Calorie restriction potentiates the therapeutic potential of GABA in managing type 2 diabetes in a mouse model

Abstract

Dysfunctional adipocytes/β-cells advance type 2 diabetes (T2D). Calorie restriction (CR) improves insulin sensitivity and fasting blood glucose (FBG) levels, while γ-aminobutyric acid (GABA) exerts regenerative effects. The impact of therapies was assessed by a high-fat diet (HFD) + streptozotocin (STZ) induced T2D mouse model. The mice were fed a CR diet (30% reduction of HFD) and treated with GABA (2.5 mg/kg i.p) for 5 weeks. Standard protocols were used to assess metabolic parameters. The mRNA expression was monitored by SYBR Green-qPCR in the targeted tissues. Oxygen consumption rate in the mitochondrial complexes was evaluated by oxytherm clark-type oxygen electrode. Pancreatic β-cell regeneration and apoptosis were analysed by immunohistochemistry. CR + GABA combination therapy showed improved metabolic parameters compared to the monotherapies. We have observed improved transcript levels of G6Pase, PEPCK, Glycogen Phosphorylase, GLUT2 and GCK in liver; ACC and ATGL in adipose tissue. Also increased SIRT-1, PGC-1α and TFAM expression; up-regulated mitochondrial complexes I-III activities were observed. We have seen increased BrdU/Insulin and PDX1/Ngn3/Insulin co-positive cells in CR + GABA treated group with a reduction in apoptotic marker (TUNEL/Insulin co-positive cells). Our results indicate that CR in combination with GABA ameliorates T2D in HFD + STZ treated mice by GABA induced β-cell regeneration, and CR mediated insulin sensitivity.