Liangbiao Gu1,2, Xiaona Cui1,3, Xiafang Lin1, Jin Yang1,3, Rui Wei1,3, Tianpei Hong4,5, Kun Yang6. 1. Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, 100191, China. 2. Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China. 3. Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, 100191, China. 4. Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, 100191, China. tpho66@bjmu.edu.cn. 5. Clinical Stem Cell Research Center, Peking University Third Hospital, Beijing, 100191, China. tpho66@bjmu.edu.cn. 6. Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, 100191, China. yangkun@bjmu.edu.cn.
Abstract
AIMS: To investigate whether treatment with γ-aminobutyric acid (GABA) alone or in combination with glucagon receptor (GCGR) monoclonal antibody (mAb) exerted beneficial effects on β-cell mass and α-cell mass, and to explore the origins of the regenerated β-cells in mice with type 1 diabetes (T1D). METHODS: Streptozotocin (STZ)-induced T1D mice were treated with intraperitoneal injection of GABA (250 μg/kg per day) and/or REMD 2.59 (a GCGR mAb, 5 mg/kg per week), or IgG dissolved in PBS for 8 weeks. Plasma hormone levels and islet cell morphology were evaluated by ELISA and immunofluorescence, respectively. The origins of the regenerated β-cells were analyzed by double-immunostaining, α-cell lineage-tracing and BrdU-tracing studies. RESULTS: After the 8-week treatment, GABA or GCGR mAb alone or in combination ameliorated hyperglycemia in STZ-induced T1D mice. GCGR mAb upregulated plasma insulin level and increased β-cell mass, and GABA appeared to have similar effects in T1D mice. However, combination treatment did not reveal any additive or synergistic effect. Interestingly, the GCGR mAb-induced increment of plasma glucagon level and α-cell mass was attenuated by the combined treatment of GABA. In addition, duct-derived β-cell neogenesis and α-to-β cell conversion but not β-cell proliferation contributed to the increased β-cell mass in T1D mice. CONCLUSION: These results suggested that GABA attenuated α-cell hyperplasia but did not potentiates β-cell regeneration induced by GCGR mAb in T1D mice. Our findings provide novel insights into a combination treatment strategy for β-cell regeneration in T1D.
AIMS: To investigate whether treatment with γ-aminobutyric acid (GABA) alone or in combination with glucagon receptor (GCGR) monoclonal antibody (mAb) exerted beneficial effects on β-cell mass and α-cell mass, and to explore the origins of the regenerated β-cells in mice with type 1 diabetes (T1D). METHODS: Streptozotocin (STZ)-induced T1D mice were treated with intraperitoneal injection of GABA (250 μg/kg per day) and/or REMD 2.59 (a GCGR mAb, 5 mg/kg per week), or IgG dissolved in PBS for 8 weeks. Plasma hormone levels and islet cell morphology were evaluated by ELISA and immunofluorescence, respectively. The origins of the regenerated β-cells were analyzed by double-immunostaining, α-cell lineage-tracing and BrdU-tracing studies. RESULTS: After the 8-week treatment, GABA or GCGR mAb alone or in combination ameliorated hyperglycemia in STZ-induced T1D mice. GCGR mAb upregulated plasma insulin level and increased β-cell mass, and GABA appeared to have similar effects in T1D mice. However, combination treatment did not reveal any additive or synergistic effect. Interestingly, the GCGR mAb-induced increment of plasma glucagon level and α-cell mass was attenuated by the combined treatment of GABA. In addition, duct-derived β-cell neogenesis and α-to-β cell conversion but not β-cell proliferation contributed to the increased β-cell mass in T1D mice. CONCLUSION: These results suggested that GABA attenuated α-cell hyperplasia but did not potentiates β-cell regeneration induced by GCGR mAb in T1D mice. Our findings provide novel insights into a combination treatment strategy for β-cell regeneration in T1D.
Authors: Ashley Untereiner; Shaaban Abdo; Alpana Bhattacharjee; Himaben Gohil; Farzaneh Pourasgari; Neke Ibeh; Mi Lai; Battsetseg Batchuluun; Anthony Wong; Nicholas Khuu; Ying Liu; Dana Al Rijjal; Neil Winegarden; Carl Virtanen; Beverley A Orser; Over Cabrera; Gabor Varga; Jonathan Rocheleau; Feihan F Dai; Michael B Wheeler Journal: FASEB J Date: 2018-12-03 Impact factor: 5.191