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).
Abstract
Exendin-4 is a 39 amino acid peptide isolated from the salivary secretions of the Gila monster (Heloderma suspectum). It shows 53% sequence similarity to glucagon-like peptide (GLP)-1. Unlike GLP-1, exendin-4 has a prolonged glucose-lowering action in vivo. We compared the potency and duration of glucose-lowering effects of exendin-4 and GLP-1 in hyperglycemic db/db and ob/ob mice. Whereas reductions in plasma glucose of up to 35% vanished within 1 h with most doses of GLP-1, the same doses of exendin-4 resulted in a similar glucose-lowering effect that persisted for >4 h. Exendin-4 was 5,530-fold more potent than GLP-1 in db/db mice (effective doses, 50% [ED50s] of 0.059 microg/kg +/-0.15 log and 329 microg/kg+/-0.22 log, respectively) and was 5,480-fold more potent in ob/ob mice (ED50s of 0.136 microg/kg+/-0.10 log and 744 microg/kg+/-0.21 log, respectively) when the percentage fall in plasma glucose at 1 h was used as the indicator response. Exendin-4 dose-dependently accelerated glucose lowering in diabetic rhesus monkeys by up to 37% with an ED50 of 0.25 microg/kg +/-0.09 log. In two experiments in which diabetic fatty Zucker rats were injected subcutaneously twice daily for 5-6 weeks with doses of exendin-4 up to 100 microg x rat(-1) x day(-1) (approximately 250 microg/kg), HbA1c was reduced relative to saline-injected control rats. Exendin-4 treatment was also associated in each of these experiments with weight loss and improved insulin sensitivity, as demonstrated by increases of up to 32 and 49%, respectively, in the glucose infusion rate (GIR) in the hyperinsulinemic euglycemic clamp. ED50s for weight loss and the increase in clamp GIR were 1.0 microg/kg+/-0.15 log and 2.4 microg/kg+/-0.41 log, respectively. In conclusion, acute and chronic administration of exendin-4 has demonstrated an antidiabetic effect in several animal models of type 2 diabetes.
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GLP-1 did not increase blood pressure in monkeys or during continuous subcutaneous infusion for 6 wk in humans.
“While GLP-1 did not increase BP in monkeys (55) or during continuous subcutaneous infusion for 6 wk in humans (56)”
From Effects of glucagon-like peptide-1, yohimbine, and nitrergic modulation on sympathetic and parasympathetic activity in humans (2008) · cites this paper as [55]
This is in contrast to data in rodents.
“This is in contrast to data in rodents (55, 56).”
From Effects of glucagon-like peptide-1, yohimbine, and nitrergic modulation on sympathetic and parasympathetic activity in humans (2008) · cites this paper as [55]
Our observations are generally consistent with previous studies demonstrating that GLP-1 did not increase blood pressure in monkeys or during continuous subcutaneous infusion for 6 wk in humans.
“Overall, our observations are generally consistent with previous studies demonstrating that GLP-1 did not increase BP in monkeys (55) or during continuous subcutaneous infusion for 6 wk in humans (56).”
From Effects of glucagon-like peptide-1, yohimbine, and nitrergic modulation on sympathetic and parasympathetic activity in humans (2008) · cites this paper as [55]
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- Authors
- Young, A. A., Gedulin, B. R., Bhavsar, S., Bodkin, N., Jodka, C., Hansen, B., & Denaro, M.
- Affiliations
- Amylin Pharmaceuticals, San Diego, California 92121, USA. ayoung@amylin.com
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 1999-05-01
- Volume
- 48
- Issue
- 5
- Pages
- 1026-1034
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2065867087
- Cited by
- 440
- References
- 16
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 7 · 2023: 9 · 2022: 5 · 2021: 14 · 2020: 7 · 2019: 7 · 2018: 8 · 2017: 9 · 2016: 16 · 2015: 13 · 2014: 20 · 2013: 30 · 2012: 33
- FWCI
- 8.99
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- exendin-4, glucagon-like peptide-1, glucose-lowering effect, insulin sensitivity, type 2 diabetes, obesity, db/db mice, ob/ob mice, Zucker diabetic fatty rats, rhesus monkeys, HbA1c, weight loss, hyperinsulinemic-euglycemic clamp, Gila monster, GLP-1 receptor agonists
- MeSH terms
- Exenatide, Animals, Blood Glucose, Diabetes Mellitus, Dose-Response Relationship, Drug, Female, Glucagon, Glycated Hemoglobin, Hypoglycemic Agents, Insulin, Kinetics, Macaca mulatta, Male, Mice, Inbred C57BL, Mice, Obese, Obesity, Peptide Fragments, Peptides, Protein Precursors, Rats, Zucker, Venoms, Sequence Homology, Mice, Rats, Glucagon-Like Peptide 1
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