Combined use of GABA and sitagliptin promotes human β-cell proliferation and reduces apoptosis

in Journal of Endocrinology
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  • 1 W Liu, Division of Endocrinology and Metabolism, Huashan hospitall, Fudan University, Shanghai, China
  • 2 H Lau, Division of Endocrinology and Metabolism, the Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, Toronto, Canada
  • 3 D Son, Division of Endocrinology and Metabolism, the Keenan Research Centre in the Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, Toronto, Canada
  • 4 T Jin, Department of Physiology, University of Toronto, Toronto, Canada
  • 5 Y Yang, Division of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
  • 6 Z Zhang, Division of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
  • 7 Y Li, Division of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China
  • 8 G Prudhomme, Department of Laboratory Medicine and Pathobiology, Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, University of Toronto, Toronto, Canada
  • 9 Q Wang, Department of Endocrinology and Metabolism, Huashan Hospital, Fudan University, Shanghai, China

Correspondence: Qinghua Wang, Email: Qinghua.Wang@unityhealth.to

γ-aminobutyric acid (GABA) and glucagon-like peptide-1 receptor agonist (GLP-1RA) improve rodent β-cell survival and function. In human β-cells, GABA exerts stimulatory effects on proliferation and anti-apoptotic effects, whereas GLP-1RA drugs have only limited effects on proliferation. We previously demonstrated that GABA and sitagliptin (Sita), a dipeptidyl peptidase-4 inhibitor which increases endogenous GLP-1 levels, mediated a synergistic β-cell protective effect in mice islets. However, it remains unclear whether this combination has similar effects on human β-cell. To address this question, we transplanted a suboptimal mass of human islets into immunodeficient NOD-scid-gamma mice with streptozotocin-induced diabetes, and then treated them with GABA, Sita, or both. The oral administration of either GABA or Sita ameliorated blood glucose levels, increased transplanted human β-cell counts and plasma human insulin levels. Importantly, combined administration of the drugs generated significantly superior results in all these responses, as compared to the monotherapy with either one of them. Proliferation and/or regeneration, improved by the combination, were demonstrated by increased Ki67+, PDX-1+, or Nkx6.1+ β-cell numbers. Protection against apoptosis was also significantly improved by the drug combination. The expression level of α-Klotho, a protein with protective and stimulatory effects on β cells, was also augmented. Our study indicates that combined use of GABA and Sita produced greater therapeutic benefits, which are likely due to an enhancement of β-cell proliferation and a decrease in apoptosis.

 

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