Tolerance develops toward GLP-1 receptor agonists' glucose-lowering effect in mice.

Glucagon-like peptide 1 (GLP-1) receptor agonists are popular antidiabetic drugs with potent glucose-lowering effects and low risk of hypoglycemia. Animal experiments and human data indicate that tolerance develops toward at least some of their effects, e.g., gastric motility. Whether tolerance develops toward the glucose-lowering effect of GLP-1 receptor agonists in mice has never been formally tested. The hypothesis of tolerance development in mice will be reported in this study. The direct glucose-lowering effect of the GLP-1 receptor agonists was measured in non-fasted mice and with intraperitoneal glucose tolerance test. Exenatide (10 µg/kg) and liraglutide (600 µg/kg) both substantially lost efficacy during the 18-day treatment as compared to the acute effect. We conclude that our results demonstrate development of tolerance toward GLP-1 receptor agonists' glucose-lowering effect in mice.

Exenatide Is an Effective Antihyperglycaemic Agent in a Mouse Model of Wolfram Syndrome 1.

Wolfram syndrome 1 is a very rare monogenic disease resulting in a complex of disorders including diabetes mellitus. Up to now, insulin has been used to treat these patients. Some of the monogenic forms of diabetes respond preferentially to sulphonylurea preparations. The aim of the current study was to elucidate whether exenatide, a GLP-1 receptor agonist, and glipizide, a sulphonylurea, are effective in a mouse model of Wolfram syndrome 1. Wolframin-deficient mice were used to test the effect of insulin secretagogues. Wolframin-deficient mice had nearly normal fasting glucose levels but developed hyperglycaemia after glucose challenge. Exenatide in a dose of 10 µg/kg lowered the blood glucose level in both wild-type and wolframin-deficient mice when administered during a nonfasted state and during the intraperitoneal glucose tolerance test. Glipizide (0.6 or 2 mg/kg) was not able to reduce the glucose level in wolframin-deficient animals. In contrast to other groups, wolframin-deficient mice had a lower insulin-to-glucose ratio during the intraperitoneal glucose tolerance test, indicating impaired insulin secretion. Exenatide increased the insulin-to-glucose ratio irrespective of genotype, demonstrating the ability to correct the impaired insulin secretion caused by wolframin deficiency. We conclude that GLP-1 agonists may have potential in the treatment of Wolfram syndrome-related diabetes.

GLP-1 receptor agonists have a sustained stimulatory effect on corticosterone release after chronic treatment.

OBJECTIVE: Glucagon-like peptide 1 (GLP-1) receptor agonists are a new group of antidiabetic medications quickly gaining popularity. We aimed to examine behavioural and neuroendocrine changes following chronic treatment with GLP-1 receptor agonists in animal models. METHODS: The effects of chronic treatment with GLP-1 receptor agonists were determined on behavioural parameters [anxiety level in the light-dark compartment test, the motor activity in automated activity cages, immobility in the forced swimming test (FST)] and on corticosterone release in mice. The possible antidepressant effect of chronic liraglutide treatment was also studied in Flinders Sensitive Line (FSL) rats, a genetic model of depression. RESULTS: Two weeks of treatment with exenatide (10 µg/kg twice daily) or liraglutide (1200 µg/kg once daily) did not affect the anxiety level in a light-dark compartment test nor induce an antidepressant-like effect in the FST in mice. Moreover, chronic treatment with liraglutide had no effect on depression-related behaviour in FSL rats. Interestingly, hypolocomotion induced by the drugs in mice disappeared after chronic dosing. Both of the GLP-1 receptor agonists induced robust increases in corticosterone levels in mice under basal conditions as well as in the case of combination with swimming stress. Remarkably, exenatide was as potent a stimulator of corticosterone release after 2 weeks as after acute administration. CONCLUSIONS: The increases in corticosterone release seen after acute exenatide or liraglutide treatment do not abate after 2 weeks of treatment demonstrating that tolerance does not develop towards this particular effect of GLP-1 agonists.

Nitric oxide is involved in the regulation of marble-burying behavior.

The aim of this study was to characterize the behavioral effect of modulators of NO synthesis in the mouse marble-burying test. We found that the non-selective NOS inhibitor 7-nitroindazole (7-NI) as well as the more selective neuronal and inducible NOS inhibitor 1-(2-trifluoromethylphenyl)imidazole (TRIM) decreased the number of marbles buried. Treatment with NO precursor l-arginine alone (500mg/kg) had no effect in this paradigm, but counteracted the effects of paroxetine (10mg/kg) and citalopram (10mg/kg). Moreover, agmatine (20 and 50mg/kg i.p), a molecule related to l-arginine metabolism, inhibited the marble-burying behavior. This effect of agmatine was not related to inhibition of NO synthesis as the drug did not decrease the nitrate and nitrite level in the brain tissue.We conclude that NOS inhibitors and agmatine dose-dependently inhibit the marble-burying behavior in mice. Inhibition of nNOS seems to play a key role in the behavioral effects of NOS inhibitors, whereas agmatine seems to have a different mechanism of action. Moreover, enhancement of NO synthesis by l-arginine reversed the effect of SSRI antidepressants, further demonstrating the role of NO in regulating the marble-burying behavior.

Antidepressant-like effect of agmatine is not mediated by serotonin.

The aim of this study was to characterize the behavioral effects of systemically administered agmatine in animal models predictive of antidepressant- and anxiolytic-like activity and clarify whether the effects of agmatine depend on the intact serotonergic system. Only the highest dose of agmatine tested (50 mg/kg) decreased immobility of mice in the forced swimming test. The magnitude of the effect was slightly smaller than that of the tricyclic antidepressant imipramine (15 mg/kg). Agmatine did not change the locomotion of mice in the open field. Pretreatment with the tryptophane hydroxylase inhibitor PCPA for 3 days resulted in more than 70% drop in the tissue levels of 5-HT and 5-HIIA but did not counteract the antidepressant-like effect of agmatine. The administration of agmatine did not modify behavior of animals in the light-dark compartment test of anxiety. We conclude that the antidepressant-like effect of agmatine seems not to be mediated by the serotonergic system. We failed to confirm the reported anxiolytic-like activity of agmatine.