Gamma-aminobutyric acid (GABA) and glucagon-like peptide-1 (GLP-1) improve rodent β cell survival and function. In human β cells, GABA exerts stimulatory effects on proliferation and anti-apoptotic effects, whereas GLP-1-based drugs have only limited effects on proliferation. We previously demonstrated that GABA and sitagliptin, 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 cells. 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, sitagliptin, or both. The oral administration of either GABA or sitagliptin ameliorated blood glucose levels, increased transplanted human β cell mass and plasma human insulin levels. However, combined administration of the drugs generated significantly superior results in all these responses, as compared to monotherapy. Proliferation and/or regeneration, improved by the combination, were demonstrated by increased Ki67+, pancreatic and duodenal homeobox-1 (PDX-1+), or Nkx6.1+ β cell numbers. Protection against apoptosis was also significantly improved by the combined therapy. GABA and GLP-1 in combination notably increased Akt phosphorylation and insulin secretion, as well as the expression of sirtuin-1 and α-Klotho, both of which have been reported to have protective effects on β-cells. Our study indicates that combined use of GABA and sitagliptin produced greater therapeutic benefits, which was likely due to an enhancement of β cell proliferation and a decrease of apoptosis.


W. Liu: None. T. Jin: None. Q. Wang: None.


National Natural Science Foundation of China (81570518, 81630020); JDRF (2-SRA-2017-64-G-R to Q.W., T.J.), (2-SRA-2015-64 to Q.W., T.J.); Canadian Diabetes Association (OG-3-13-4066 to Q.W.)

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