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Original Studies |
Laboratory of Clinical Physiology, Gerontology Research Center, National Institute on Aging, National Institutes of Health (J.M.E., D.E.); and the Division of Gerontology, Department of Medicine, University of Maryland School of Medicine (A.S.R., D.E.), Baltimore, Maryland 21201; and the Department of Medicine, Massachusetts General Hospital (J.F.H., D.E.), and the Laboratory of Molecular Endocrinology, Howard Hughes Medical Institute (J.F.H.), Harvard Medical School, Boston, Massachusetts 02114
Address all correspondence and requests for reprints to: Dariush Elahi, Ph.D., Geriatrics Research Laboratory GRJ-1215, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114.
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Abstract |
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Introduction |
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TopAbstractIntroductionExperimental SubjectsMaterials and MethodsResultsDiscussionReferences |
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We, among others, have proposed that GLP-1 might also have insulinomimetic, or at least insulin-augmenting, properties in peripheral tissues. In 3T3-L1 adipocytes, we demonstrated increased insulin-mediated glucose uptake (7). Others, using in vitro systems in rat hepatocytes, adipocytes, and muscle, also seem to favor GLP-1 having actions in the periphery (8, 9, 10). An insulinomimetic effect of GLP-1 has been reported in both normal and type 1 and 2 diabetic subjects (11, 12). However, similar to the in vitro observations, these findings are controversial (13, 14). It would be important to know whether GLP-1 has insulinomimetic properties with respect to glucose uptake in peripheral tissues, because this would imply that, as a therapeutic agent, GLP-1 would not only stimulate insulin release, but also have a direct effect on glucose utilization, possibly mediated via an improvement in insulin sensitivity. Thus, the present study was undertaken to evaluate the insulin-like effects of this gastrointestinal hormone on glucose utilization in hyperinsulinemic-euglycemic states in the presence and absence of GLP-1 in healthy young subjects. Additionally, to rule out the possible differences in stress or gut functions between studies, we measured cortisol, ACTH, and somatostatin.
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Experimental Subjects |
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Materials and Methods |
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In the initial clamp (study 1), the plasma GLP-1 level was rapidly raised and then maintained stable with a primed continuous GLP-1 infusion. The priming dose was modified from that previously described (6), as that priming dose had resulted in an initial overshoot in plasma GLP-1 levels. Instead, data obtained from that study (6) were used to predict a priming pattern that would give a more satisfactory square wave of plasma GLP-1. The infusion rate (picomoles per kg/min) was changed at 2-min intervals during the first 10 min. Initially it was 5.91, at 2 min it was changed to 2.53, at 4 min it was changed to 2.34, at 6 min it was changed to 2.20, at 8 min it was changed to 2.02, and at 10 min it was changed to 1.5. It was then held at this rate for the next 50 min. GLP-1-(7–37), synthesized at the Massachusetts General Hospital Biopolymer Core Facility (5), has a peptide content of 70%. This preparation is more than 99% pure and displays a single peak on high performance liquid chromatography. The peptide was filtered through 0.2 µm/L nitrocellulose filters (Millipore, Bedford, MA) before it was lyophilized in vials under sterile conditions for single volunteer use. Samples were analyzed and were shown to be both sterile and pyrogen free; the net peptide content was used for dose calculations. Approximately 5 min before the start of hormone infusion, the peptide was dissolved in a 50-mL solution of normal saline containing 2 mL of the subject’s own blood. It has been established that GLP-1 is degraded by a serum enzyme, dipeptidyl peptidase IV, into biologically inactive products. The degradation of GLP-1 into an insulinotropically inactive form in the presence of 20% serum at 37 C has been reported to have a half-life of approximately 15–20 min (16, 17). The peptide is essentially 100% intact at 4 C. It should be noted that the GLP-1 used in the present studies was dissolved in a saline solution that contained approximately 2% serum, and that the temperature of the infusate was never greater than 21 C. Thus, although we cannot rule out that some of the peptide may have been degraded during the 60-min infusion protocol, this did not occur to any great extent. Furthermore, a stable insulinotropic effect that persisted throughout the infusion period was documented in each volunteer.
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 the infusion of regular insulin (Humulin, Eli Lilly Co., Indianapolis, IN) in place of GLP-1. We have conducted numerous hyperinsulinemic-euglycemic clamps at doses varying from 5–10,000 mU/m2·min with empirical experience of insulin doses and their resultant plasma levels. Thus, 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 insulin infusion was terminated, and all parameters were followed for an additional 60 min.
In each clamp study, glucose production and utilization rates were determined by means of the primed constant rate infusion technique with tritiated glucose (18). A priming dose of 8.5 kilobecquerels/kg sterile and pyrogen-free [3-3H]glucose (New England Nuclear, Boston, MA) was administered at -120 min, followed by a constant iv infusion of 85 becquerels/kg·min for the duration of the experiment. Four arterialized blood samples (19) 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 (20) and using an infusion of 20% glucose solution (Travenol, Dearfield, IL), glucose levels were maintained at the basal concentration for the duration of the study (120 min). The glucose solution was "spiked" with tritiated glucose to maintain a constant glucose specific activity as previously described (21). This "hot Ginf" method (20% glucose infusate that contains radioactive tracer matching the specific activity of plasma glucose before the start of the clamp) has been shown to eliminate the implausible negative rate of appearance that results when only unlabeled glucose is used in a hyperinsulinemic-euglycemic clamp procedure (22).
Analytical technique
Blood samples were collected in heparinized syringes. Samples were obtained every 5 min for plasma glucose determination and every 10 min for determinations of plasma insulin, GLP-1, C peptide, glucagon, cortisol, ACTH, and somatostatin and glucose specific activity. Plasma glucose was immediately assayed by the glucose oxidase method (Beckman Glucose Analyzer II, Beckman Instruments, Fullerton, CA). Blood samples were collected in a prechilled test tube containing kallikrein-trypsin inhibitor (Trasylol, Miles, NY) and ethylenediamine tetraacetate as previously described (6). Plasma samples were aliquoted for determination of glucose specific activity and hormones. All determinations were performed in duplicate. Plasma insulin, GLP-1, C peptide, glucagon, cortisol, ACTH, and somatostatin and the specific activity of glucose were determined as previously described (6, 23, 24, 25, 26, 27, 28).
Statistical analyses
The rate of total appearance (Ra) and the rate of disappearance (Rd) of glucose were calculated according to the nonsteady state equations of Steele (18), as modified for the use of hot Ginf (22). The volume of distribution of glucose was assumed to be 210 mL/kg (29). 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 (30).
The mean concentrations of glucose, insulin, C peptide, glucagon, GLP-1, cortisol, ACTH, and somatostatin and the Ra and Rd were calculated for each time point for the 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 these individual values were calculated for all parameters assayed. The differences between studies were evaluated with paired t test and repeated measures ANOVA (31). Except where otherwise stated, results are presented as the mean ± SEM.
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Results |
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. Fasting glucose
values were similar between studies 1 and 2 (5.2 ± 0.2
vs. 5.3 ± 0.1 mmol/L). During the clamp, stable plasma
glucose levels were maintained in all studies for each subject. The
mean plasma glucose level during the 120-min clamp period was computed
for each study. The mean glucose levels for the two studies were
identical at 5.2 ± 0.1 mmol/L. The mean ± SD
plasma glucose concentration for the 120-min clamp period was also
expressed as a percentage of the fasting glucose level for each study
and averaged 99.8 ± 1.0% and 98.0 ± 0.6% for studies 1
and 2, respectively. The coefficient of variation (CV) of the glucose
concentration during the clamp was also computed for each study. The
mean CVs for studies 1 and 2 were 4.6 ± 0.4% and 4.8 ±
0.7% (±SD), respectively.
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Basal plasma insulin levels were also similar in the two studies
(43 ± 7 vs. 54 ± 5 pmol/L). In study 1 in
response to the GLP-1 infusion and while plasma glucose levels remained
constant, plasma insulin increased in each volunteer (Fig. 1
). The
increase in plasma insulin levels was both physiological and
statistically significant (P < 0.001). In study 2, the
plasma insulin profile obtained in study 1 was simulated for each
subject, and the two profiles were nearly identical. The 30–60 min
insulin levels averaged 151 ± 48 and 146 ± 31 pmol/L in
studies 1 and 2, respectively. In both studies, plasma insulin levels
returned to baseline after termination of either the GLP-1 or the
insulin infusion, and the 90–120 min levels were 46 ± 9 and
51 ± 6 pmol/L, respectively. Thus, there was no difference in
insulin levels between the studies at 30–60 min or from 90–120
min.
The basal C peptide levels were similar in the two studies and averaged
0.31 ± 0.05 in study 1 and 0.35 ± 0.04 nmol/L in study 2.
In response to the GLP-1 infusion and similar to the plasma insulin
profile, a square wave of C peptide was observed (Fig. 2). The 30–60 min levels averaged
1.32 ± 0.41 nmol/L. With the termination of the GLP-1 infusion, C
peptide levels promptly fell. The 120 min level averaged 0.37 ±
0.07 nmol/L. In study 2, C peptide levels changed little throughout the
study, and the 120 min level averaged 0.27 ± 0.04 nmol/L.
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). In response to the
GLP-1 infusion, plasma glucagon levels were suppressed, and the level
at 60 min averaged 9.3 ± 0.6 pmol/L (P < 0.002).
During the insulin infusion study, plasma glucagon levels were also
suppressed, and the level at 60 min averaged 12.1 ± 0.6 pmol/L
(P < 0.005). The suppression of glucagon levels was
greater during the GLP-1 infusion than that observed during the insulin
infusion (by ANOVA, P < 0.01). After the termination
of the hormone infusions, glucagon levels returned toward the basal
concentration. The glucagon levels at 120 min in studies 1 and 2 were
13.1 ± 0.9 and 12.6 ± 0.6 pmol/L, respectively.
Basal plasma cortisol and ACTH levels were not significantly different
during all euglycemic clamps, averaging 403 ± 35 and 316 ±
33 nmol/L in studies 1 and 2, respectively, for cortisol and 9.1
± 2.2 and 8.3 ± 1.3 pmol/L, respectively, for ACTH (Fig. 3). In response to the GLP-1 infusion,
plasma cortisol began to increase, was elevated by 20 min, and reached
a peak by 60 min (P = 0.07). With termination of the
GLP-1 infusion, plasma cortisol levels began to fall promptly and had
returned to the basal level within 20 min. Plasma cortisol levels
during the clamp period in study 2 were not statistically significantly
different from those during the basal period. During study 1, ACTH
levels increased promptly, with a peak at the earliest point assayed
(10 min), and had returned to the basal level at the end of the GLP-1
infusion period (60 min); they then changed very little during the
following hour. In study 2, ACTH levels deviated only slightly from
basal during the entire study period (Fig. 3). The mean basal level of
each hormone for each individual was subtracted from the levels
obtained during the study. The mean change (
) cortisol and ACTH
levels for the successive 30-min periods from 0–120 min for studies 1
and 2 are presented in Table 1. Basal
plasma somatostatin levels were not significantly different and
averaged 228 ± 22 and 282 ± 34 pmol/L in studies 1 and 2,
respectively. During the entire clamp period, somatostatin changed very
little in either study (Fig. 3).
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In response to either the GLP-1 or the insulin infusion and their
concomitant hyperinsulinemia, Rd increased during both studies (Fig. 4). The increase was similar in studies 1
(GLP-1) and 2 (insulin) and averaged 27.21 ± 3.50 and 23.59
± 3.42 µmol/kg·min during the last 30 min of the hormone
infusions. After the termination of the GLP-1 or insulin infusion, with
the fall in insulin levels (in addition to a fall in the GLP-1 in study
1), Rd returned toward the basal level. The 110–120 min rates were
10.99 ± 1.80 vs. 15.03 ± 1.39
µmol/kg·min.
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Discussion |
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In type 1 and type 2 diabetic subjects, Gutniak et al. (12) showed that the insulin requirement for 3 h after a standard meal was lower when GLP-1 was infused (0.75 pmol/kg·min, for 3.5 h) than that on the control day without an infusion of GLP-1. Serum somatostatin levels were also decreased. This work is often cited as the best evidence for insulin-like effects in response to GLP-1 infusions. However, two groups recently reported that an infusion of GLP-1 (0.91 or 1.2 pmol/kg·min for 1.5 h or 4.5 h) is associated with an inhibition of gastric emptying that results in diminished rates of glucose absorption (32, 33). The latter report concluded that the magnitude of the inhibition is sufficient to completely explain the reduced insulin requirements observed in the study of Gutniak et al. (12). Another group has also demonstrated a reduction of glycemic levels after meals in type 1 diabetics (34) during GLP-1 infusions (1.2 pmol/kg·min, for 2 h), which again can be attributed to delayed gastric emptying. In our study we did not observe a reduction in somatostatin levels, which may be observed only with gastric emptying after a meal. Additionally, it has been recently demonstrated that GLP-1 in type 1 subjects reduces plasma glucagon levels, an action of GLP-1 that may also contribute to the improvement, but not the normalization, of hyperglycemia (4). Our data from normal subjects also demonstrate that GLP-1 suppresses plasma glucagon and that the degree of suppression is greater than that induced by insulin alone.
After an iv glucose tolerance test, glucose effectiveness was improved in normal subjects during either a GLP-1 infusion (0.75 pmol/kg·min, for 1 h) (11) or by endogenously stimulated GLP-1 in response to fat ingestion (35). Glucose effectiveness is a derived model estimate [minimal model technique of Bergman (36)] of noninsulin-mediated glucose uptake. Thus, the improvement in glucose effectiveness was interpreted as a direct action of GLP-1 on peripheral tissue. In contrast to the present report and all studies performed to date to our knowledge (2, 4, 6), in the study cited above the GLP-1 infusion was not insulinotropic at euglycemic conditions. Furthermore, although glucose effectiveness was not altered by the different insulin administrations, the validity of the determination of glucose effectiveness is questionable because insulin sensitivity determined by the minimal model can be affected by the dose of insulin administered (37).
Additional support for the lack of an insulin-like effect that can be attributed to GLP-1 per se has recently been demonstrated during an infusion of somatostatin (14). The glucose disappearance constant, kg, as measured during an iv glucose tolerance test, was not different during a GLP-1 infusion (0.83 pmol/kg·min, for 2.5 h) from that during the control study in which saline was infused (0.42 ± 0.03% vs. 0.40 ± 0.3%min) in normal nonobese young subjects. Thus, our data taken together with other in vivo data do not support an insulin-like effect per se on glucose disposal during euglycemic conditions in lean nondiabetic male subjects. However, it is possible that a prolonged administration of GLP-1 may have such an effect, or that GLP-1 may only enhance glucose utilization in hyperglycemic conditions, such as in hyperinsulinemic obese individuals with glucose intolerance, individuals with diabetes mellitus, or even female subjects lean or obese.
Of potential interest are our unanticipated findings that ACTH levels rose in response to the priming dose of GLP-1, whereas no effect on ACTH levels was seen during the priming dose of insulin. The rise in ACTH was followed by a rise in cortisol levels. To our knowledge this is the first time that an effect of a systemic pharmacological level of GLP-1 on pituitary corticotropin function has been shown. GLP-1 has been shown in vitro to increase TSH secretion from thyrotropes (38). Central administration of GLP-1 in Wistar rats has been recently shown to activate the CRH-containing neurons of the hypothalamo-pituitary-adrenocortical tract and the oxytocinergic neurons of the hypothalamo-neuro-hypophysial tract (39). The activation of hypothalamic neuroendocrine neurons may be the mechanism by which GLP-1 infusion (0.83 pmol/kg·min, for 4.5 h) suppresses appetite, as recently reported in healthy young men (40) with similar characteristics as those in the present study.
In conclusion, the present study examined the role of GLP-1 on glucose disposal under well controlled conditions, i.e. both stable glucose concentrations and nearly identical levels of hyperinsulinemia with either a GLP-1 or an insulin infusion. Our results do not provide evidence for a role of GLP-1 to augment insulin-mediated glucose uptake during euglycemia in lean healthy young men, but do demonstrate an activation of hypothalamic neuroendocrine neurons.
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Acknowledgments |
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Footnotes |
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2 Investigator with the Howard Hughes Medical Institute.
Received March 3, 1998.
Revised April 10, 1998.
Accepted April 17, 1998.
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