1 Diabetes Section, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224; 2 Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada V6T-2B5; and 3 Geriatric Research Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston Massachusetts 02114
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ABSTRACT |
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A gut insulinotropic peptide,
glucagon-like peptide-1 (GLP-1), when given continuously
subcutaneously, has been shown to be an effective agent to treat type 2 diabetes. Because of inactivation by dipeptidyl peptidase IV (DPP IV),
it has a very short half-life (90-120 s), hence the need for
continuous administration. Exendin-4 is an agonist of the GLP-1
receptor. It is not a substrate for DPP IV, and we previously
demonstrated that intravenous administration has potent insulinotropic
properties in type 2 diabetic volunteers. We evaluated the efficacy of
bolus subcutaneous exendin-4 in insulin-naive type 2 diabetic
volunteers. Ten patients aged 44-72 yr with mean fasting glucose
levels of 11.4 ± 0.9 mmol/l were enrolled, and daily or
twice-daily bolus subcutaneous exendin-4 was self-administered for 1 mo. Glycosylated hemoglobin, multiple daily capillary blood glucose,
-cell sensitivity to glucose, and peripheral tissue sensitivity to
insulin were compared before and after treatment. The greatest decline
in capillary blood glucose was seen before bed, with a drop from 15.5 to 9.2 mmol/l (P < 0.0001). Glycosylated hemoglobin
improved significantly with treatment, from 9.1 to 8.3%
(P = 0.009).
-Cell sensitivity to glucose was
improved, as assessed by C-peptide levels during a hyperglycemic clamp. No significant adverse effects were noted or reported. Our data suggest
that, even with this short duration of therapy, exendin-4 treatment had
a significant effect on glucose homeostasis.
insulinotropic effect; glucose disposal; glucagon; C-peptide; hemoglobin A1C
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INTRODUCTION |
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GLUCAGON-LIKE
PEPTIDE-1 (GLP-1) is an enteric hormone that is
released into the portal vein following a meal. GLP-1 also plays a role
in the central control of feeding behavior and has other extrapancreatic effects: it inhibits gastric emptying, has cardiac effects, and has insulinomimetic effects on glucose uptake and disposal
(2). It acts to regulate islet hormone secretion, insulin
biosynthesis, islet cell proliferation, and gastrointestinal motility
through a specific G protein-coupled receptor (3). Its
exogenous administration to nondiabetic and type 2 diabetic subjects
results in lowering blood glucose (6, 15). However, its
therapeutic potential is limited in that its rapid degradation by
dipeptidyl peptidase IV (DPP IV) within a few minutes of administration represents a significant impediment to the chronic use of the native
peptide (12). One way to circumvent this is to give GLP-1 subcutaneously continuously via a pump so that the active and degraded
GLP-1 reaches a steady state (29). Another way is to use
an agonist of the GLP-1 receptor that is not a substrate for DPP IV.
Exendin-4, a peptide and GLP-1 receptor agonist produced in the
salivary glands of the Gila monster (Heloderma suspectum), exhibits increased GLP-1 receptor binding, has a longer biological half-life, and is a more potent insulinotropic agent than GLP-1 (4, 5, 14). Because the amino acid sequence of exendin-4 does not contain a position 2 alanine recognized by DPP IV, this partially explains its longer half-life. Long-term experiments that we
(8, 24) performed in diabetic mice and rats showed that
twice-daily exendin-4 injections lowered mean blood glucose after
glucose tolerance testing, lowered hemoglobin A1c, and
decreased body weight and, in Zucker rats, decreased total body fat.
The enhanced potency and duration of action of exendin-4 in multiple mammalian species suggest that human studies with exendin-4 are warranted. Having demonstrated its prolonged insulinotropic effects and
glucose lowering capacity in an acute experiment of both nondiabetic and diabetic volunteers (5), we initiated a long-term
study using exendin-4 administered by subcutaneous injections. We began with one daily subcutaneous injection of exendin-4, but it became clear
after four volunteers that this was not maintaining 24-h coverage, so
we then gave the exendin-4 twice daily. We also used a sequential clamp
consisting of three parts to examine the dynamics of exendin-4
treatment on glucose uptake and insulin secretion: a 1-h hyperglycemic
clamp followed by 1 h of recovery followed by a 2-h
hyperinsulinemic euglycemic clamp and a 0.5-h recovery. Thus we were
able to assess -cell sensitivity to glucose and peripheral tissue
sensitivity to insulin before and after 1 mo of therapy with exendin-4.
Volunteers also kept a diary of capillary blood glucose (CBG), which
was monitored at least eight times per day for 1 mo. We show, in type 2 diabetic volunteers, that exendin-4 lowers blood glucose and that Hb
A1C is improved.
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METHODS |
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Selection of volunteers.
Nineteen sequential hyperglycemic euglycemic clamps were performed in
nine insulin-naive type 2 diabetic volunteers before and 1 mo after
therapy with synthetic, full-length exendin-4 (AC2993: Amylin
Pharmaceuticals, San Diego, CA). The volunteers' clinical characteristics are presented in Table 1.
Normal electrocardiogram, serum electrolytes, liver and renal function,
a fasting glucose of >6.4 mmol/l, and hematocrits of 38 in males and
36 in females were requirements for entrance into the study.
Volunteers' exclusion criteria included any significant history
(physical or laboratory evidence) of hepatic, renal, pulmonary,
endocrine (other than type 2 diabetes mellitus), or gastrointestinal
disease or any evidence of autonomic insufficiency. Therapy with
insulin, steroids (sex or adrenal), diuretics, amphetamines,
diphenylhydantoin, or enteroactive agents or any medications that might
influence carbohydrate metabolism (other than hypoglycemic agents) were also exclusion criteria. Oral hypoglycemic agents were stopped for a
7-day washout period before the first clamp study. All methods and
procedures were approved by the Johns Hopkins Bayview Medical Center/Gerontology Research Center Institutional Review Board (99-02-99-01), along with an
investigator-initiated investigational new drug from the Food and Drug
Administration. All volunteers provided written informed
consent in accordance with the Helsinki II declaration.
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Hyperglycemic and hyperinsulinemic euglycemic clamps.
All volunteers were weight and activity stable before the initial
clamp. Volunteers consumed 200 g of carbohydrates for 3 days before
the clamp. This clamp procedure has been previously reported in detail
(19). The clamp consisted of three steps: 1) a
hyperglycemic clamp (5.4 mmol/l above basal) for 1 h and 2) 1 h of glycemic recovery to basal glucose
immediately followed by 3) a hyperinsulinemic euglycemic
clamp for 2 h with a 0.5-h recovery. The 10-min falling priming of
insulin was followed by a continuous infusion of insulin (480 pmol · m
2 · min
1,
Humulin; Eli Lilly, Indianapolis, IN). In type 2 diabetic volunteers, during the recovery period (step 2) the plasma
glucose level did not drop to "normal" levels. Therefore, during
the hyperinsulinemic euglycemic clamp period (step
3), we did not start the glucose infusion until the plasma
glucose level approached 5.3 mmol/l. This level was chosen to clamp the
plasma glucose of all of our diabetic volunteers, since it was the mean
level encountered in our normal volunteers. The use of sequential clamp
for the assessment of glucose uptake during the hyperinsulinemic
euglycemic clamp has been validated for diabetic volunteers at this
dose of insulin by performing hyperinsulinemic euglycemic clamps
without the preceding hyperglycemic clamp (19).
Body composition. Fat mass, lean tissue mass, and bone mineral content were determined by dual-energy X-ray absorptiometry (Model Prodigy, LUNAR Radiation, Madison, WI) on the day of each clamp.
Treatment with exendin-4. Insulin-naive patients were recruited from the Baltimore area. They had to be willing to stay in the area for the duration of the study, and they had to commit to CBG monitoring and recording no less than eight times every day: before and 1 h after breakfast, lunch, and dinner, 1 h after subcutaneous injection of exendin-4, and before retiring to bed. They were also asked to monitor and record CBG any time they perceived symptoms that they interpreted as possibly due to a drop in blood sugar. After their first clamp, they were instructed how to administer the injections and given instructions on recognition and treatment of low blood sugar. Then, every week for the duration of the study, they were seen at our General Clinical Research Center. At that time, their previous week's CBG record was checked, and adjustments were made as necessary.
Each volunteer was started on a test dose of 1.2 pmol/kg exendin-4 at 2100. All subjects reported no skin irritation after the 1st day at the injection site, so on subsequent nights they received a dose of 12 pmol/kg, which was adjusted upward to a final total dose ofAnalytical techniques. We collected blood samples in heparinized syringes. An aliquot of plasma glucose was immediately assayed by the glucose oxidase method (Beckman Instruments, Fullerton, CA), and the remaining blood samples were processed and stored as previously described (20). Plasma insulin, C-peptide, and glucagon were also determined as previously described (5, 20). Specific activity of [3-3H]glucose was determined on deproteinized and evaporated aliquots of plasma by use of the Somogi-Nelson method of deproteinization (21). Hb A1C was measured with a Bio-Rad DiaSTAT (Hercules, CA).
Statistical analysis.
The rates of total appearance (Ra) and disappearance
(Rd) of glucose were calculated according to the
non-steady-state equations of Steele (22), as modified for
the use of hot Ginf. The volume of distribution of glucose
was assumed to be 210 ml/kg (11). During the basal period,
glucose Ra is equal to hepatic glucose production (HGP)
because the liver is the principal source of glucose. When glucose is
infused (i.e., during the clamp), endogenous glucose production is
estimated as the difference between its calculated total glucose
Ra and the exogenous glucose infusion rate for the
appropriate time interval. Glucose turnover rates were calculated at
10-min intervals from 40 to 270 min. The trapezoidal rule was used to
calculate the integrated responses of the first-phase insulin release
(0-10 min) and over 30-min intervals. The integrated responses
were divided by the time interval, which resulted in mean concentration
or rates. All data were analyzed using Statistical Analysis
System version 8.1 (Cary, NC). Standard methods were used to compute
means, standard errors of the mean, and Pearson correlation
coefficients. Mixed-model analysis for repeated-measures design was
used to analyze hormone and metabolite responses. Differences between
clamps were evaluated using a paired t-test. All statistical tests were two tailed. Except where otherwise stated, data are means ± SE, and P values of <0.05 were regarded as
statistically significant.
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RESULTS |
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Clinical characteristics.
The clinical characteristics before and after treatment are presented
in Table 1. Specifically, exendin-4 did not alter body mass index or
percent body fat. The fasting metabolic characteristics obtained on the
morning of the clamp, before and after treatment, are presented in
Table 2. After treatment, there was a
significant decrease in Hb A1C levels from 9.08 ± 0.42 to 8.29 ± 0.46% (P = 0.009).
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CBG.
Daily glucose excursion throughout the day during treatment with
exendin-4 is shown in Fig. 1. The mean
levels before breakfast and before initiation of therapy were 13.9 mmol/l and dropped to the 8.3-11.1 mmol/l range while subjects
were on daily therapy and were always below 11.1 mmol/l after
twice-daily therapy was initiated. The decrease in fasting CBG during
the 1-mo therapy before breakfast and bed is significant compared with
the levels 10 days before therapy (P < 0.05). The highest levels during the day were seen 1 h
after breakfast in the average range of 13.9-18.1 mmol/l while on
daily therapy, which dropped to the 11.1-13.9 mmol/l range after
twice daily therapy was started. The decrease in CBG during the 1-mo
therapy with exendin-4 at 1 h after breakfast is significant
(P < 0.0001) as determined by repeated measures in a
mixed model. These levels dropped further to the ~11.1 mmol/l range
before lunch and increased by ~2.8 mmol/l 1 h after lunch. The
levels 1 h after dinner were similar to the levels seen 1 h
after lunch. The lowest average levels were observed before bed in the
range of 5.6-11.1 mmol/l. With >2,000 CBG measurements, only nine
incidents of blood glucose 3.6 mmol/l were recorded. The lowest value
was 3.3 mmol/l.
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Hyperglycemic and hyperinsulinemic euglycemic clamps.
The data for the first nine patients enrolled in the study (Table 1)
are presented for the clamp figures. One additional patient
(n = 10) completed 4 wk of exendin-4, but during the
last week of therapy she developed an upper respiratory tract infection (unrelated to exendin-4 therapy) for which she was actively being medicated with antibiotic and nasal decongestant at the time when her
second clamp study was due. Consequently, her second clamp was not
performed, as we thought that the data would be compromised by the new
medication. The plasma glucose levels and the glucose infusion rates
for the sequential hyperglycemic euglycemic clamp before and after 1 mo
of therapy with exendin-4 are presented in Fig.
2. Fasting plasma glucose was 11.4 ± 0.9 and 11.1 ± 0.7 mmol/l before and after treatment,
respectively. The fasting plasma glucose levels were rapidly raised by
5.4 mmol/l, and a square wave of hyperglycemia was established from 0 to 60 min (16.4 ± 0.7 and 16.5 ± 0.7 mmol/l). With the
termination of the glucose infusion at 60 min, plasma glucose began to
fall and reached a level of 13.6 ± 0.7 and 13.3 ± 0.8 mmol/l at 120 min in the pre- and posttreatment clamps, respectively.
At 120 min, a square wave of hyperinsulinemia was then created for
2 h. During this period, plasma glucose was allowed to fall to 5.3 mmol/l and was then maintained at this level until 270 min. The glucose
infusion required to maintain hyperglycemia and euglycemia during these
clamps is shown in Fig. 2. The glucose infusion rates were similar
before and after therapy.
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Glucose turnover rates.
Basal HGP before therapy was 18.61 ± 0.89 µmol · kg1 · min
1.
HGP dropped to 11.9 ± 4.3 µmol · kg
1 · min
1
during the last 30 min of the hyperglycemic portion of the clamp. However, during the euglycemic portion of the clamp, HGP fell further
and reached a rate of 6.3 ± 2.1 µmol · kg
1 · min
1
during the last 0.5 h of the insulin infusion. Glucose disposal rates
during the last 30 min of the hyperglycemic portion of the clamp and
last 30 min of the hyperinsulinemic euglycemic portion of the clamp
were 14.4 ± 1.3 and 22.8 ± 4.6 µmol · kg
1 · min
1.
After 1 mo of therapy, basal HGP was 16.5 ± 1.5 µmol · kg
1 · min
1.
During the last 30 min of the hyperglycemic clamp, HGP dropped to
5.0 ± 1.6 µmol · kg
1 · min
1.
During the euglycemic portion of the clamp, HGP was further suppressed
to 2.4 ± 1.7 µmol · kg
1 · min
1.
Glucose disposal rates during the last 30 min of the hyperglycemic and
hyperglycemic euglycemic portions of the clamp were 9.4 ± 1.2 and
18.2 ± 3.2 µmol · kg
1 · min
1.
Although both basal and stimulated HGP and glucose disposal rates were
lower during all portions of the clamp following therapy, changes were
not significant.
Safety. Two patients experienced nausea after the subcutaneous injection, one for three evenings and one for four evenings, during the 1st wk of exendin-4 treatment. Thereafter, even with addition of a second dose or escalation of the previous nighttime dose, there was no more nausea recorded.
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DISCUSSION |
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We demonstrate that exendin-4 administered subcutaneously, even in this limited study, can impact positively on blood glucose levels in poorly controlled, community-dwelling, insulin-naive type 2 diabetic subjects. CBG levels were clearly lower before bedtime (2200-2400) than at any other time of the day, reflecting the fact that exendin-4 had been given at ~2100. The nighttime injection also lowered fasting blood glucose levels, although at the dose we used levels were still in the 11.1 mmol/l range. The nighttime dose did not control postbreakfast blood glucose levels, and this was evident in the first four volunteers for the entire month. Introduction of a second injection in the morning, just before breakfast after the 1st wk of once-daily nighttime treatment in the rest of the volunteers, resulted in lower blood glucose 1 h after eating. However, it can be seen that, even with the introduction of the second morning injection, postlunch and -dinner blood glucose levels were not lowered. This means that twice-daily subcutaneous exendin-4, at this dose, does not give full 24-h blood glucose control. Therefore, exendin-4, should it become a treatment for type 2 diabetes, is unlikely to be used in the present mode and/or dose of administration.
We were restricted from altering the upper limit of the total 24-h dose by the conditions of the protocol. Despite the imperfect blood glucose control, exendin-4 lowered mean blood glucose levels, and there was a decrease in Hb A1C, even though the study was only of 1-mo duration.
We did not obtain blood for assessment of various metabolic factors during the 1-mo treatment. However, we can undoubtedly attribute the control of the plasma glucose levels mainly to the well-established insulinotropic effect of exendin-4 (1, 4, 5, 8, 18, 23, 24, 27, 28). Another mechanism, which also may have contributed to the improvement in glucose homeostasis during this treatment, is reduction in gastric emptying, which would retard postprandial absorption of carbohydrates and which is a well-known feature of GLP-1 and exendin-4 (4, 16).
The effect on prebedtime CBG lasted for the duration of the treatment, indicating that there was probably no desensitization of the GLP-1 receptor to exendin-4 in the islets over time.
In the clamps performed after 1 mo of therapy with exendin-4, the last
dose of the peptide was administered 12 h before the start of the
hyperglycemic portion of the clamp. Therefore, it is not surprising
that neither first-phase nor second-phase insulin responses were
augmented during the hyperglycemic portion of the clamp. C-peptide
levels, on the other hand, were significantly augmented by exendin-4
treatment. Therefore, it appears that insulin secretion is indeed
augmented following exendin-4 treatment but that insulin extraction
from the portal vein from the first pass through the liver must also be augmented.
An assay for exendin-4 in not commercially available at this time. However, the pharmacokinetic actions of exendin-4 have been reported with a two-site immunoradiometric assay that measures the full-length molecule (17). When exendin is administered intravenously or subcutaneously, the half-life is reported to be 18-41 min or 90-216 min, respectively. Bioavailability of subcutaneously administered exendin-4 was estimated to be 65-75%, and plasma clearance rate of intravenously administered exendin-4 was 4-8 ml/min. For GLP-1, the corresponding estimates of intravenously and subcutaneously administered peptide are 0.8-4.7 and 0.6-13.5 min, respectively. Estimates of bioavailability and clearance rates are 36-67% and 35-38 ml/min.
This 1-mo treatment with exendin-4 resulted in a significant increase in NEFA. We have no explanation for this, and further studies are underway to elucidate the mechanism involved. However, during the clamp, NEFA levels were suppressed following treatment in the same pattern as before treatment. This is undoubtedly due to their exquisite sensitivity to hyperinsulinemia. Furthermore, NEFA were suppressed at a significantly faster rate following treatment, indicating improved adipose tissue sensitivity.
We did not instruct our patients to modify their daily habits in any way. None reported changes in appetite and none had any change in body weight. GLP-1 has been reported to decrease food intake with short-term administration (7, 9, 25, 26) but not with longer administration. Two patients complained of nausea the 1st wk of treatment. Nothing else of note was seen.
To our knowledge, there are relatively few studies that have used exendin-4 in vivo (1, 8, 18, 23, 24, 27, 28), and most studies have utilized animal models. The duration of treatment with exendin-4 in those studies ranged from acute studies to 13 wk. There are two reports of acute intravenous administration of exendin-4 in humans (4, 5). Infusion of exendin-4 has been shown to reduce postprandial glucose profile in normal volunteers (4). We (5) have previously reported the acute effects of exendin-4 administered intravenously in normal and diabetic volunteers during a hyperglycemic clamp. A very potent insulinotropic effect of exendin-4 with a long biological half-life was demonstrated. The exendin-4 dose used in the present study was calculated from our own experience with this agent and with reported effects observed in acute studies by our colleagues (13). Studies using different doses and modes of administration as well as longer durations of therapy are needed.
In summary, subcutaneously administered exendin-4 lowers blood glucose, but the manner of administration and the dosing need optimizing. There was no indication of desensitization to its effects. We are working on a continuous subcutaneous delivery system that would deliver exendin-4 from a transdermal-type formulation.
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ACKNOWLEDGEMENTS |
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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 Denis Muller, Metabolism Section, National Institute on Aging, National Institutes of Health, for statistical assistance. We thank Gail Chin, Elizabeth Misiura, Elizabeth Bannon, and Howard Baldwin for excellent technical support. We thank Brenda I. Vega for assistance with the preparation of this manuscript. We thank Amylin Pharmaceutical Inc. for their generous donation of exendin-4 (AC2993) and for financial support for this study.
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FOOTNOTES |
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This study was supported in part by a grant from the intramural research program of the National Institute on Aging (NIA), the Canadian Diabetes Association, the Juvenile Diabetes Foundation International through the JDF Center for Islet Transplantation at Harvard Medical School, and General Clinical Research Center Grant (M01 RR-02719) at Johns Hopkins Bayview Medical Center.
Address for reprint requests and other correspondence: D. Elahi, Massachusetts General Hospital, Geriatric Research Laboratory, GRB SB 0015, 55 Fruit St., Boston, MA 02114 (E-mail: delahi{at}partners.org).
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.
First published December 10, 2002;10.1152/ajpendo.00315.2002
Received 15 July 2002; accepted in final form 27 November 2002.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Aspelund G, Egan J, Slezak L, Sritharan K, Elahi D, and Andersen
D. Glucagon-like peptide-1 and exendin-4 improve glucose tolerance
and induce islet cell growth during chronic pancreatitis in rats.
Surgical Forums: L1, 2000.
2.
Drucker, D.
Glucagon-like peptides.
Diabetes
47:
159-169,
1998[Abstract].
3.
Drucker, D.
Minireview: the glucagon-like peptides.
Endocrinology
142:
521-527,
2001
4.
Edwards, C,
Stanley S,
Davis R,
Brynes A,
Frost G,
Seal L,
Ghatei M,
and
Bloom S.
Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers.
Am J Physiol Endocrinol Metab
281:
E155-E161,
2001
5.
Egan, J,
Clocquet A,
and
Elahi D.
The insulinotropic effect of acute exendin-4 administered to humans: comparison of non-diabetic state to type 2 diabetes.
J Clin Endocrinol Metab
87:
1282-1290,
2002
6.
Elahi, D,
McAloon-Dyke M,
Fukagawa NK,
Meneilly GS,
Sclater AL,
Minaker KL,
Habener JF,
and
Andersen DK.
The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7-37) in normal and diabetic subjects.
Regul Pept
51:
63-74,
1994[ISI][Medline].
7.
Flint, A,
Raben A,
Astrup A,
and
Holst J.
Glucagon-like peptide-1 promotes satiety and suppresses energy intake in humans.
J Clin Invest
101:
515-520,
1998
8.
Greig, N,
Holloway H,
De Ore K,
Jani D,
Wang Y,
Zhou J,
Garant M,
and
Egan J.
Once daily injection of exendin-4 to diabetic mice achieves long-term beneficial effects on blood glucose concentrations.
Diabetologia
42:
45-50,
1999[ISI][Medline].
9.
Gutzwiller, J,
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 Regul Integr Comp Physiol
276:
R1541-R1544,
1999
10.
Hother-Nielsen, O,
and
Beck-Nielsen H.
On the determination of basal glucose production rate in patients with type 2 (non-insulin-dependent) diabetes mellitus using primed-continuous 3-3H-glucose infusion.
Diabetologia
33:
603-610,
1990[ISI][Medline].
11.
Insel, PA,
Liljenquist JE,
Tobin JD,
Sherwin RS,
Watkins P,
Andres R,
and
Berman M.
Insulin control of glucose metabolism in man: a new kinetic analysis.
J Clin Invest
55:
1057-1066,
1975[ISI].
12.
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:
3585-3596,
1995[Abstract].
13.
Kolterman, O,
Fineman M,
Gottlied A,
Petrella E,
Pricket K,
and
Young A.
AC2993 (synthetic exendin-4) lowered postprandial plasma glucose concentrations in people with type 2 diabetes (Abstract).
Diabetolgia Suppl
42:
A149,
1999.
14.
Montrose-Rafizadeh, C,
Yang H,
Rodgers B,
Beday A,
Pritchette L,
and
Eng J.
High potency antagonists of the pancreatic glucagon-like peptide-1 receptor.
J Biol Chem
272:
21201-21206,
1997
15.
Nauck, M,
Kleine N,
Orskov C,
Holst J,
Willms B,
and
Creutzfeldt W.
Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients.
Diabetologia
36:
741-744,
1993[ISI][Medline].
16.
Nauck, MA,
Niedereichholz U,
Ettler R,
Holst JJ,
Ørskov C,
Ritzel R,
and
Schmiegel 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
17.
Parkes, D,
Jodka C,
Smith P,
Nayak S,
Rinehart L,
Gingerich R,
Chen K,
and
Young A.
Pharmacokinetic actions of exendin-4 in the rat: comparison with glucagon-like peptide-1.
Drug Dev Res
53:
260-267,
2001[ISI].
18.
Parkes, D,
Pittner R,
Jodka C,
Smith P,
and
Young A.
Insulinotropic actions of exendin-4 and glucagon-like peptide-1 in vivo and in vitro.
Metabolism
50:
583-589,
2001[ISI][Medline].
19.
Ryan, A,
Muller D,
and
Elahi D.
Sequential hyperglycemic-euglycemic clamp to assess -cell and peripheral tissue: studies in female athletes.
J Appl Physiol
91:
872-881,
2001
20.
Ryan, AS,
Egan JM,
Habener JF,
and
Elahi D.
Insulinotropic hormone glucagon-like peptide-1-(7-37) appears not to augment insulin-mediated glucose uptake in young men during euglycemia.
J Clin Endocrinol Metab
83:
2399-2409,
1998
21.
Somogi, M.
Determination of blood sugar.
J Biol Chem
10:
69-73,
1945.
22.
Steele, R.
Influences of glucose loading and of injected insulin on hepatic glucose output.
Ann NY Acad Sci
82:
420-430,
1959[ISI].
23.
Stoffers, D,
Kieffer T,
Hussain M,
Drucker D,
Bonner-Weir S,
Habener J,
and
Egan J.
Insulinotropic glucagon-like peptide-1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas.
Diabetes
49:
741-748,
2000[Abstract].
24.
Szayna, M,
Doyle M,
Betkey J,
Holloway H,
Spencer R,
Greig N,
and
Egan J.
Exendin-4 decelerates food intake, weight gain, and fat deposition in Zucker rats.
Endocrinology
141:
1936-1941,
2000
25.
Toft-Nielsen, M,
Madsbad S,
and
Holst J.
Continuous subcutaneous infusion of glucagon-like peptide 1 lowers plasma glucose and reduces appetite in type 2 diabetes patients.
Diabetes Care
22:
1137-1143,
1999[Abstract].
26.
Verdich, C,
Flint A,
Gutzwiller J,
Naslund E,
Beglinger C,
Hellstrom P,
Long S,
Morgan L,
Holst J,
and
Astrup A.
A meta-analysis of the effect of glucagon-like peptide-1 (7-36) amide on ad libitum energy intake in humans.
J Clin Endocrinol Metab
86:
4382-4389,
2001
27.
Xu, G,
Stoffers D,
Habener J,
and
Bonner-Weir S.
Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats.
Diabetes
48:
2270-2276,
1999[Abstract].
28.
Young, A,
Gedulin B,
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].
29.
Zander, M,
Madsbad S,
Madsen J,
and
Holst J.
Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study.
Lancet
359:
824-830,
2002[ISI][Medline].