Resistance Exercise Training Attenuates the Loss of Endogenous GLP-1 Receptor in the Hypothalamus of Type 2 Diabetic Rats

Abstract

The aim of this study was to investigate the effects of resistance exercise training on hypothalamic GLP-1R levels and its related signaling mechanisms in T2DM. The animals were separated into three groups: a non-diabetic control (CON), diabetic control (DM), and diabetic with resistance exercise (DM + EXE) group. The resistance exercise training group performed ladder climbing (eight repetitions, three days per week for 12 weeks). Body weight was slightly lower in the DM + EXE group than the DM group, but difference between the groups was not significant. Food intake and glucose were significantly lower in the DM + EXE group than in the DM group. The blood insulin concentration was significantly higher and glucagon was significantly lower in the DM + EXE group. The DM + EXE group in the hypothalamus showed significant increases in GLP-1R mRNA, protein kinase A (PKA), glucose transporter 2 (GLUT2), and protein kinase B (AKT) and significant decrease in protein kinase C-iota (PKC-iota). Antioxidant enzymes and apoptosis factors were significantly improved in the DM + EXE group compared with the DM group in the hypothalamus. The results suggest that resistance exercise contributes to improvements the overall health of the brain in diabetic conditions.

Keywords: glucagon-like pepetide-1 receptor; glucose transporter 2; hypothalamus; resistance exercise; type 2 diabetes.

Figure 1

Schematic of experimental design. T2DM: type 2 diabetes mellitus; LETO: Long-Evans Tokushima Otsuka; OLETF: Otsuka Long-Evans Tokushima Fatty; GLP-1R: Glucagon-like peptide-1 receptor; GLUT2: glucose transporter 2; AMPK: adenosine monophosphate-activated protein kinase; AKT: protein kinase B; PKC-iota: protein kinase C-iota; PKA: protein kinase A; Epac2: exchange protein directly activated by cAMP 2; SOD: superoxide dismutase; Bax: BCL2-associated X protein; Bcl-2:. B-cell lymphoma 2.

Figure 2

Resistance exercise training decreased food intake, glucose, and glucagon levels and increased insulin levels in T2DM rats. All data are presented as the Mean ± SD. (A) body weight, (B) food intake, (C) glucose, (D) insulin, (E) glucagon. CON: non-diabetic control group; DM: diabetic control group; DM + EXE: diabetic with resistance exercise training group. ^{a, b, c} Different letters indicate a significant difference between groups (p < 0.05).

Figure 3

Resistance exercise training inhibited loss of GLP-1R and enhanced signaling pathway in the hypothalamus of T2DM rats by decreasing PKC-iota level. All data are presented as the Mean ± SD. (A) glucagon-like peptide-1 receptor mRNA (GLP-1R mRNA), (B) protein kinase C-iota (PKC-iota), (C) protein kinase A (PKA), (D) representative western blotting band, (E) exchange protein directly activated by cAMP 2 (Epac2), (F) phosphorylation protein kinase B/total protein kinase B (P-AKT/T-AKT). CON: non-diabetic control group; DM: diabetic control group; DM + EXE: diabetic with resistance exercise training group. ^{a, b, c} Different letters indicate a significant difference between groups (p < 0.05).

Figure 4

Resistance exercise training increased GLUT2 and attenuated AMPK protein levels in the hypothalamus of T2DM rats. All data are presented as the Mean ± SD. (A) representative western blotting band, (B) glucose transporter 2 (GLUT2), (C) phosphorylation-adenosine monophosphate-activated protein kinase (P-AMPK)/total-adenosine monophosphate-activated protein kinase (T-AMPK). CON: non-diabetic control group; DM: diabetic control group; DM + EXE: diabetic with resistance exercise training group. ^{a, b, c} Different letters indicate a significant difference between groups (p < 0.05).

Figure 5

Resistance exercise training improved antioxidant enzymes and apoptosis protein levels such as, caspase-3 and Bax/Bcl-2 in the hypothalamus of T2DM rats. All data are presented as the Mean±SD. (A) representative western blotting band, (B) superoxide dismutase 1 (SOD1), (C) superoxide dismutase 2 (SOD2), (D) Caspase 3, (E) BCL2-associated X protein (Bax), (F) B-cell lymphoma 2 (Bcl-2). CON: non-diabetic control group; DM: diabetic control group; DM + EXE: diabetic with resistance exercise training group. ^{a, b, c} Different letters indicate a significant difference between groups (p < 0.05). ns: not significant.

Figure 6

Schematic diagram of the mechanisms for the resistance exercise in hypothalamus of type 2 diabetic rats.