Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers. Am J Physiol Endocrinol Metab 281: E155-E161, 2001.-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 ⅐ kg Ϫ1 ⅐ min Ϫ1 ) 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 Ϯ 0.3 vs. saline, 2.2 Ϯ 0.3 mmol/l, P Ͻ 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 Ϯ 79 vs. saline 1,075 Ϯ 93 kcal, P ϭ 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 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 Ϯ 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 hu...