 plasma levels promptly fell and at 120 min were 12 ± 4 and 8 ± 3 pmol/liter. During the insulin infusion study, total GLP-1 levels were unchanged (Fig. 2A) and active GLP-1 was not measured as we considered it unnecessary to do so.
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). In response to GLP-1 or insulin, glucagon levels fell in both studies while the hormones were being infused (0–60 min). After the termination of the hormone infusions, glucagon levels started to recover (60–120 min). The change in glucagon levels during each study was significant (P < 0.001). There was also a significant difference in plasma glucagon levels between the two studies (P = 0.015). Furthermore, there was a significant time, experiment effect between the two studies, indicating that the pattern of fall and recovery of glucagon levels was different between the two studies (P = 0.006). Glucagon levels were suppressed faster during the GLP-1 infusion study and upon termination of the GLP-1 infusion, glucagon levels recovered more quickly.
Fasting plasma insulin levels were also similar in the two studies (82 ± 11 and 92 ± 13 pmol/liter). In study 1, in response to GLP-1 infusion and while maintaining euglycemia, plasma insulin levels increased in each subject (Fig. 3A). The increase was both physiologically and statistically significant (P < 0.0001). In study 2, the plasma insulin profile obtained in study 1 was simulated for each subject, and the two plasma insulin profiles were very similar (Fig. 3A). The 0- to 30-min and 30- to 60-min insulin levels in study 1 were 316 ± 53 and 258 ± 34 pmol/liter. The corresponding values in study 2 were 354 ± 73 and 362 ± 76 pmol/liter. There was no significant difference between the two 30-min periods within or between the two studies. In both studies, plasma insulin returned to fasting levels after the termination of either hormone and the 120-min levels were 84 ± 13 and 96 ± 17 pmol in studies 1 and 2.
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). In response to GLP-1 infusion and similar to the insulin profile, a square wave C-peptide profile was achieved. The 0- to 30-min and 30- to 60-min levels were 1.44 ± 0.15 and 1.58 ± 0.15 pmol/liter. On termination of GLP-1 infusion, C-peptide levels rapidly fell and at 120 min were 0.74 ± 0.08 pmol/liter. In study 2, C-peptide levels were unchanged throughout.
The Ra of glucose in the fasted state was similar in the two studies and averaged at 10.0 ± 1.0 and 9.1 ± 0.8 µmol · kg-1 · min-1 in study 1 and 2 (Fig. 4A). With the start of GLP-1 or insulin infusion Ra was suppressed (P < 0.001) and remained suppressed for approximately 40 min after the termination of the GLP-1 or insulin infusion, after which it started to recover. There was no significant difference in the suppression of Ra between the two studies (P = 0.123) and there also was no significant time, experiment effect (P = 0.727).
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). The increase during each study was significant (P < 0.001). However, there was a significant difference between the two studies, with study 1 having a greater increase compared with study 2 (P = 0.033). There was no significant time, experiment effect between the two studies, indicating that both the pattern of increase and recovery of Rd was the same between the two studies (P = 0.461)
The fasting NEFA levels were similar in studies 1 and 2, averaging 0.53 ± 0.03 and 0.56 ± 0.04 mmol/liter (Fig. 5). NEFA are exquisitely sensitive to insulin and were seen to rapidly drop as hyperinsulinemia was established in both studies and reached their nadir at 70 min (0.19 ± 0.04 and 0.17 ± 0.04 mmol/liter). With termination of the hormone infusions (GLP-1 or insulin) and return of plasma insulin to approximately fasting values, at about 70 min NEFA levels began to rise again.
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This study was designed to evaluate the possibility that GLP-1 has effects on glucose utilization, independent of effects on plasma insulin levels, i.e. having intrinsic insulinomimetic effects. We chose to study obese subjects (mean BMI of 
35 kg/m2) because we felt such effects would be unmasked in a situation where glucose utilization is not maximally efficient. Because a GLP-1 infusion results in the release of endogenous insulin we needed to devise a methodology to quantify the effects of GLP-1 on glucose homeostasis independent of its insulinotropic effects. The increase in endogenous insulin stimulated by GLP-1 results in both insulin-mediated glucose uptake and suppression of hepatic glucose output. Therefore, any noninsulin-mediated effects of GLP-1 on glucose utilization would not be quantifiable. To address this issue, we infused GLP-1 for 1 h while maintaining euglycemia and in a subsequent study we infused exogenous insulin for 1 h to precisely match the individual plasma insulin values due to the endogenous release of insulin by GLP-1. We postulated that any difference in glucose utilization would be attributable to the presence of elevated plasma GLP-1 levels during the GLP-1 infusion part of our study. We succeeded in matching the plasma insulin levels such that there was no significant difference in plasma insulin levels between the GLP-1 infusion and insulin infusion clamps.
In the present study of obese subject volunteers, the maximum glucose disposal rates during the insulin infusion protocol were 12 µmol · kg-1 · min-1 compared with 25 µmol · kg-1 · min-1 in our study of lean subjects who had normal glucose tolerance (5). Thus, the obese subjects were relatively insulin resistant compared with the lean subjects studied earlier. We found that during the GLP-1 infusions, insulin-mediated glucose uptake (IMGU) was improved by 30% compared with the insulin infusions (an increase of 3.8 ± 1.3 µmol · kg-1 ·· min-1), and approached the levels observed in lean individuals (5). These findings demonstrate that GLP-1 has significant insulin-like effects with respect to glucose utilization that can be attributed to GLP-1 per se. The Rd data corroborates the glucose infusion data. To maintain euglycemia during the GLP-1 and insulin infusions, a simultaneous glucose infusion at a varying rate was necessary. The glucose infusion rate was greater during the GLP-1 infusion study, compared with the insulin infusion study. We showed previously that GLP-1 enhances both non-IMGU (9) and IMGU in elderly patients with diabetes (10). Our studies demonstrate that in obese individuals GLP-1 also enhances both IMGU and non-IMGU. The increased glucose disposal rates during the GLP-1 infusion were not due to increased levels of insulin in the portal circulation. Ra was the same during both the GLP-1 and insulin infusion studies and fasting insulin levels were elevated 4-fold during both studies, hepatic glucose output was comparably suppressed. In addition, the greater suppression of plasma glucagon levels cannot be a contributing factor on Rd, because there was no difference in the degree or the pattern of suppression of Ra during the GLP-1compared to the insulin infusion protocols. The increase in Rd may be due, in part, to an increased glucose uptake by the liver in the presence of GLP-1. It has been shown that when an antagonist of the GLP-1 receptor, exendin-(9–39), is coinfused with glucose into the portal vein of mice, the increased uptake of glucose (280%) is decreased by 54% (21). Furthermore, in the same study it was shown that infusion of glucose in the portal vein of GLP-1 receptor null mice does not result in any significant increase of glucose uptake by the liver. Therefore, it is possible that infusion of GLP-1 in insulin-resistant states improves hepatic glucose uptake by GLP-1 actions or of GLP-1 receptors in the liver.
It remains somewhat controversial whether or not GLP-1 has insulinomimetic actions on peripheral tissues independently of its known insulinotropic incretin actions. On the one hand, GLP-1 has been shown to decrease isoglycemic meal-related insulin requirements in type 1 diabetic subjects studied with a closed loop insulin infusion system (2) and to enhance glucose disposal in healthy volunteers (3, 4, 22). On the other hand, no effects of GLP-1 on insulin sensitivity were seen in type 2 diabetic subjects (8, 23) or in healthy subjects (5, 7). Studies in diabetic dogs report that GLP-1 does (24) or does not (25) have insulin-like effects. In a diabetic rat model, GLP-1 was capable of augmenting insulin action in peripheral tissues (26).
The tissue distribution of the GLP-1 receptor is also controversial. GLP-1 receptor mRNA has been detected in pancreatic islets, lung, stomach, duodenum, kidney, heart, hypothalamus, but not in liver, skeletal muscle, and adipose tissue (27, 28, 29, 30). However, it is reported that GLP-1 has binding sites on rat hepatic membranes (31) and stimulates glycogenesis in rat hepatocytes (32). The GLP-1 agonist, exendin-4, was shown to stimulate glycogen synthesis in rat liver and was inhibited by the antagonist exendin-(9–39) amide (33). In contradistinction to these findings, another study did not demonstrate any insulin-like effects of GLP-1 on glucose metabolism in isolated rat hepatocytes (34). Similarly to the hepatocyte studies, controversy exists regarding effects of GLP-1 on skeletal muscle, a major site of insulin action. Potent glycogenic effects of GLP-1 on rat skeletal muscle are reported (33, 35), whereas other studies report a failure of GLP-1 to affect glycogenesis in rat skeletal muscle (34, 36).
Because the existent data regarding the mechanisms of action of GLP-1 on extrapancreatic peripheral tissues are highly conflicting, it seems appropriate to present a summarized, although somewhat speculative, summary of the situation. The weight of the evidence indicates that the authentic, known GLP-1 receptor is not expressed in liver, skeletal muscle (or adipocytes). Rather, there exists another GLP-1-like receptor, either novel and as yet unidentified, or a structurally altered form of a known receptor in the glucagon super family of related peptide receptors, e.g. glucagon, pituitary adenylyl cyclase activating peptide, calcitonin gene-related peptide. Such a hypothetical GLP-1 receptor may only be physiologically functional and detectable in conditions of insulin resistance, such as in obese individuals (our studies) and may be below the threshold of experimental detection in healthy, nondiabetic individuals. The putative novel receptor may be variably labile when studied in in vitro systems. One possibility that comes to mind is that tissue-specific G protein-coupled receptor associated proteins may be at play that alter ligand interaction and specificity (37).
GLP-1 would appear to be an ideal candidate in treating type 2 diabetes. It improves insulin release, attenuates glucagon release, and improves glucose disposal independent of its release of endogenous insulin from the pancreas. No other agent currently available to treat type 2 diabetes has been shown to do likewise, although insulin and its analogs attenuate glucagon release and improve glucose disposal rates.
Acknowledgments
We thank Denis Muller (Metabolism Section, National Institute on Aging, NIH) for statistical assistance. We are grateful to Gail Chin, Elizabeth Misiura, Mary Bannon, Howard Baldwin, Karen McManus and the staff of the Clinical Research Center for technical assistance and to Brenda I. Vega for assistance with the preparation of the manuscript.
Footnotes
This work was supported in part by NIA Intramural funds; General Clinical Research Center Grant M01-RR-02719 from the National Center for Research Resources, NIH; NIA Grant AG-00599, Canadian Diabetes Association.
J.F.H. is an investigator with the Howard Hughes Medical Institute.
Abbreviations: BMI, Body mass index; GLP-1, glucagon-like peptide-1; IMGU, insulin-mediated glucose uptake; NEFA, nonesterified fatty acids; Ra, rate of appearance; Rd, rate of disappearance.
Received February 19, 2002.
Accepted May 3, 2002.
References
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