The Role of GABA Shunt and Hepatic GABA Transporters on Hyperinsulinemia and Insulin Resistance

Abstract

Hepatic lipid accumulation, a hallmark of type 2 diabetes (T2D), increases hepatic gamma-aminobutyric acid (GABA) production through the GABA shunt and release by electrogenic GABA transporters. Inhibition of either GABA production or GABA release limits obesity-associated hyperinsulinemia and insulin resistance in obese mice. In turn, we assessed the role of GABA producing enzymes within the GABA shunt and GABA transporters (TAUT, CRT, BGT1 and GAT2) in development of hyperinsulinemia and insulin resistance in diet induced obese mice. We established that liver slice GABA release was increased in obesity, and positively associated with serum insulin and insulin tolerance test area under the curve (ITT AUC). To understand the regulation of GABA production we showed that media GABA was positively associated with Aldh5a1 mRNA and negatively associated with Abat mRNA. In turn, Aldh5a1 mRNA expression was positively associated with 4h fasted insulin, HOMA-IR, and ITT AUC, while Abat mRNA was negatively associated with 4h fasted insulin, and ITT AUC. Because we have previously shown that SLC6A6 was associated with worsened insulin resistance and SLC6A12 was associated with improved insulin sensitivity in humans, we created adeno associated virus (AAVs) to induce hepatic overexpression of hSLC6A6 and hSLC6A12 in mice. Surprisingly, after 3 weeks of HFD exposure, mice expressing hSLC6A6 had improved insulin sensitivity as assessed by ITT or HOMA-IR. Still despite the improved insulin sensitivity, both hSLC6A6 and hSLC6A12 expression worsened glucose tolerance in 3-week high fat diet fed mice. Together the data presented here supports a role for the GABA shunt and electrogenic GABA transporters in regulating glucose homeostasis.