Excessive loss of islet beta cells is a major cause for the development of type 2 diabetes (T2D) , and seeking an effective method to enhance beta cell proliferation is a promising therapeutic strategy for T2D. In this study, we examined whether combined therapy of GABA and sitagliptin is effective in promoting beta cell proliferation and ameliorating the impairment of beta-cell function caused by high-fat diet (HFD) feeding in mice. Male C57BL/6J mice were fed with normal chow diet, HFD, or HFD combined with GABA, sitagliptin, or both drugs. Daily oral drug administration was initiated one week before HFD and maintained for two weeks. After two weeks of intervention, we found that GABA or sitagliptin administration ameliorated the impairment of glucose tolerance induced by HFD. This was associated with improved insulin secretion in vivo. Notably, combined administration of GABA and sitagliptin significantly enhanced these effects as compared to each of the monotherapies. Combined GABA and sitagliptin was superior at increasing beta-cell mass, and associated Ki67+ and PDX-1+ beta-cell counts. In addition, we found that HFD-induced compensatory beta-cell proliferation was associated with increased activation of unfolded protein response (UPR) , as indicated by BiP expression. This could be an important mechanism of compensatory beta-cell proliferation, and beta cells treated with GABA and sitagliptin showed greater UPR activation. Our results suggest that the combined use of these agents produces superior therapeutic outcomes.


Z. Wang: None. Q. Wang: None. L. Fan: None. Y. Ni: None. A. Ma: None. D. Wu: None. Q. Cui: None. Y. Zhou: None. Y. Lou: None. G. J. Prud'homme: None.


The National Natural Science Foundation of China (No.81630020, 81570518, and 81800751) , the Ministry of Science and Technology (No. 2017ZX09303001) , Shanghai Science and Technology Department (No. 2017ZX09303001) , and Juvenile Diabetes Research Foundation (JDRF, 2-SRA-2017-64-G-R to G P, QW, and T J; and 2-SRA-2015-64 to Q W, G P and T J) .

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