GABA Promotes Human β-Cell Proliferation and Modulates Glucose Homeostasis

Abstract

γ-Aminobutyric acid (GABA) exerts protective and regenerative effects on mouse islet β-cells. However, in humans it is unknown whether it can increase β-cell mass and improve glucose homeostasis. To address this question, we transplanted a suboptimal mass of human islets into immunodeficient NOD-scid-γ mice with streptozotocin-induced diabetes. GABA treatment increased grafted β-cell proliferation, while decreasing apoptosis, leading to enhanced β-cell mass. This was associated with increased circulating human insulin and reduced glucagon levels. Importantly, GABA administration lowered blood glucose levels and improved glucose excursion rates. We investigated GABA receptor expression and signaling mechanisms. In human islets, GABA activated a calcium-dependent signaling pathway through both GABA A receptor and GABA B receptor. This activated the phosphatidylinositol 3-kinase–Akt and CREB–IRS-2 signaling pathways that convey GABA signals responsible for β-cell proliferation and survival. Our findings suggest that GABA regulates human β-cell mass and may be beneficial for the treatment of diabetes or improvement of islet transplantation.

Immunological GABAergic interactions and therapeutic applications in autoimmune diseases

“…GABA considerably improved islet-cell survival in vitro. Moreover, it protected islet cells against apoptosis induced by cytokines [55], as well as rapamycin, tacrolimus, and mycophenolate mofetil [34]. As noted previously, these protective effects appear dependent on increased SIRT1 [38].…”

“…A major limitation of clinical islet transplantation is that the majority of islets die soon after transplantation due to a combination of factors; most notably hypoxia and an acute inflammatory response [52][53][54]. In studies with human cells, we demonstrated that GABA markedly reduced islet-cell apoptosis in culture, and stimulated insulin production [34,55]. Islet cells die spontaneously in culture, and commonly used immunosuppressive drugs further impair islet-cell survival [34,56].…”

Baclofen Protects Primary Rat Retinal Ganglion Cells from Chemical Hypoxia-Induced Apoptosis Through the Akt and PERK Pathways

“…Numerous studies have shown that the phosphatidylinositol 3-kinase–Akt (PI3K/AKT) signaling pathway plays a major role in cell apoptosis (Tu et al, 2010; Shilpa et al, 2013; Purwana et al, 2014; Di et al, 2015; Liu et al, 2015). The specific involvement of the GABA B receptor in Akt activation has been investigated in several types of cells.…”

Vitamin D3 supplementation increases insulin level by regulating altered IP3 and AMPA receptor expression in the pancreatic islets of streptozotocin-induced diabetic rat

“…Insulin secretion is controlled by a variety of neurotransmitters and hormones [1][2][3]. The insulin-secreting pancreatic β cells share many features with other neuroendocrine cells.…”