GLP-1 receptor agonist liraglutide exerts central action to induce β-cell proliferation through medulla to vagal pathway in mice

Mar 31, 2018Biochemical and biophysical research communications

Liraglutide stimulates insulin-producing cell growth through brainstem signals to the vagus nerve in mice

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Abstract

Intracerebroventricular injections of liraglutide increased pancreatic β-cell proliferation in C57BL/6J mice.

Liraglutide administration via both subcutaneous and intracerebroventricular routes resulted in elevated expression of proliferation markers Ki67 and PCNA in pancreatic β-cells.
A single intracerebroventricular dose of liraglutide was effective at a relatively low concentration that did not suppress food intake.
Pretreatment with atropine, a muscarinic receptor blocker, inhibited the effects of liraglutide by 50% via subcutaneous injection and 70% via intracerebroventricular injection.
Intracerebroventricular liraglutide increased c-Fos expression in brain regions associated with autonomic regulation, including the area postrema, nucleus tractus solitaries, and dorsal motor nucleus of the vagus.
The findings suggest a brain pathway involving the area postrema and vagus nerve that may link central GLP-1 action to pancreatic β-cell proliferation.

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Endogenous GLP-1 and GLP-1 receptor agonists (GLP-1RAs) regulate glucose metabolism via common and distinct mechanisms. Postprandial release of GLP-1 is modest and it is degraded by DPP-4 within 2 min, and hence it cannot enter the brain in substantial amount. In contrast, DPP-4-resistant GLP-1RAs are administered at 10 times higher concentration than endogenous GLP-1 level, which enables them to reach several brain regions including ARC and AP, the areas implicated in glucose metabolism. Hence, some of the effects of GLP-1RAs observed clinically and experimentally, including pancreatic β-cell proliferation, are thought to involve the brain. However, the effects of centrally acting GLP-1/GLP-1RAs on glucose metabolism and underlying neural mechanism are unclear. This study aimed to establish the link of central GLP-1/GLP-1RA action to pancreatic β-cell proliferation. Both subcutaneous (SC) and intracerebroventricular (ICV) injections of liraglutide increased the number of pancreatic β-cells expressing Ki67 and PCNA, proliferation markers, in C57BL/6J mice. This effect was induced by single ICV administration of liraglutide at relatively low dose that was incapable of suppressing food intake. These SC and ICV liraglutide-induced effects were inhibited by 50% and 70%, respectively, by pretreatment with atropine, a muscarinic receptor blocker. ICV liraglutide induced c-Fos expression in the area postrema (AP), nucleus tractus solitaries (NTS), and dorsal motor nucleus of the vagus (DMX) of the brain stem. These results demonstrate that central action of liraglutide induces pancreatic β-cell proliferation via the pathway involving the brain stem AP/NTS/DMX area and vagus nerve. This route is highly sensitive to GLP-1/GLP-1RA. Hence, this brain-pancreatic β-cell pathway may operate in type 2 diabetic patients treated with GLP-RAs and serve to counteract the reduction of β-cell mass.

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GLP-1 receptor agonist liraglutide exerts central action to induce β-cell proliferation through medulla to vagal pathway in mice

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