Abstract
Pancreatic β-cell neogenesis in vivo holds great promise for cell replacement therapy in diabetic patients, and discovering the relevant clinical therapeutic strategies would push it forward to clinical application. Liraglutide, a widely used antidiabetic glucagon-like peptide-1 (GLP-1) analog, has displayed diverse β-cell-protective effects in type 2 diabetic animals. Glucagon receptor (GCGR) monoclonal antibody (mAb), a preclinical agent that blocks glucagon pathway, can promote the recovery of functional β-cell mass in type 1 diabetic mice. Here, we conducted a 4-week treatment of the two drugs alone or in combination in type 1 diabetic mice. Although liraglutide neither lowered the blood glucose level nor increased the plasma insulin level, the immunostaining showed that liraglutide expanded β-cell mass through self-replication, differentiation from precursor cells, and transdifferentiation from pancreatic α cells to β-cells. The pancreatic β-cell mass increased more significantly after GCGR mAb treatment, while the combination group did not further increase the pancreatic β-cell area. However, compared with the GCGR mAb group, the combined treatment reduced the plasma glucagon level and increased the proportion of β-cells/α-cells. Our study evaluated the effects of liraglutide, GCGR mAb monotherapy, and combined strategy in glucose control and islet β-cell regeneration and provided useful clues for the future clinical application in type 1 diabetes.
Highlights
Pancreatic β-cell dysfunction and cell mass loss are a pivotal pathogenesis in both type 1 diabetes (T1D) and type 2 diabetes (T2D) [1, 2]
We investigated the possible effect of liraglutide, a commonly used glucagon-like peptide-1 (GLP-1) receptor agonist, on β-cell regeneration in T1D mice, and evaluated the combined effect of liraglutide with Glucagon receptor (GCGR) monoclonal antibody (mAb)
Compared with the normal control group, the body weight of the T1D mice displayed a significant decrease while the blood glucose level showed obvious increment (Figures 1(a)–1(c))
Summary
Pancreatic β-cell dysfunction and cell mass loss are a pivotal pathogenesis in both type 1 diabetes (T1D) and type 2 diabetes (T2D) [1, 2]. It is highly necessary to preserve β-cell function and expand β-cell mass for diabetes treatment. Glucagon-like peptide-1- (GLP-1-) based therapies, including GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, have several beneficial effects on pancreatic β-cells, including upregulating insulin gene transcription and biosynthesis, potentiating glucose-stimulated insulin secretion, and promoting β-cell regeneration by promoting β-cell proliferation, inhibiting β-cell apoptosis, and inducing stem cells to differentiate into β-cells [3, 4]. Recent researches have proven that GLP-1 overexpression or GLP-1 receptor agonists promoted β-cell regeneration via α- to βcell transdifferentiation [5,6,7]. Whether GLP-1-based therapy has similar effects on βcell protection, especially for β-cell regeneration in T1D, needs to be determined, and which therapy should be combined with GLP-1 should be evaluated
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