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

• Published in: Life sciences (1973) Vol. 295; p. 120382
• Main Authors: Rathwa, Nirali, Parmar, Nishant, Palit, Sayantani Pramanik, Patel, Roma, Bhaskaran, Ravi Sankar, Ramachandran, A.V., Begum, Rasheedunnisa
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 15.04.2022
• Subjects: Animals; Blood Glucose - metabolism; Caloric Restriction; Calorie restriction; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Type 2 - diet therapy; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - physiopathology; Diet, High-Fat; Disease Models, Animal; gamma-Aminobutyric Acid - metabolism; gamma-Aminobutyric Acid - pharmacology; Insulin - metabolism; Insulin Resistance - physiology; Insulin-Secreting Cells - metabolism; Male; Mice; Mice, Inbred C57BL; Obesity; Streptozocin - pharmacology; Type 2 diabetes; β-Cell regeneration; γ-Aminobutyric acid; Type 2 diabetes; Obesity; T2D; HFD; FBG; TC; CR; HDL; γ-Aminobutyric acid; TG; LDL; Calorie restriction; STZ; GABA; β-Cell regeneration; BMI
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2022.120382

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. •CR + GABA showed reduced FBG levels, improved lipid profile and insulin sensitivity•Improved transcript expressions of glucoregulatory and lipid metabolism markers•Enhanced mitochondria biogenesis markers and complex activities•Significant reduction in apoptotic marker•Significant increase in proliferation and neogenesis markers