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

• Published in: Journal of endocrinology Vol. 248; no. 2; pp. 133 - 143
• Main Authors: Liu, Wenjuan, Lau, Harry Kevin, Son, Dong Ok, Jin, Tianru, Yang, Yehong, Zhang, Zhaoyun, Li, Yiming, Prud’homme, Gerald J, Wang, Qinghua
• Format: Journal Article
• Language: English
• Published: England Bioscientifica Ltd 01.02.2021
• Subjects: Animals; Apoptosis - drug effects; Blood Glucose - drug effects; Cell Proliferation - drug effects; Diabetes Mellitus - drug therapy; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Dipeptidyl-Peptidase IV Inhibitors - therapeutic use; Drug Evaluation, Preclinical; Drug Therapy, Combination; GABA Agents - pharmacology; GABA Agents - therapeutic use; gamma-Aminobutyric Acid - pharmacology; gamma-Aminobutyric Acid - therapeutic use; Humans; Islets of Langerhans - drug effects; Islets of Langerhans Transplantation; Male; Mice; Mice, Inbred NOD; Middle Aged; Sitagliptin Phosphate - pharmacology; Sitagliptin Phosphate - therapeutic use; GABA; type 1 diabetes; human islet; sitagliptin; β-cell
• ISSN: 0022-0795; 1479-6805
• DOI: 10.1530/JOE-20-0315

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, the combined administration of the drugs generated significantly superior results in all these responses, as compared to the monotherapy with either one of them. The 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.