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Endocrinology Vol. 141, No. 6 1936-1941
Copyright © 2000 by The Endocrine Society

ARTICLES

Exendin-4 Decelerates Food Intake, Weight Gain, and Fat Deposition in Zucker Rats

Margarzata Szayna, Máire E. Doyle, Jennifer A. Betkey, Harold W. Holloway, Richard G. S. Spencer, Nigel H. Greig and Josephine M. Egan

Diabetes Section (M.E.D., J.A.B., J.M.E.), NMR Unit (M.S., R.G.S.S.), and Drug Design and Development Section (H.W.H., N.H.G.), Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224

Address all correspondence and requests for reprints to: Josephine M. Egan, M.D., Diabetes Section, no. 23, GRC/NIA/NIH, 5600 Nathan Shock Drive, Baltimore, Maryland 21224. E-mail: eganj{at}vax.grc.nia.nih.gov


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Exendin-4 is a 39 amino acid peptide produced in the salivary gland of the Gila monster lizard. It has a 53% amino acid homology to the incretin hormone glucagon-like peptide-1 (GLP-1). Exendin-4 induces insulin release through activation of the GLP-1 receptor but is a much more potent insulinotropic agent than GLP-1. Of critical importance for its potential use as a treatment for diabetes is its much longer biological effect in vivo. Previous studies involving once daily administration of exendin-4 over 13 weeks to db/db mice demonstrated that it lowers hemoglobin A1c (HbA1c), a marker of mean blood glucose levels. Food consumption in the treated animals dropped over the first 4 days and then increased to a level comparable with that of the untreated animals. In this study, we initially examined the effect of once daily injections (over 14 days) on the food consumption of Zucker fatty rats. We observed an immediate reduction in food intake which then leveled off (after 5 days) to match that of the untreated animals. Subsequently we injected the same animals twice daily (treatment period of 56 days in total) and observed a sustained reduction in food intake and weight-gain. This was matched by a reduction in the critical parameters of HbA1c, fasting blood glucose and plasma insulin. MRI imaging of the abdominal regions of the animals showed that initially only the amount of fat deposited in the sc region was reduced after 4 weeks exendin-4 treatment. At the 8-week time point there was a corresponding decrease in the amount of visceral fat deposition. The combination of appetite reduction, decreased fat deposition and an improvement in the parameters associated with glucose intolerance makes a case for the use of exendin-4 as a treatment for diabetes.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
EXENDIN-4 IS A 39 amino acid peptide produced in the salivary glands of the Gila monster lizard Heloderma suspectum (1). Although it is the product of a uniquely nonmammalian gene and appears to be expressed only in the salivary gland (2), it shares a 53% amino acid sequence with mammalian glucagon-like peptide-1 (GLP-1) and in mammals it is an agonist at the GLP-1 receptor (3, 4, 5). GLP-1, a peptide produced from the endocrine L-cells of the gut in response to food intake, functions as an incretin hormone. It is also a potential therapeutic agent in the treatment of type 2 diabetes mellitus (6). Infusions of GLP-1 in the hyperglycemic state lead to euglycemia in a glucose-dependent manner by increasing insulin release and synthesis in ß-cells of the pancreas, inhibiting glucagon release and decreasing gastric emptying (7, 8, 9, 10, 11). It also has a potential role in appetite regulation (12). Unfortunately, GLP-1 has limitations as a therapeutic agent because of its short biological half-life (11), even when given by a bolus injection sc (13). We (3), and others (14), have reported that exendin-4 is a far more potent insulinotropic agent than is GLP-1 and, when given chronically, it caused a marked and sustained improvement in glucose control in a rodent model of type 2 diabetes (the db/db mouse), with just once daily dosing (3). Most important, when given to type 2 diabetic and nondiabetic subjects it proved to be a more potent insulinotropic agent than GLP-1, it controlled the postprandial rise in blood glucose that occurs in type 2 diabetes and its biological effects are on the order of hours, unlike the case of GLP-1, where they are on the order of minutes (15). In addition, it has been shown that chronic exendin-4 treatment led to a reduction in weight gain in Zucker fatty rats due to reduced food intake when given for up to 42 days (14). This particular strain of rat has a mutation in the leptin receptor (Lepr) due to a Gln269Pro mutation; consequently, the binding of the leptin molecule is greatly reduced. Hence the rats overeat, become obese, and develop diabetes.

Exendin-4 would appear to have a favorable profile as an agent for the treatment of type 2 diabetes. Specifically, its biological effect as an insulinotropic agent is long lasting, its lowers hemoglobin A1c (HbA1c) when given long-term, reflecting a lowering of the mean blood glucose, and it appears to decrease food intake. In the present study, we gave exendin-4 daily for the first 14 days and twice daily thereafter for the next 42 days to Zucker fatty rats. As well as monitoring food intake, body weight, and various metabolic parameters, we used MRI technology to study fat distribution before and after treatment.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Materials
The exendin-4 used in these studies was from Amylin Pharmaceuticals, Inc. (San Diego, CA). Plasma insulin and leptin levels were measured by ELISA (Crystal Chem Inc., Chicago, IL). HbA1c was measured as before (3). .Blood glucose levels were measured using a Glucometer Elite (Bayer Corp. Diagnostics, Tarrytown, NY).

Animals
Obese male (fa/fa) 8-week old Zucker rats were obtained from The Jackson Laboratory (Bar Harbor, ME). They were cared for in accordance with protocols approved by the Animal Care and Use Committee of the Gerontology Research Center, National Institute on Aging (Baltimore, MD). They were allowed ad libidum access to chow and water. Animals were on a 12-h light, 12-h dark cycle (lights on 0700 h). During acclimatization, blood was taken from the tip of the tail for baseline HbA1c determination. Control animals were tagged and housed together in one cage (n = 4). Treated animals were also tagged and housed in two cages of four animals each (n = 8). For MRI analysis a mixture of oxygen and isoflurane was used for anesthesia. Each study took approximately 20 min.

Protocol (Fig. 1Go)
Animals were acclimatized in our facilities for 2 weeks, during which time they had a baseline MRI, before beginning exendin-4 treatment. For the first 14 days of treatment, the animals were given exendin-4 (10 µg/kg) by ip injection daily at 0900 h. Thereafter, animals received ip 10 µg/kg exendin-4 at approximately 0900 h and 2100 h for the following 42 days. At the end of the first 10 days, of the treatment protocol blood glucose levels were measured. No day was missed in the schedule. Animals were weighed daily for the 70-day duration. Food intake was measured daily for the first 21 days, and weekly subsequently. For the glucose tolerance test, performed after 42 days of treatment, the animals were anesthetized with 50 mg/kg ip pentobarbital. A catheter was placed in the femoral artery for blood sampling and fasting blood samples obtained for glucose, insulin, leptin, and HbA1c determinations. An ip glucose tolerance test (IPGTT, 1 g glucose/kg BW) was administered. Blood samples were subsequently obtained at 15, 30, 45, 60, and 90 min to assay glucose and insulin levels. Blood (200 µl) was drawn into heparinized tubes containing EDTA and Trasylol for leptin and insulin determination. Control animals were injected with saline.



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  		Figure 1. Experimental design. IP, ip; IPGTT, IP glucose tolerance test (1 g glucose/kg BW).

 
MRI
MRI measurements were obtained with a 1.9 Tesla, 31-cm Bruker BioSpec MRI Scanner (Bruker Medizintechnik GmbH, Ettlingen, Germany) system using a shielded gradient set of 20 cm inside diameter and an imaging resonator of 15 cm inside diameter. Standard 2-dimensional spin echo T1 weighted images (TR = 500 msec, TE = 14.1 msec) were obtained with a slice thickness of 4 mm and an imaging matrix of 256 [times 128. The FOV was varied between 12 x 12 and 18 x 18 to accommodate animal growth. A total of 22 transverse slices was obtained to cover the entire abdomen caudal to the diaphragm, with the distance between the center of the slices ranging between 5 mm and 8 mm. Each image was formed from 16 acquisitions. Total imaging time was approximately 20 min for each study. Measurements were obtained on all animals (n = 12) during acclimatization and after 28 and 56 days of treatment. Image analysis was performed using Bruker Paravision and Medx (Sensor Systems, Inc.) software. The fat compartments were identified by manual selection on each slice. Total abdominal sc and visceral fat volumes were obtained by summing the fat volumes from individual slices and linear interpolation between slices (16).

Statistical methods
All results are given as mean ± SEM. t tests were based on the results of an F test that assessed the equality of variance of the two means. If the variances were statistically significantly different, then the t test was based on unequal variances.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Baseline parameters
On day 10 of once daily exendin-4 injections, blood was taken from the tip of the tail (between 1000 and 1100 h) to ascertain whether exendin-4, at the concentration used, was lowering blood glucose. Blood glucose level was 93 ± 5 mg/dl (n = 8) in the treated group vs. 201 ± 17 mg/dl in the control group (n = 4), P < 0.001 as determined by unpaired t test.

Body weight and food intake
In exendin-4-treated animals, food consumption decreased vs. controls during the first 5 days of therapy but thereafter was the same as in the control animals. Body weight dropped in the treated rats initially, but by the 14-day point were the same as that of control animals (Fig. 2AGo). From days 7–14, food intake was indistinguishable between control and treated animals (Fig. 2BGo). This is similar to our report in db/db mice where once daily exendin-4 treatment decreased food intake during the initial 4 days of treatment (3).



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  		Figure 2. Daily body weights (A) and food intake (B) for the first 21 days of a 56-day protocol in control Zucker fatty rats and fatty rats that received exendin-4 (10 µg/kg ip) daily for 14 days and twice daily thereafter. The results are means ± SEM.

 
At the 14-day point, when an additional ip injection of exendin-4 was introduced every night as well as every morning, a significant drop in food intake occurred. While food intake increased after 5 days of treatment (Fig. 3BGo), the treated animals continued to eat less than control animals for the remainder of the study. This drop in food intake was reflected in the body weights of the animals. Treated animals continued to gain weight after the third week of treatment (Fig. 3AGo) but at a significantly slower rate (P < 0.01: slope measured between days 21–42 = 4.31 vs. 2.04 [R2 = 0.99 for both linear fits], control vs. treated, respectively) than the control group.



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  		Figure 3. Weekly body weights (A) and average daily food intake (B) in control Zucker fatty rats and fatty rats that received exendin-4 (10 µg/kg ip) twice daily from 14 days, as a continuation of the data shown in Fig. 1Go, for a total of 56 days. The results are means ± SEM. **, P < 0.01.

 
HbA1c
Baseline HbA1c (6.7± 0.3%) was taken before beginning any treatment. At the 42-day point control rats, which were on average 68 g heavier than the exendin-4-treated rats and had a mean HbA1c level that was 60% higher than it had been at baseline. This was probably due to the continued rise in mean blood glucose. The fasting blood glucose of 285 ± 37 mg/dl before glucose administration for the IPGTT in the control animals was higher than was the postprandial blood glucose of 201 ± 17 mg/dl at 10 days. In contrast, HbA1c levels in exendin-4-treated animals were only 20% higher than at their baseline, P < 0.000001.

Glucose tolerance test (IPGTT) performed after 42 days of treatment (Fig. 4Go)
Fasting blood glucose levels were clearly higher in the control compared with treated animals (285 ± 37 vs. 176 ± 16 mg/dl, P < 0.01). Fasting plasma insulin levels were lower in the treated animals (10.0 ± 1.0 vs. 5.4 ± 0.7 ng/ml, P < 0.01), presumably reflecting better glucose tolerance. Insulin levels rose in response to glucose in the treated animals (peak insulin level of 9.1 ± 1.2 ng/ml, P < 0.05) compared with their fasting levels. In contrast, the untreated animals had no insulin increase in response to glucose. Plasma leptin levels, assayed from the 0 time points taken before administration of the glucose, showed control levels to be 75 ± 7 vs. 75 ± 4 ng/ml in the treated animals.



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  		Figure 4. Blood glucose (A) and plasma insulin (B) levels during an ip glucose tolerance test (IPGTT, 1 g/kg glucose given after the 0 time point) in control Zucker fatty rats and fatty rats treated with exendin-4 (10 µg/kg ip daily for 14 days and twice daily thereafter for a total of 56 days) at the 42-day time point. The results are means ± SEM. a, P < 0.01, fasting levels of glucose and insulin, control vs. treated; *, P < 0.05, insulin levels after the IPGTT in the treated animals vs. their own fasting level.

 
MRI results (Fig. 5Go)
Twenty-eight days of exendin-4 therapy clearly impacted on the deposition of the fat in the sc space. The percent increase during this period was 34 ± 5% vs. 48 ± 3% in treated vs. control, respectively (P < 0.01). The percent increase in the visceral fat during the same period was 65 ± 5% vs. 54 ± 9%, treated vs. control, which was not significantly different. These changes were even more obvious after 56 days of treatment, at which point there was a decrease in the amount of fat deposition from 70 ± 1% to 42 ± 3% (P < 0.01) in the sc fat. At this point there was also less visceral fat deposition from 127 ± 8% in control animals compared with 83 ± 7% (P < 0.01) in treated animals.



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  		Figure 5. Percent change in abdominal sc (A) and visceral (B) fat using MRI in control Zucker fatty rats and fatty rats treated with exendin-4 (10 µg/kg ip daily for 14 days and twice daily thereafter). MRI measurements were take during the 2-week acclimatization period and at 28 and 56 days of treatment. The results are means ± SEM. **, P < 0.01, treated vs. control.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Forty-two days of exendin-4 treatment in Zucker fatty rats significantly reduced the mean glucose levels, as judged by HbA1c determination. There were no blood draws between 10 and 42 days, when the IPGTT was performed and blood assayed for the amount of HbA1c present. Thus, the results of the HbA1c are not diluted by new red blood cell formation that would have occurred if the animals had been frequently phlebotomized during the protocol (14). This would have seriously confounded the results. Glucose tolerance was also improved, as judged by the lower mean fasting blood glucose and plasma insulin levels, and greater insulin responses to administered glucose during the ip glucose tolerance test. In the control animals, insulin release did not increase in response to the glucose tolerance test.

While a once daily injection of exendin-4 produced a dramatic decrease in food intake, only a twice daily injection of the compound suppressed appetite over a time period long enough to result in a sustained reduction in weight gain. The treated animals continued to gain weight on the twice daily regimen, albeit at a significantly slower rate than the control animals. Obesity is one of the major risk factors in type 2 diabetes. Therefore, an agent that can control appetite as well as improve glucose tolerance would be an extremely beneficial treatment.

Plasma leptin levels reflect the amount of fat tissue that is present in mammals (17). Zucker fatty rats (fa/fa) are homozygous for the fatty mutation in the leptin receptor gene, which is due to an amino acid substitution of proline for glutamine at position 269 (18). As a result there is greatly reduced binding of leptin to its receptor. Therefore, the rats have high plasma leptin levels that do not reflect the degree of adiposity, and they are unresponsive to its satiety effect. As a consequence, they overeat compared with lean (+/+) wild-type rats and become obese. Despite the receptor defect, the fatty rats had an obvious deceleration in weight gain while receiving exendin-4 twice daily. Leptin levels were unchanged with exendin-4 treatment, indicating that exendin-4 does not alter the responsivity of the mutated receptor to leptin. The alteration in the appetite of the treated animals is probably due to a combination of peripheral and central effects. Gastrointestinal effects that have been demonstrated with GLP-1 (9, 12) include a delayed gastric emptying that would be expected to give rise to a sensation of fullness in the animals. Similar effects have been seen with exendin-4 (19). Central effects of GLP-1 and exendin-4 on satiety have likewise been demonstrated in rodents (20).

An upper body distribution of adipose tissue increases the risk of insulin resistance and increases the risk of expression of the metabolic syndrome (21). Recently, studies using anthropometric measurements, such as waist-to-hip ratio and truncal-to-peripheral skinfold ratio as indices of obesity, have been supplemented by CT and MRI measurements to enable investigators to more specifically examine which components of central fat distribution contribute to insulin resistance and other metabolic abnormalities. Despite the very strong consensus with regard to the importance of centralized fat deposition, controversy has arisen as to the unique importance of the visceral (portal) fat compartment. Recent studies (22) using the euglycemic clamp to measure insulin sensitivity indicate that abdominal sc fat is a more potent indicator of insulin resistance than visceral fat. In addition, in another study of a large group of lean and obese healthy sedentary men and women, abdominal sc fat was a moderately more robust correlate of insulin resistance than visceral fat (23). Hence, any treatment that decreases sc ± visceral fat would be expected to decrease insulin resistance. As the former was the compartment most clearly effected by exendin-4 treatment, we consider that this primarily explains the reported effects wherein 5 weeks of treatment improved insulin sensitivity by 49% (14) and 6 weeks treatment improved glucose tolerance.

In summary, twice daily exendin-4 treatment in Zucker rats resulted in a deceleration in weight gain. This was due to a reduction in food intake. It resulted, initially, in a significant reduction in sc fat compared with control animals, followed by a significant reduction in visceral fat. The treatment also resulted in a reduction in HbA1c, and an amelioration in fasting glucose level and insulin response to administered glucose.

Received November 19, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Eng J, Kleinman WA, Singh G, Raufman JP 1992 Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom: further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem 267:7402–7405[Abstract/Free Full Text]
  2. Chen YE, Drucker DJ 1997 Tissue-specific expression of unique mRNAs that encode pro-glucagon-derived peptides or exendin 4 in the lizard. J Biol Chem 272:4108–4115[Abstract/Free Full Text]
  3. Greig NH, Holloway HW, De Ore KA, Jani D, Wang Y, Zhou J, Garant MJ, Egan JM 1999 Once daily injection of exendin-4 to diabetic mice achieves long-term beneficial effects on blood glucose concentrations. Diabetologia 42:45–50
  4. Goke R, Fehmann H-C, Linn T, Schmidt H, Krause M, Eng J, Goke B 1993 Exendin-4 is a potent agonist and truncated exendin-(9–39)-amide an antagonist at the GLP-1-(7–36)-amide receptor of insulin-secreting ß-cells. J Biol Chem 268: 19650–19655
  5. Thorens B, Porret A, Buhler L, Deng SP, Morel P, Widman C 1993 Cloning and functional expression of the GLP-1 receptor: demonstration that exendin-4 is an agonist and exendin-3 (9–39) is an antagonist of the receptor. Diabetes 42:1678–1672[Abstract]
  6. Gutniak M, Orskov C, Holst JJ, Ahren B, Efendic S 1994 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[Abstract]
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  8. Elahi D, McAloon-Dyke M, Fukagawa NK, Meneilly GS, Sclater AL, Minaker KL, Habener JF, Andersen DK 1994 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[CrossRef][Medline]
  9. Willms B, Werner J, Holst JJ, Orskov C, Creutzfeldt W, Nauck MA 1996 Gastric emptying, glocose responses, and insulin secretion after a liquid test meal: effects of exogenous glucagon-like peptide-1-(7–36) amide in Type 2 (non-insulin-dependent) diabetic patients. J Clin Endocrinol Metab 81:327–332[Abstract]
  10. Nathan D, Scheiber E, Fogel H, Mosjov S, Habener JF 1992 Insulinotropic action of glucagonlike peptide-1-(7–37) in diabetic and non-diabetic subjects. Diabetes Care 15:270–276[Abstract]
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  13. Ritzel R, Orskov C, Holst JJ, Nauck MA 1995 Pharmacokinetic, insulinotropic, and glucagonostatic properties of GLP-1 [7–36 amide] after subcutaneous injection in healthy volunteers. Dose-response-relationships. Diabetologia 38:720–725[Medline]
  14. Young AA, Gedulin BR, Bhavsar S, Bodkin N, Jodka C, Hansen B, Denaro M 1999 Glucose-lowering and insulin-sensitizing actions of exendin-4: studies on obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta). Diabetes 48:1026–1034[Abstract]
  15. Elahi D, Clocquet A, Egan JM 1999 Exendin-4 is insulinotropic in non-diabetic and diabetic subjects (Abstract). Diabetologia 42:148A
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B. R. Gedulin, S. E. Nikoulina, P. A. Smith, G. Gedulin, L. L. Nielsen, A. D. Baron, D. G. Parkes, and A. A. Young
Exenatide (Exendin-4) Improves Insulin Sensitivity and {beta}-Cell Mass in Insulin-Resistant Obese fa/fa Zucker Rats Independent of Glycemia and Body Weight
Endocrinology, April 1, 2005; 146(4): 2069 - 2076.
[Abstract] [Full Text] [PDF]

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 Am J Health Syst PharmHome page
O. G. Kolterman, D. D. Kim, L. Shen, J. A. Ruggles, L. L. Nielsen, M. S. Fineman, and A. D. Baron
Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus
Am. J. Health Syst. Pharm., January 15, 2005; 62(2): 173 - 181.
[Abstract] [Full Text] [PDF]

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 The Annals of PharmacotherapyHome page
S. V Joy, P. T Rodgers, and A. C Scates
Incretin Mimetics as Emerging Treatments for Type 2 Diabetes
Ann. Pharmacother., January 1, 2005; 39(1): 110 - 118.
[Abstract] [Full Text] [PDF]

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 DiabetesHome page
L. L. Baggio, J.-G. Kim, and D. J. Drucker
Chronic Exposure to GLP-1R Agonists Promotes Homologous GLP-1 Receptor Desensitization In Vitro but Does Not Attenuate GLP-1R-Dependent Glucose Homeostasis In Vivo
Diabetes, December 1, 2004; 53(suppl_3): S205 - S214.
[Abstract] [Full Text] [PDF]

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 Diabetes CareHome page
J. B. Buse, R. R. Henry, J. Han, D. D. Kim, M. S. Fineman, A. D. Baron, and for the Exenatide-113 Clinical Study Group
Effects of Exenatide (Exendin-4) on Glycemic Control Over 30 Weeks in Sulfonylurea-Treated Patients With Type 2 Diabetes
Diabetes Care, November 1, 2004; 27(11): 2628 - 2635.
[Abstract] [Full Text] [PDF]

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 DiabetesHome page
C. F. Deacon
Therapeutic Strategies Based on Glucagon-Like Peptide 1
Diabetes, September 1, 2004; 53(9): 2181 - 2189.
[Abstract] [Full Text] [PDF]

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 JRSMHome page
C M. B Edwards
GLP-1: target for a new class of antidiabetic agents?
J R Soc Med, June 1, 2004; 97(6): 270 - 274.
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 J. Clin. Endocrinol. Metab.Home page
J. Korner and L. J. Aronne
Pharmacological Approaches to Weight Reduction: Therapeutic Targets
J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2616 - 2621.
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 Diabetes CareHome page
D. J. Drucker
Enhancing Incretin Action for the Treatment of Type 2 Diabetes
Diabetes Care, October 1, 2003; 26(10): 2929 - 2940.
[Abstract] [Full Text] [PDF]

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 Diabetes CareHome page
M. S. Fineman, T. A. Bicsak, L. Z. Shen, K. Taylor, E. Gaines, A. Varns, D. Kim, and A. D. Baron
Effect on Glycemic Control of Exenatide (Synthetic Exendin-4) Additive to Existing Metformin and/or Sulfonylurea Treatment in Patients With Type 2 Diabetes
Diabetes Care, August 1, 2003; 26(8): 2370 - 2377.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
O. G. Kolterman, J. B. Buse, M. S. Fineman, E. Gaines, S. Heintz, T. A. Bicsak, K. Taylor, D. Kim, M. Aisporna, Y. Wang, et al.
Synthetic Exendin-4 (Exenatide) Significantly Reduces Postprandial and Fasting Plasma Glucose in Subjects with Type 2 Diabetes
J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3082 - 3089.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Endocrinol. Metab.Home page
J. M. Egan, G. S. Meneilly, and D. Elahi
Effects of 1-mo bolus subcutaneous administration of exendin-4 in type 2 diabetes
Am J Physiol Endocrinol Metab, June 1, 2003; 284(6): E1072 - E1079.
[Abstract] [Full Text] [PDF]

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 Pharmacol. Rev.Home page
M. E. Doyle and J. M. Egan
Pharmacological Agents That Directly Modulate Insulin Secretion
Pharmacol. Rev., March 1, 2003; 55(1): 105 - 131.
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 DiabetesHome page
P. E. MacDonald, W. El-kholy, M. J. Riedel, A. M. F. Salapatek, P. E. Light, and M. B. Wheeler
The Multiple Actions of GLP-1 on the Process of Glucose-Stimulated Insulin Secretion
Diabetes, December 1, 2002; 51(90003): S434 - 442.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
J. Movassat, G. M. Beattie, A. D. Lopez, and A. Hayek
Exendin 4 Up-Regulates Expression of PDX 1 and Hastens Differentiation and Maturation of Human Fetal Pancreatic Cells
J. Clin. Endocrinol. Metab., October 1, 2002; 87(10): 4775 - 4781.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Endocrinol. Metab.Home page
B. Rolin, M. O. Larsen, C. F. Gotfredsen, C. F. Deacon, R. D. Carr, M. Wilken, and L. B. Knudsen
The long-acting GLP-1 derivative NN2211 ameliorates glycemia and increases beta -cell mass in diabetic mice
Am J Physiol Endocrinol Metab, October 1, 2002; 283(4): E745 - E752.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
E. E. Daniel, M. Anvari, J. E. T. Fox-Threlkeld, and T. J. McDonald
Local, exendin-(939)-insensitive, site of action of GLP-1 in canine ileum
Am J Physiol Gastrointest Liver Physiol, September 1, 2002; 283(3): G595 - G602.
[Abstract] [Full Text] [PDF]

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 J. Pharmacol. Exp. Ther.Home page
T. Perry, D. K. Lahiri, D. Chen, J. Zhou, K. T. Y. Shaw, J. M. Egan, and N. H. Greig
A Novel Neurotrophic Property of Glucagon-Like Peptide 1: A Promoter of Nerve Growth Factor-Mediated Differentiation in PC12 Cells
J. Pharmacol. Exp. Ther., March 1, 2002; 300(3): 958 - 966.
[Abstract] [Full Text] [PDF]

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 DiabetesHome page
P. J. Larsen, C. Fledelius, L. B. Knudsen, and M. Tang-Christensen
Systemic Administration of the Long-Acting GLP-1 Derivative NN2211 Induces Lasting and Reversible Weight Loss in Both Normal and Obese Rats
Diabetes, November 1, 2001; 50(11): 2530 - 2539.
[Abstract] [Full Text] [PDF]

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 J. Clin. Endocrinol. Metab.Home page
C. Verdich, A. Flint, J.-P. Gutzwiller, E. Naslund, C. Beglinger, P. M. Hellstrom, S. J. Long, L. M. Morgan, J. J. Holst, and A. Astrup
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., September 1, 2001; 86(9): 4382 - 4389.
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 J. Nutr.Home page
C. T. Peters, Y.-H. Choi, P. L. Brubaker, and G. H. Anderson
A Glucagon-Like Peptide-1 Receptor Agonist and an Antagonist Modify Macronutrient Selection by Rats
J. Nutr., August 1, 2001; 131(8): 2164 - 2170.
[Abstract] [Full Text] [PDF]

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 Am. J. Physiol. Endocrinol. Metab.Home page
C. M. B. Edwards, S. A. Stanley, R. Davis, A. E. Brynes, G. S. Frost, L. J. Seal, M. A. Ghatei, and S. R. Bloom
Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers
Am J Physiol Endocrinol Metab, July 1, 2001; 281(1): E155 - E161.
[Abstract] [Full Text] [PDF]