Combined Oral Administration of GABA and DPP-4 Inhibitor Prevents Beta Cell Damage and Promotes Beta Cell Regeneration in Mice

Abstract

γ-aminobutyric acid (GABA) or glucagon-like peptide-1 based drugs, such as sitagliptin (a dipeptidyl peptidase-4 inhibitor), were shown to induce beta cell regenerative effects in various diabetic mouse models. We propose that their combined administration can bring forth an additive therapeutic effect. We tested this hypothesis in a multiple low-dose streptozotocin (STZ)-induced beta cell injury mouse model (MDSD). Male C57BL/6J mice were assigned randomly into four groups: non-treatment diabetic control, GABA, sitagliptin, or GABA plus sitagliptin. Oral drug administration was initiated 1 week before STZ injection and maintained for 6 weeks. GABA or sitagliptin administration decreased ambient blood glucose levels and improved the glucose excursion rate. This was associated with elevated plasma insulin and reduced plasma glucagon levels. Importantly, combined use of GABA and sitagliptin significantly enhanced these effects as compared with each of the monotherapies. An additive effect on reducing water consumption was also observed. Immunohistochemical analyses revealed that combined GABA and sitagliptin therapy was superior in increasing beta cell mass, associated with increased small-size islet numbers, Ki67+ and PDX-1+ beta cell counts; and reduced Tunel+ beta cell counts. Thus, beta cell proliferation was increased, whereas apoptosis was reduced. We also noticed a suppressive effect of GABA or sitagliptin on alpha cell mass, which was not significantly altered by combining the two agents. Although either GABA or sitagliptin administration delays the onset of MDSD, our study indicates that combined use of them produces superior therapeutic outcomes. This is likely due to an amelioration of beta cell proliferation and a decrease of beta cell apoptosis.

GABA promotes β‐cell proliferation, but does not overcome impaired glucose homeostasis associated with diet‐induced obesity

“…In contrast, after T2D development and great b-cell loss, the effects of GABA on b-cell mass and function could very well be more evident. Mouse models with obvious b-cell loss (e.g., STZ treatment) (16,17,38,59) could provide a better alternative to observe the beneficial effects of GABA on impaired glucose tolerance. Therefore, the effectiveness of GABA in the treatment of T2D in its various stages of pathophysiologic development merits further investigation.…”

Spironolactone Protects against Diabetic Cardiomyopathy in Streptozotocin-Induced Diabetic Rats

“…Left ventricles were fixed with 4% paraformaldehyde overnight and then embedded in paraffin. Expression of nitrotyrosine (2459610, Millipore, Billerica, MA), collagen 1 (ab34710, Abcam), TGF- β 1 (sc-146, Santa Cruz Biotechnology Inc.), TNF- α (ab6671, Abcam), and F4/80 (70076, Cell Signaling Technology) on tissue sections (5 mm) was examined by immunohistochemical analysis as previously described [ 32 ]. The dilution factor was 1 : 100, 1 : 200, 1 : 100, 1 : 250, and 1 : 100, respectively.…”

Homotaurine Treatment Enhances CD4+ and CD8+ Regulatory T Cell Responses and Synergizes with Low-Dose Anti-CD3 to Enhance Diabetes Remission in Type 1 Diabetic Mice

“…The few residual b-cells in the islets of mice that had been severely diabetic make this model ill-suited for studies of GABA-R agonist's ability to induce b-cell replication because these agonists increase the frequency of replicative b-cells by only about 2-3-fold over the baseline level of ,1% in adult mice [reviewed in (68)]. However, we, and other groups, have observed GABA-enhanced b-cell replication in newly diabetic mice, which generally have a larger residual b-cell mass (11,26,69). In this study, we observed that homotaurine enhanced the replication of b-cells severalfold in human islet xenografts, similar to past observations of GABA's actions on human islet xenografts (26,27).…”