1 Endocrine Unit, and 2 Department of Dietetics, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London W12 0NN, United Kingdom
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Exendin-4 is a long-acting potent
agonist of the glucagon-like peptide 1 (GLP-1) receptor and may be
useful in the treatment of type 2 diabetes and obesity. We examined the
effects of an intravenous infusion of exendin-4 (0.05 pmol · kg1 · min
1) compared
with a control saline infusion in healthy volunteers. Exendin-4 reduced
fasting plasma glucose levels and reduced the peak change of
postprandial glucose from baseline (exendin-4, 1.5 ± 0.3 vs.
saline, 2.2 ± 0.3 mmol/l, P < 0.05). Gastric
emptying was delayed, as measured by the paracetamol absorption method. Volunteers consumed 19% fewer calories at a free-choice buffet lunch
with exendin-4 (exendin-4, 867 ± 79 vs. saline 1,075 ± 93 kcal, P = 0.012), without reported side effects. Thus
our results are in accord with the possibility that exendin-4 may be a
potential treatment for type 2 diabetes, particularly for obese
patients, because it acts to reduce plasma glucose at least partly by a delay in gastric emptying, as well as by reducing calorie intake.
glucagon-like peptide 1; glycemia; gastric emptying; type 2 diabetes
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
GLUCAGON-LIKE PEPTIDE 1 (GLP-1) is released from the intestine in response to nutrient ingestion (20). Exogenous administration to humans has a number of effects that result in a decrease in plasma glucose levels. It stimulates plasma insulin levels (20), suppresses glucagon levels (22), and delays gastric emptying (27, 45). There is some evidence that GLP-1 may also increase peripheral insulin sensitivity (4, 16), although this is controversial (30). GLP-1 has been shown to decrease food intake and body weight in rats when administered into the third cerebral ventricle (24, 42). A number of groups have looked at the effect of GLP-1 on satiety and food intake in humans, and it appears to parallel the effect seen in rats, although not always (11, 18, 23, 25). Recently, we infused the GLP-1 antagonist, exendin-(9-39), in humans and demonstrated that endogenous GLP-1 regulates plasma glucose levels (10), and its effects on plasma glucagon and gastric emptying appear to be physiological (10). GLP-1 has also been shown to have a physiological role in glucose homeostasis in the rat (21, 44), mouse (38), and baboon (5), although it appears that this is not always the case, as exogenous administration has little effect in the calf (9).
Exendin-4 is a 39-amino acid peptide isolated from the Gila monster salivary gland and acts as an agonist of the GLP-1 receptor (13, 40). Exendin-4 appears to have a considerably greater biological half-life than GLP-1 (14, 39, 46). We (10) have shown that the circulating half-life of the truncated exendin-4, exendin-(9-39), is 33 ± 4 min in humans; this compares with a half-life for the biologically active intact GLP-1 of 1-3 min in a number of species (6, 19, 32). Thus it would appear likely that exendin-4 has a longer circulating and biological half-life than GLP-1 in humans. Exendin-4 in vivo seems considerably more potent than GLP-1 (14, 28, 39, 46) and may have potential as a therapeutic agent for use in type 2 diabetes. A number of GLP-1 analogs have been tested in vitro and in vivo in both rats and mice (2, 20, 29, 34). They also appear to have greater plasma stability and a longer action than GLP-1, indicating a number of potential therapeutic agents acting at the GLP-1 receptor. Before investigation of exendin-4 in patients, its actions and possible side effects needed to be elucidated in healthy volunteers. Thus we infused exendin-4 into healthy volunteers to assess the effect on fasting and postprandial glucose and hormones, gastric emptying rate, and calorie consumption, as well as scores of nausea and satiety.
![]() |
SUBJECTS, MATERIALS, AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Peptides. Exendin-4 was synthesized using fluorenylmethoxycarbonyl chemistry on an Advanced Chemtech 396MPS peptide synthesizer. The product comprised one major peak, which was purified to homogeneity by reversed-phase HPLC on a C8 column (Phenomenex, Macclesfield, UK). Electrospray mass spectrometry was used to confirm the identity of the peptide. The Limulus Amoebocyte Lysate assay test for pyrogen was negative, and the peptide was sterile on culture.
Subjects. Eight healthy subjects [1 male and 7 female, age 25.5 ± 1.4 (mean ± SE) yr, body mass index 21.8 ± 0.7 kg/m2] participated in the study. Subjects gave informed, written consent, and ethical approval was obtained from the local Research Ethics Committee. The study was carried out in accordance with the principles of the Declaration of Helsinki. We had previously infused the exendin-4 fragment, exendin-(9-39), at 1,000× the concentration of exendin-4 infused here, without side effects (10). Subjects were taking no regular medication and had no allergies or abnormalities on physical examination and electrocardiogram. They had no evidence of abnormal renal function. Hemoglobin, fasting plasma glucose, and insulin levels were normal. Volunteers filled out a food diary for the 3 days before the first infusion to standardize intake before each infusion. Subjects refrained from alcohol and strenuous exercise for 24 h before infusion. All subjects were fasted of food and drink except water from 8:00 PM on the evening before each study day.
Protocol.
Each subject was studied on two occasions with 1 wk between each
study. On the morning of study, a cannula was inserted into a large
forearm vein for collection of blood, and another was inserted into a
vein in the opposite forearm for infusion of exendin-4 or saline.
Subjects sat at a 45° angle throughout the studies. Subjects were
infused with saline or exendin-4 in a randomized, double-blind manner;
four received exendin-4 first and four saline first. Exendin-4 was
diluted in saline and mixed with volunteer's plasma (5% by volume) to
reduce adsorption to infusion tubing.
Analytical methods.
Blood was collected into heparinized tubes containing 5,000 kallikrein
inhibitor units (0.2 ml) of aprotinin and centrifuged, and plasma was
separated and stored at 20°C until analysis. Plasma glucose was
measured using a YSI 2000 glucose analyzer. Plasma insulin, glucagon,
GLP-1, and gastric inhibitory polypeptide (GIP) levels were measured
using established radioimmunoassays (RIAs) (12, 22, 36).
Plasma exendin-4-like immunoreactivity (exendin-4-LI) levels were
measured using our recently described RIA for
exendin-(9-39) (10), which used an
antiserum raised against exendin-4. The assay standard was synthetic
exendin-4, and the assay had a sensitivity of 1.2 pmol/l. Gastric
emptying rate was assessed by measurement of plasma paracetamol levels
with an enzymatic colorimetric assay with the use of an Olympus AU600
analyzer. Peak plasma paracetamol concentrations (Cmax) and
time of Cmax (Tmax) were recorded.
Calculations. The decay curve of exendin-4-LI concentrations was converted to natural logarithms and plotted against time. The resulting straight line plot was used to derive the half-time of disappearance (t1/2) for infused exendin-4-LI for each subject. The metabolic clearance rate (MCR) of exendin-4-LI was calculated for each volunteer from the steady-state concentration (CSS; taken as the value at t 210, the end of the infusion) and infusion rate at which this concentration was stable, where MCR = infusion rate/CSS. The apparent volume of distribution (VD) was calculated from the half-life and the CSS, where VD = MCR × t1/2 × 1.44.
Statistical analysis.
All results are presented as means ± SE. The incremental or
decremental area under the curve (AUC) for glucose and each hormone was
calculated using the trapezoidal rule. AUC values for postprandial glucose, insulin, glucagon, GLP-1, and GIP were calculated from 0 min
immediately before consumption of the standard test breakfast to 180 min immediately before the buffet lunch, or earlier if stated. To
assess an effect on fasting, AUC was calculated between 60 min, the
time of initiation of the infusion, and 0 min; the absolute change
between
60 and 0 min was also calculated. Comparisons of AUCs, peak
postprandial plasma glucose levels, Cmax and
Tmax of plasma paracetamol levels, absolute
differences between the infusion groups, and food consumption between
the exendin-4 and control studies were by paired t-test.
Visual analog scores were compared by the Wilcoxon signed-rank test.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
No side effects were reported by any subject with either exendin-4
(0.05 pmol · kg1 · min
1) or
saline infusion. Exendin-4 infusion had no effect on blood pressure or
pulse rate.
Plasma exendin-4-LI was undetectable in the fasted state before
infusion. The measured infusion rate of exendin-4 was 0.028 ± 0.001 pmol · kg1 · min
1,
presumably less than the concentration in the syringe secondary to
peptide adhesion to the infusion tubing. The plateau level of
exendin-(9-39)-LI was 16.4 ± 0.9 pmol/l. The
course of exendin-4-LI disappearance followed first-order kinetics. The
plasma half-life of exendin-4-LI was calculated to be 26 ± 3 min.
The mean MCR was 1.8 ± 0.2 ml · kg
1 · min
1, and the
apparent volume of distribution was 64 ± 7 ml/kg.
Exendin-4 decreased plasma glucose over the 60 min in the fasted state
from 4.5 ± 0.1 to 4.0 ± 0.1 vs. saline 4.6 ± 0.1 to 4.5 ± 0.1 mmol/l (Fig. 1). The
absolute decrease in plasma glucose level was significant (0.47 ± 0.05 vs. 0.10 ± 0.04 mmol/l, P < 0.005); the
decrease was also significant as measured by incremental AUC
(60-0: exendin-4
13.7 ± 1.9 vs. saline
3.9 ± 1.9 mmol · min · l
1, P < 0.03).
|
Plasma glucose levels were decreased by 35% with exendin-4 infusion
for the 180-min postprandial period; however, this effect failed to
reach statistical significance (AUC 0-180: exendin-4 100 ± 26 vs. saline 155 ± 50 mmol · min · l1, P = 0.21; Fig. 1). The peak change from baseline of postprandial glucose for each individual was decreased with exendin-4 infusion (exendin-4 1.5 ± 0.3 vs. saline 2.2 ± 0.3 mmol/l,
P < 0.05) without change in the time of the peak.
There was no change in plasma insulin levels in the fasted state with
exendin-4 infusion compared with saline [AUC 60-0: exendin-4
160 ± 260 vs. saline
230 ± 140 pmol · min · l
1, P = not
significant (NS); Fig. 2]. However, this
effect was in the face of a reduction in plasma glucose that would be
expected to be associated with a reduction in insulin if no
insulinotropic agent was present. Plasma insulin was decreased by 23%
with exendin-4 infusion for the 180-min postprandial period (AUC
0-180: exendin-4 13,180 ± 2,200 vs. saline 17,140 ± 1,530 pmol · min · l
1, P < 0.03; Fig. 2). There was no effect of exendin-4 infusion on the
average peak postprandial insulin level or on the time of the peak.
|
There was a tendency toward a decrease in plasma glucagon levels in the
fasted (AUC 60-0: exendin-4 11 ± 20 vs. saline 55 ± 39 pmol · min · l
1, P = NS)
and postprandial states, although this did not attain statistical
significance (AUC 0-180: exendin-4
95 ± 70 vs. saline
13 ± 158 pmol · min · l
1, P
= NS).
Exendin-4 decreased gastric emptying as measured by the paracetamol
absorption test (Tmax saline 79 ± 20 vs.
exendin-4 120 ± 23 min, P < 0.05; Fig.
3). There was a tendency toward a
decrease in Cmax (saline 0.14 ± 0.02 vs. exendin-4
0.1 ± 0.02 mmol/l, P = 0.07).
|
Exendin-4 infusion reduced postprandial GLP-1 levels by 75% (AUC:
exendin-4 210 ± 137 vs. saline 866 ± 260 pmol · min · l1, P < 0.05; Fig. 4). Exendin-4 reduced
GLP-1 greater than control in the fasted state (exendin-4
4.3 ± 1 vs. saline
0.7 ± 1.4 pmol/l, P < 0.02; Fig.
4).
|
Exendin-4 reduced plasma GIP levels by 32%, although this effect
failed to reach significance (AUC: exendin-4 19,600 ± 3,100 vs.
saline 28,700 ± 5,600 pmol · min · l1, P = 0.1). There was no effect of exendin-4 on fasting plasma GIP levels.
Exendin-4 reduced food intake at the buffet lunch by 19% (exendin-4
867 ± 79 vs. saline 1,075 ± 93 kcal, P = 0.012; Fig. 5A), with all
eight subjects reducing their caloric intake (range 2-41%; Fig.
5B). Addition of the food intake at lunch to that of the evening gave a total voluntary food intake for the day 21% less after
exendin-4 (exendin-4 1,694 ± 192 vs. saline 2,152 ± 207 kcal, P = 0.023). Food intake on the following day was
not different between the two infusions (P = 0.81).
|
There was no difference in the sensations of fullness or nausea
reported by the volunteers between the two infusions at any point (Fig.
6).
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
We have shown that exendin-4 infusion caused a significant decrease in fasting plasma glucose levels, although not into the hypoglycemic range. It reduced postprandial glucose excursions after a standard test breakfast by approximately one-third, and the peak rise in plasma glucose was also decreased.
It is now well documented that long-term improvement in glycemic control is of benefit to patients with type 2 diabetes (43). However, it is a matter of some debate whether reduction of peak plasma glucose levels or average plasma glucose, or both, is particularly important. Exendin-4 infusion appears to decrease both parameters, at least in healthy subjects. The reduction in postprandial plasma glucose appears to be mediated, at least in part, by a delay in gastric emptying. It seems most likely that the decrease in postprandial plasma insulin levels that we found with exendin-4 was secondary to the fall in glucose caused by this delay in gastric emptying.
The cause of the exendin-4-induced drop in fasting plasma glucose is difficult to interpret. There was no statistically significant effect of exendin-4 on plasma glucagon levels, in contrast to the effect of GLP-1, which potently suppresses glucagon (10, 22). Similarly, there was no significant effect of exendin-4 on fasting plasma insulin levels. Given that the fasting plasma glucose level was lower with exendin-4 infusion, it would be expected that insulin be suppressed and glucagon stimulated compared with saline infusion. The fact that this did not occur implies that exendin-4 was having an insulinotropic effect and was suppressing plasma glucagon in the fasted state, although the effect was apparently of insufficient magnitude to be significant. In addition, it is possible that a small and transient effect on plasma insulin and/or plasma glucagon levels did occur, which we did not see with the limited number of sampling points in the fasted state. Such effects have been reported with GLP-1 (31, 33).
Plasma GLP-1 levels were greatly decreased in the postprandial state, and there also appeared to be a decrease in the fasted state. It has been suggested that a minimal delivery rate of nutrients into the duodenum is necessary for release of GLP-1 (37). The delay in gastric emptying caused by exendin-4 in our study may have caused duodenal nutrient delivery to decrease to such an extent that very little endogenous GLP-1 was released. Levels of the other incretin hormone, GIP (7), showed a tendency to decrease; this could also be secondary to the delay in gastric emptying. Why fasting plasma GLP-1 levels were reduced is not explained by this mechanism. An alternative explanation is that exogenous administration of exendin-4 causes a reduction in or downregulation of endogenous production of GLP-1 from the L-cell. A similar effect has been noted with infusion of exogenous GLP-1-(7-37), causing a reduction in mean levels of endogenous GLP-1-(7-36) amide, although this effect failed to reach significance (41).
Exendin-4 has been reported to be insulinotropic (46); however, in this study we found a small decrease in postprandial plasma insulin, although not to the extent of the plasma glucose. The delay in gastric emptying would be expected to decrease plasma insulin as well as the plasma glucose. Small changes in plasma glucose are usually associated with relatively larger changes in plasma insulin. The small postprandial decrease in plasma glucose found here would thus be expected to have a larger effect on plasma insulin. The observation that the decrease in insulin was smaller than the decrease in glucose suggests that exendin-4 was having an insulinotropic effect in our study; however, the many potentially compensating factors made it impossible to quantify the magnitude of the effect (8). This study was not designed to assess whether exendin-4 was affecting peripheral insulin sensitivity or having an insulin-like effect in either the fasting or the postprandial state; however, such an effect cannot be ruled out.
Pharmacokinetics of exendin-4 in humans were assessed. The MCR of
exendin-4-LI at 1.8 ml · kg1 · min
1 is similar
in magnitude to the normal glomerular filtration rate. The volume of
distribution is similar to total body water volume and does not suggest
that exendin-4 is extensively tissue bound. The relatively long
half-life and the MCR being similar to the glomerular filtration rate
suggest that the peptide is stable and that its main clearance is
renal. No endogenous plasma exendin-4-LI was detectable by RIA before
the onset of infusion.
Overall, the effects of exendin-4 on plasma glucose and insulin are similar to those reported for GLP-1 in a number of studies (3, 10, 16, 22, 26), except that exendin-4 appears considerably more potent than GLP-1 and has a half-life in the circulation considerably longer than that of GLP-1. However, it should be noted that the plateau plasma concentration of exendin-4-LI in this study is 16 pmol/l, not dissimilar to the concentration of bioactive GLP-1 that produces similar effects on plasma glucose and insulin (41); the proportion of exendin-4-LI that is bioactive in our study is unknown. The observation that twice the concentration of exendin-4 infused here caused side effects may suggest that exendin-4 has a narrow therapeutic range.
Infusion of exendin-4 also caused a highly significant decrease in caloric consumption, amounting to 19% for the free-choice buffet meal, and this was apparently long lasting, with a 21% decrease in food intake when the lunch and intake for the rest of the day were combined. All eight subjects decreased their caloric consumption with exendin-4 infusion and in the absence of any symptoms or signs of nausea.
A number of recent studies have assessed the effects of GLP-1 infusion
on caloric intake (11, 17, 18, 23, 25, 41). In the first
published study, a 12% reduction of caloric intake was found
with infusion of GLP-1 at a rate of 50 pmol · kg1 · h
1 to healthy
volunteers, well over 10 times the concentration of exendin-4 that we
infused here (11). Those authors also found a decrease in
subjective feelings of hunger, although those effects were not large.
Two other groups have also demonstrated a decrease in caloric intake
with infusion of GLP-1 (18, 25). This is contrasted with
one report showing no effect of GLP-1 on energy intake or scores of
satiety with infusion of GLP-1 at a rate of 1.2 pmol · kg
1 · min
1
(23). However, that infusion of GLP-1 was short, and there was a tendency for a reduction in both caloric intake and satiety scores. More recently, these findings have been confirmed in patients with type 2 diabetes (17, 41).
Overall, our findings of a reduction in caloric intake are consistent with those previously found with GLP-1, although exendin-4 appears to be at least an order of magnitude more potent. The delay in gastric emptying found with exendin-4 may be one mechanism; however, a direct satiety effect cannot be ruled out.
A number of studies have now been published concerning the use of exendin-4 in vivo. It has been demonstrated that exendin-4 reduces plasma glucose in mice, rats, and monkeys (14, 39, 46). Peripheral exendin-4 has also been shown to reduce food intake and body weight in lean and obese Zucker rats (1, 35). We have found that infusion of exendin-4 into healthy volunteers was well tolerated and, similar to the results found in animal studies, caused a reduction in fasting and postprandial glucose, a delay in gastric emptying, and a long-lasting reduction in food intake.
Taken together, these findings are in line with the possibility that exendin-4, given to produce concentrations similar to those found here, may be a potential treatment particularly likely to benefit obese patients with type 2 diabetes.
![]() |
ACKNOWLEDGEMENTS |
---|
C. M. B. Edwards was a British Diabetic Association R. D. Lawrence Research Fellow. S. A. Stanley and L. J. Seal were Wellcome Trust Clinical Training Fellows.
![]() |
FOOTNOTES |
---|
Address for reprint requests and other correspondence: S. R. Bloom, ICSM Endocrine Unit, Hammersmith Hospital, London W12 0NN, UK (E-mail: s.bloom{at}ic.ac.uk).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 30 August 2000; accepted in final form 27 February 2001.
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Al-Barazanji, KA,
Arch JR,
Buckingham RE,
and
Tadayyon M.
Central exendin-4 infusion reduces body weight without altering plasma leptin in (fa/fa) Zucker rats.
Obes Res
8:
317-323,
2000
2.
Burcelin, R,
Dolci W,
and
Thorens B.
Long-lasting anti-diabetic effect of a dipeptidyl peptidase IV-resistant analog of glucagon-like peptide-1.
Metabolism
48:
252-258,
1999[ISI][Medline].
3.
Byrne, MM,
and
Goke B.
Human studies with glucagon-like-peptide-1: potential of the gut hormone for clinical use.
Diabet Med
13:
854-860,
1996[ISI][Medline].
4.
D'Alessio, DA,
Kahn SE,
Leusner CR,
and
Ensinck JW.
Glucagon-like peptide 1 enhances glucose tolerance both by stimulation of insulin release and by increasing insulin-independent glucose disposal.
J Clin Invest
93:
2263-2266,
1994[ISI][Medline].
5.
D'Alessio, DA,
Vogel R,
Prigeon R,
Leschansky E,
Koerker D,
Eng J,
and
Ensinck JW.
Elimination of the action of glucagon-like peptide 1 causes an impairment of glucose tolerance after nutrient ingestion in healthy baboons.
J Clin Invest
97:
133-138,
1996
6.
Deacon, CF,
Pridal L,
Klarskov L,
Olesen M,
and
Holst JJ.
Glucagon-like peptide 1 undergoes differential tissue-specific metabolism in the anesthetized pig.
Am J Physiol Endocrinol Metab
271:
E458-E464,
1996
7.
Dupre, J,
Ross SA,
Watson D,
and
Brown JC.
Stimulation of insulin secretion by gastric inhibitory polypeptide in man.
J Clin Endocrinol Metab
37:
826-828,
1973[ISI][Medline].
8.
Edwards, CM,
and
Bloom SR.
The incretinsoutdated terminology in man?
Diabetologia
42:
1148,
1999[ISI][Medline].
9.
Edwards, CM,
Edwards AV,
and
Bloom SR.
Cardiovascular and pancreatic endocrine responses to glucagon-like peptide-1(7-36) amide in the conscious calf.
Exp Physiol
82:
709-716,
1997[Abstract].
10.
Edwards, CM,
Todd JF,
Mahmoudi M,
Wang Z,
Wang RM,
Ghatei MA,
and
Bloom SR.
Glucagon-like peptide 1 has a physiological role in the control of postprandial glucose in man. Studies with the antagonist exendin 9-39.
Diabetes
48:
86-93,
1999[Abstract].
11.
Flint, A,
Raben A,
Astrup A,
and
Holst JJ.
Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans.
J Clin Invest
101:
515-520,
1998
12.
Ghatei, MA,
Uttenthal LO,
Christofides ND,
Bryant MG,
and
Bloom SR.
Molecular forms of human enteroglucagon in tissue and plasma: plasma responses to nutrient stimuli in health and in disorders of the upper gastrointestinal tract.
J Clin Endocrinol Metab
57:
488-495,
1983[Abstract].
13.
Goke, R,
Fehmann HC,
Linn T,
Schmidt H,
Krause M,
Eng J,
and
Goke B.
Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting beta-cells.
J Biol Chem
268:
19650-19655,
1993
14.
Greig, NH,
Holloway HW,
De Ore KA,
Jani D,
Wang Y,
Zhou J,
Garant MJ,
and
Egan JM.
Once daily injections of exendin-4 to diabetic mice achieves long-term beneficial effects on blood glucose concentrations.
Diabetologia
42:
45-50,
1999[ISI][Medline].
15.
Gutniak, MK,
Linde B,
Holst JJ,
and
Efendic S.
Subcutaneous injection of the incretin hormone glucagon-like peptide 1 abolishes postprandial glycemia in NIDDM.
Diabetes Care
17:
1039-1044,
1994[Abstract].
16.
Gutniak, M,
Ørskov C,
Holst JJ,
Ahren B,
and
Efendic S.
Antidiabetogenic effect of glucagon-like peptide-1 (7-36) amide in normal subjects and patients with diabetes mellitus.
N Engl J Med
326:
1316-1322,
1992[Abstract].
17.
Gutzwiller, JP,
Drewe J,
Goke B,
Schmidt H,
Rohrer B,
Lareida J,
and
Beglinger C.
Glucagon-like peptide 1 promotes satiety and reduces food intake in patients with diabetes mellitus type 2.
Am J Physiol Regulatory Integrative Comp Physiol
277:
R1541-R1544,
1999
18.
Gutzwiller, JP,
Goke B,
Drewe J,
Hildebrand P,
Ketterer S,
Handschin D,
Winterhalder R,
Conen D,
and
Beglinger C.
Glucagon-like peptide-1: a potent regulator of food intake in humans.
Gut
44:
81-86,
1999
19.
Kieffer, TJ,
McIntosh CH,
and
Pederson RA.
Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV.
Endocrinology
136:
3585-96,
1995[Abstract].
20.
Knudsen, LB,
Nielsen PF,
Huusfeldt PO,
Johansen SL,
Madsen K,
Pedersen FZ,
Thøgersen H,
Wilken M,
and
Agersø H.
Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration.
J Med Chem
43:
1664-1669,
2000[ISI][Medline].
21.
Kolligs, F,
Fehmann HC,
Goke R,
and
Goke B.
Reduction of the incretin effect in rats by the glucagon-like peptide 1 receptor antagonist exendin (9-39) amide.
Diabetes
44:
16-19,
1995[Abstract].
22.
Kreymann, B,
Williams G,
Ghatei MA,
and
Bloom SR.
Glucagon like peptide 1 (7-36): a physiological incretin in man.
Lancet
ii:
1300-1303,
1987.
23.
Long, SJ,
Sutton JA,
Amaee WB,
Giouvanoudi A,
Spyrou NM,
Rogers PJ,
and
Morgan LV.
No effect of glucagon-like peptide-1 on short-term satiety and energy intake in man.
Br J Nutr
81:
273-279,
1999[ISI][Medline].
24.
Meeran, K,
O'Shea D,
Edwards CM,
Turton MD,
Heath MM,
Gunn I,
Abusnana S,
Rossi M,
Small CJ,
Goldstone AP,
Taylor GM,
Sunter D,
Steere J,
Choi SJ,
Ghatei MA,
and
Bloom SR.
Repeated intracerebroventricular administration of glucagon-like peptide-1-(7-36) amide or exendin-(9-39) alters body weight in the rat.
Endocrinology
140:
244-250,
1999
25.
Naslund, E,
Barkeling B,
King N,
Gutniak M,
Blundell JE,
Holst JJ,
Rossner S,
and
Hellstrom PM.
Energy intake and appetite are suppressed by glucagon-like peptide-1 (GLP-1) in obese men.
Int J Obes
23:
304-311,
1999[ISI].
26.
Nathan, DM,
Schreiber E,
Fogel H,
Mojsov S,
and
Habener JF.
Insulinotropic action of glucagonlike peptide-I-(7-37) in diabetic and nondiabetic subjects.
Diabetes Care
15:
270-226,
1992[Abstract].
27.
Nauck, MA,
Niedereichholz R,
Ettler R,
Holst JJ,
Ørskov C,
Ritzel R,
and
Schmeigel WH.
Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans.
Am J Physiol Endocrinol Metab
273:
E981-E988,
1997
28.
Navarro, M,
Rodriquez de Fonseca F,
Alvarez E,
Chowen JA,
Zueco JA,
Gomez R,
Eng J,
and
Blazquez E.
Colocalization of glucagon-like peptide-1 (GLP-1) receptors, glucose transporter GLUT-2, and glucokinase mRNAs in rat hypothalamic cells: evidence for a role of GLP-1 receptor agonists as an inhibitory signal for food and water intake.
J Neurochem
67:
1982-1991,
1996[ISI][Medline].
29.
O'Harte, FP,
Mooney MH,
Lawlor A,
and
Flatt PR.
N-terminally modified glucagon-like peptide-1 (7-36) amide exhibits resistance to enzymatic degradation while maintaining its antihyperglycaemic activity in vivo.
Biochim Biophys Acta
1474:
13-22,
2000[ISI][Medline].
30.
Ørskov, L,
Holst JJ,
Møller J,
Ørskov C,
Møller N,
Alberti KGMM,
and
Schmitz O.
GLP-1 does not acutely affect insulin sensitivity in healthy man.
Diabetologia
39:
1227-1232,
1996[ISI][Medline].
31.
Ørskov, C,
Wettergren A,
and
Holst JJ.
Biological effects and metabolic rates of glucagonlike peptide-1 7-36 amide and glucagonlike peptide-1 7-37 in healthy subjects are indistinguishable.
Diabetes
42:
658-661,
1993[Abstract].
32.
Pridal, L,
Deacon CF,
Kirk O,
Christensen JV,
Carr RD,
and
Holst JJ.
Glucagon-like peptide-1(7-37) has a larger volume of distribution than glucagon-like peptide-1(7-36)amide in dogs and is degraded more quickly in vitro by dog plasma.
Eur J Drug Metab Pharmacokinet
21:
51-59,
1996[ISI][Medline].
33.
Qualmann, C,
Nauck MA,
Holst JJ,
Ørskov C,
and
Creutzfeldt W.
Insulinotropic actions of intravenous glucagon-like peptide-1 (GLP-1) [7-36 amide] in the fasting state in healthy subjects.
Acta Diabetol
32:
13-16,
1995[ISI][Medline].
34.
Ritzel, U,
Leonhardt U,
Ottleben M,
Rühmann A,
Eckart K,
Spiess J,
and
Ramadori G.
A synthetic glucagon-like peptide-1 analog with improved plasma stability.
J Endocrinol
159:
93-102,
1998
35.
Rodriquez de Fonseca, F,
Navarro M,
Alvarez E,
Roncero I,
Chowen JA,
Maestre O,
Gómez R,
Muñoz RO,
Eng J,
and
Blázquez E.
Peripheral versus central effects of glucagon-like peptide-1 receptor agonists on satiety and body weight loss in Zucker obese rats.
Metabolism
49:
709-717,
2000[ISI][Medline].
36.
Sarson, DL,
Bryant MG,
and
Bloom SR.
A radioimmunoassay of gastric inhibitory polypeptide in human plasma.
J Endocrinol
85:
487-496,
1980[Abstract].
37.
Schirra, J,
Katschinski M,
Weidmann C,
Schafer T,
Wank U,
Arnold R,
and
Goke B.
Gastric emptying and release of incretin hormones after glucose ingestion in humans.
J Clin Invest
97:
92-103,
1996
38.
Scrocchi, LA,
Brown TJ,
Maclusky N,
Brubaker PL,
Auerbach AB,
Joyner AL,
and
Drucker DJ.
Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene.
Nat Med
2:
1254-1258,
1996[ISI][Medline].
39.
Szayna, M,
Doyle ME,
Betkey JA,
Holloway HW,
Spencer RG,
Greig NH,
and
Egan JM.
Exendin-4 decelerates food intake, weight gain and fat deposition in Zucker rats.
Endocrinology
141:
1936-1941,
2000
40.
Thorens, B,
Porret A,
Buhler L,
Deng SP,
Morel P,
and
Widmann C.
Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9-39) an antagonist of the receptor.
Diabetes
42:
1678-1682,
1993[Abstract].
41.
Toft-Nielsen, MB,
Madsbad S,
and
Holst JJ.
Continuous subcutaneous infusion of glucagon-like peptide 1 lowers plasma glucose and reduces appetite in type 2 diabetic patients.
Diabetes Care
22:
1137-1143,
1999[Abstract].
42.
Turton, MD,
O'Shea D,
Gunn I,
Beak SA,
Edwards CM,
Meeran K,
Choi SJ,
Taylor GM,
Heath MM,
Lambert PD,
Wilding JP,
Smith DM,
Ghatei MA,
Herbert J,
and
Bloom SR.
A role for glucagon-like peptide-1 in the central regulation of feeding.
Nature
379:
69-72,
1996[ISI][Medline].
43.
United Kingdom Prospective Diabetes Study Group.
UK prospective diabetes study 33: intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes.
Lancet
352:
837-853,
1998[ISI][Medline].
44.
Wang, ZL,
Wang RM,
Owji AA,
Smith DM,
Ghatei MA,
and
Bloom SR.
Glucagon-like peptide-1 is a physiological incretin in rat.
J Clin Invest
95:
417-421,
1995[ISI][Medline].
45.
Wettergren, A,
Schjoldager B,
Mortensen PE,
Myhre J,
Christiansen J,
and
Holst JJ.
Truncated GLP-1 (proglucagon 78-107-amide) inhibits gastric and pancreatic functions in man.
Dig Dis Sci
38:
665-673,
1993[ISI][Medline].
46.
Young, AA,
Gedulin BR,
Bhavsar S,
Bodkin N,
Jodka C,
Hansen B,
and
Denaro M.
Glucose-lowering and insulin-sensitizing actions of exendin-4: studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta).
Diabetes
48:
1026-1034,
1999[Abstract].