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.

BACKGROUND: Peptide YY (PYY) is a 36 amino-acid peptide secreted from ileal L cells following meals. The cleaved subpeptide PYY is biologically active and may constitute the majority of circulating PYY-like immunoreactivity. The peptide family that includes PYY, pancreatic peptide and neuropeptide Y is noted for its orexigenic effect following intracerebroventricular administration. OBJECTIVE: To investigate the effects of peripheral (intraperitoneal and chronic subcutaneous) infusions of PYY[3-36] on food intake, body weight and glycemic indices. DESIGN/RESULTS: Food intake was measured in normal mice and in several rodent models of obesity and type II diabetes. In marked contrast to the reported central orexigenic effects, in the present study, PYY acutely inhibited food intake by up to 45%, with an ED 50 of 12.5 mg/kg in fasted female NIH/Swiss mice. A 4-week infusion reduced weight gain in female ob/ob mice, without affecting the cumulative food intake. In diet-induced obese male mice, PYY[3-36] infusion reduced cumulative food intake, weight gain and epididymal fat weight (as a fraction of carcass) with similar ED 50 's (466, 297 and 201 mg/kg/day, respectively) and prevented a diet-induced increase in HbA1c. Infusion at 100 mg/kg/day for 8 weeks in male fa/fa rats reduced the weight gain (288711 vs 326712 g in saline-infused controls; Po0.05), similar to effects in a pair-fed group. In female ob/ob and db/db mice, there was no acute effect of PYY on plasma glucose concentrations. In male diabetic fatty Zucker rats, PYY infused for 4 weeks reduced HbA1c and fructosamine (ED 50 's 30 and 44 mg/kg/day). CONCLUSION: Peripheral PYY[3-36] administration reduced the food intake, body weight gain and glycemic indices in diverse rodent models of metabolic disease of both sexes. These findings justify further exploration of the potential physiologic and therapeutic roles of PYY .

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Exendin-4, originally isolated from saliva of the lizard Heloderma suspectum, shares 53% sequence homology and several potentially antidiabetic actions with the mammalian hormone glucagonlike peptide-1(7-36)amide (GLP-1). It shows a higher potency and longer duration of effect in vivo, which may be partly attributed to pharmacokinetic properties. The present study compares the pharmacokinetics of GLP-1 and exendin-4 in rats after intravenous (iv), subcutaneous (sc), or intraperitoneal (ip) administration. Samples were assayed for active GLP-1 (7-36) amide using an enzyme-linked immunosorbent assay that does not detect GLP-1 (1-36-amide), (1-37), (9-36-amide) or (9-37). In parallel experiments, samples were assayed for exendin-4 using a two-site immunoradiometric assay that reacts specifically with fulllength exendin-4. The estimated half-life for GLP-1 and exendin-4 were 0.8-4.7 min and 18-41 min for iv bolus, and 4.6-7.1 min and 90-216 min for SC administration, respectively. Half-lives after ip injection were 0.6-13.5 min for GLP-1 and 125-174 min for exendin-4. Bioavailability for GLP-1 and exendin-4 was 44-71% and 65-75%, respectively, for sc injection. For ip injection, bioavailability for GLP-1 and exendin-4 was 36-67% and 74-76%, respectively. Plasma clearance, as determined from iv infusion data, was 35-38 ml/min for GLP-1 and 4-8 ml/min for exendin-4. Both Co/C max and AUC values were proportional to dose with each route of administration. Plasma clearance of exendin-4 was reduced by 4.4-fold in nephrectomized animals. In conclusion, exendin-4 exhibited a much longer plasma half-life than GLP-1 in rats after iv, sc, or ip injection, which may contribute in some part to reported differences in duration of biological action of the two peptides. Drug Dev. Res. 53:260-267, 2001.

Objective: The current set of studies describe the in vivo metabolic actions of the novel amylin-mimetic peptide davalintide (AC2307) in rodents and compares these effects with those of the native peptide. Research design and methods: The anti-obesity effects of davalintide were examined after intraperitoneal injection or sustained peripheral infusion through subcutaneously implanted osmotic pumps. The effect of davalintide on food intake after lesioning of the area postrema (AP) and neuronal activation as measured by c-Fos, were also investigated. Results: Similar to amylin, davalintide bound with high affinity to amylin, calcitonin and calcitonin gene-related peptide receptors. Acutely, davalintide displayed greater suppression of dark-cycle feeding and an extended duration of action compared with amylin (23 versus 6 h). Davalintide had no effect on locomotor activity or kaolin consumption at doses that decreased food intake. Davalintide-induced weight loss through infusion was dose dependent, durable up to 8 weeks, fat-specific and lean-sparing, and was associated with a shift in food preference away from high-fat (palatable) chow. Metabolic rate was maintained during active weight loss. Both davalintide and amylin failed to suppress food intake after lesioning of the AP and activated similar brain nuclei, with davalintide displaying an extended duration of c-Fos expression compared with amylin (8 versus 2 h). Conclusion: Davalintide displayed enhanced in vivo metabolic activity over amylin while retaining the beneficial properties possessed by the native molecule. In vitro receptor binding, c-Fos expression and AP lesion studies suggest that the metabolic actions of davalintide and amylin occur through activation of similar neuronal pathways.