Combined Use Of Gaba And Sitagliptin Promotes Human Beta-Cell Proliferation And Reduces Apoptosis

gamma-Aminobutyric acid (GABA) and glucagon-like peptide-1 receptor agonist (GLP-1RA) improve rodent beta-cell survival and function. In human beta-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 beta-cell protective effect in mice islets. However, it remains unclear whether this combination has similar effects on human beta-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 beta-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(+) beta-cell numbers. Protection against apoptosis was also significantly improved by the drug combination. The expression level of a-Klotho, a protein with protective and stimulatory effects on beta 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 beta-cell proliferation and a decrease in apoptosis.