Klotho’s Role in GABA-Stimulated Pancreatic Beta Cell Protection and Stimulation

The anti-aging Klotho protein is induced by GABA treatment and exerts stimulatory and protective effects on beta cells of the pancreas

GABA (gamma aminobutyric acid) is a systemic therapy that can prevent or improve type 1 diabetes by suppressing the autoimmune response and stimulating beta cells in the pancreas. It increases insulin secretion in beta cells and prevents apoptosis. How GABA mediates the effects is not clear. Klotho was hypothesized to be involved. It is a multifunctional protein that is expressed in kidneys, brains, pancreatic beta-cells and other tissues. It can be soluble or cell-bound. Klotho knockouts show accelerated aging in mice, and Klotho levels decrease with age, diabetes, and renal disease. We report here that GABA increased the circulating levels Klotho significantly in streptozotocin-induced diabetes. GABA increased Klotho levels in the kidneys and islets of STZ-treated mice as well as normal mice’s islet of Langerhans. In vitro GABA stimulated the production and secretion Klotho from human islet cells. Knockdown of Klotho using siRNA in INS-1E cells insulinoma abrogated GABA’s protective effect against STZ toxicity. After KD, the soluble Klotho reversed Klotho’s effects. In human islet cell, soluble Klotho stimulated insulin secretion and proliferation. Both GABA and Klotho inhibit the NF-kB pathway that triggers beta cell apoptosis. Klotho KD augmented NFKB p65 expression and prevented GABA from blocking NFKB activation. This is the very first report to show that GABAergic stimuli increase Klotho. Klotho stimulated and protected beta cells, and the lack of Klotho was reversed with soluble Klotho. These findings are important for treating T1D.


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