Abstract
Liraglutide, an acylated analog of glucagon-like peptide 1 (GLP-1), could improve glycemic control in diabetes. Moreover, endogenous opioid peptides play a role in blood sugar regulation. Since GLP-1 receptors are also expressed in extra-pancreatic tissues, this study investigates the effect of liraglutide on endogenous opioid secretion in type 1-like diabetes. The endogenous opioid level was determined by enzyme-linked immunosorbent assay. The direct effect of liraglutide on endogenous opioid secretion was determined in the isolated adrenal medulla. Acute treatment with liraglutide dose-dependently attenuated hyperglycemia, and increased the plasma opioid neuropeptide, beta-endorphin (BER) levels in diabetic rats. These effects have been blocked by GLP-1 receptor antagonist, naloxone. Additionally, the effects of liraglutide were markedly reduced in adrenalectomized diabetic rats. In the isolated adrenal medulla, liraglutide induced BER secretion and increased the BER mRNA levels. Subcellular effects of liraglutide on the adrenal gland were further identified to mediate through the exchange proteins directly activated by cAMP, mainly using the pharmacological blockade. After repeatedly administering liraglutide, metabolic changes in diabetic rats were investigated, and genes associated with gluconeogenesis in the liver were downregulated. Naloxone pretreatment inhibited these effects of liraglutide, indicating the involvement of endogenous opioids. The present study indicated that liraglutide had an acute effect of reducing hyperglycemia by regulating endogenous opioid BER and modifying the glucose homeostasis.
Highlights
Liraglutide is a clinical agent with an acylated glucagon-like peptide 1 (GLP-1) analog developed using recombinant DNA technology
Liraglutide binds to the GLP-1 receptor (GLP-1R), a G-protein-coupled receptor located on the membrane cell surface, and it induces intracellular activation by increasing the level of cyclic adenosine monophosphate
The total blockade of liraglutide-induced action by Exendin 9-39 (Ex9) at 100 μg/kg IP was consistent with a previous report [20]
Summary
Liraglutide is a clinical agent with an acylated GLP-1 analog developed using recombinant DNA technology. The most important effect of liraglutide is the glucose-dependent stimulation of insulin secretion that reduces blood glucose It reduces glucagon secretion from pancreatic beta-cells by targeting GLP-1R, inhibiting hepatic glucose production. In isolated human pancreatic islet cells, liraglutide was found to promote beta-cell proliferation and inhibit interleukin-1β-induced apoptosis after a 4 day incubation period [3]. This implies that liraglutide is useful in treating type 2 diabetes because progressive islet dysfunction is associated with hyperglycemia. Liraglutide is associated with a lower incidence of hypoglycemic events compared to other antidiabetic drugs, which has contributed to its applications in clinical practice Owing to such pleiotropic effects, liraglutide is the drug of choice after metformin. Liraglutide is widely used in treating patients with type 2 diabetes, as it is effective and well-tolerated, has a low risk of hypoglycemia and cardiovascular disorders, and induces sustained weight loss
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