PMID- 37488560 OWN - NLM STAT- MEDLINE DCOM- 20230727 LR - 20230727 IS - 2662-7671 (Electronic) IS - 2662-7671 (Linking) VI - 23 IP - 1 DP - 2023 Jul 24 TI - Stevia (Stevia rebaudiana) extract ameliorates insulin resistance by regulating mitochondrial function and oxidative stress in the skeletal muscle of db/db mice. PG - 264 LID - 10.1186/s12906-023-04033-5 [doi] LID - 264 AB - BACKGROUND: Type 2 diabetes mellitus (T2DM), a growing health problem worldwide, is a metabolic disorder characterized by hyperglycemia due to insulin resistance and defective insulin secretion by pancreatic beta-cells. The skeletal muscle is a central organ that consumes most of the insulin-stimulated glucose in the body, and insulin resistance can damage muscles in T2DM. Based on a strong correlation between diabetes and muscles, we investigated the effects of stevia extract (SE) and stevioside (SV) on the skeletal muscle of diabetic db/db mice. METHODS: The mice were administered saline, metformin (200 mg/kg/day), SE (200 and 500 mg/kg/day), and SV (40 mg/kg/day) for 35 days. During administration, we checked the levels of fasting blood glucose twice a week and conducted the oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). After administration, we analyzed serum biochemical parameters, triglyceride (TG), total cholesterol (TC), insulin and antioxidant enzymes, and the cross-sectional area of skeletal muscle fibers of db/db mice. Western blots were conducted using the skeletal muscle of mice to examine the effect of SE and SV on protein expression of insulin signaling, mitochondrial function, and oxidative stress. RESULTS: SE and SV administration lowered the levels of fasting blood glucose, OGTT, and ITT in db/db mice. The administration also decreased serum levels of TG, TC, and insulin while increasing those of superoxide dismutase (SOD) and glutathione peroxidase (GPx). Interestingly, muscle fiber size was significantly increased in db/db mice treated with SE500 and SV. In the skeletal muscle of db/db mice, SE and SV administration activated insulin signaling by increasing the protein expression of insulin receptor substrate, Akt, and glucose transporter type 4. Furthermore, SE500 administration markedly increased the protein expression of AMP-activated protein kinase-alpha, sirtuin-1, and peroxisome proliferator-activated receptor-gamma coactivator-1alpha. SV administration significantly reduced oxidative stress by down-regulating the protein expression of 4-hydroxynonenal, heme oxygenase-1, SOD, and GPx. In addition, SE500 and SV administration suppressed the expression of apoptosis-related proteins in the skeletal muscle of db/db mice. CONCLUSION: SE and SV administration attenuated hyperglycemia in diabetic mice. Moreover, the administration ameliorated insulin resistance by regulating mitochondrial function and oxidative stress, increasing muscle fiber size. Overall, this study suggests that SE and SV administration may serve as a potential strategy for the treatment of diabetic muscles. CI - (c) 2023. The Author(s). FAU - Han, Jin-Young AU - Han JY AD - Institute for Aging and Clinical Nutrition Research, Gachon University, Seongnam-Si, 13120, Gyeonggi-Do, Korea. FAU - Park, Miey AU - Park M AD - Institute for Aging and Clinical Nutrition Research, Gachon University, Seongnam-Si, 13120, Gyeonggi-Do, Korea. mpark@gachon.ac.kr. AD - Department of Food and Nutrition, College of BioNano Technology, Gachon University, Seongnam-Si, 13120, Gyeonggi-Do, Korea. mpark@gachon.ac.kr. FAU - Lee, Hae-Jeung AU - Lee HJ AD - Institute for Aging and Clinical Nutrition Research, Gachon University, Seongnam-Si, 13120, Gyeonggi-Do, Korea. skysea@gachon.ac.kr. AD - Department of Food and Nutrition, College of BioNano Technology, Gachon University, Seongnam-Si, 13120, Gyeonggi-Do, Korea. skysea@gachon.ac.kr. LA - eng PT - Journal Article DEP - 20230724 PL - England TA - BMC Complement Med Ther JT - BMC complementary medicine and therapies JID - 101761232 RN - 0 (Blood Glucose) RN - 0 (Insulin) RN - EC 1.11.1.9 (Glutathione Peroxidase) RN - EC 1.15.1.1 (Superoxide Dismutase) SB - IM MH - Mice MH - Animals MH - *Insulin Resistance MH - *Diabetes Mellitus, Type 2/drug therapy MH - *Stevia/metabolism MH - Blood Glucose MH - *Diabetes Mellitus, Experimental/drug therapy MH - Insulin MH - Oxidative Stress MH - *Hyperglycemia MH - Muscle, Skeletal MH - Glutathione Peroxidase/metabolism MH - Mitochondria/metabolism MH - Superoxide Dismutase/metabolism PMC - PMC10367355 OTO - NOTNLM OT - Insulin resistance OT - Mitochondrial function OT - Muscle fiber size OT - Oxidative stress OT - Stevia rebaudiana OT - T2DM COIS- The authors declare that they have no conflicts of interest and have given their consent for this manuscript's scientific content and authorship. Experimental research and field studies on plants (either cultivated or wild) were performed in accordance with the relevant guidelines and legislation. This study was conducted in accordance with the guidelines stipulated by the Ministry of Food and Drug Safety for the Care and Use of Laboratory Animals. All experimental protocols were approved by the Institutional Animal Care and Use Committee of Gachon University for the Care and Use of Laboratory Animals (GIACUC-R2020012). This study is reported in accordance with ARRIVE guidelines for animal experiments. The authors declare no competing interests. EDAT- 2023/07/25 01:09 MHDA- 2023/07/27 06:42 PMCR- 2023/07/24 CRDT- 2023/07/24 23:43 PHST- 2022/12/22 00:00 [received] PHST- 2023/06/09 00:00 [accepted] PHST- 2023/07/27 06:42 [medline] PHST- 2023/07/25 01:09 [pubmed] PHST- 2023/07/24 23:43 [entrez] PHST- 2023/07/24 00:00 [pmc-release] AID - 10.1186/s12906-023-04033-5 [pii] AID - 4033 [pii] AID - 10.1186/s12906-023-04033-5 [doi] PST - epublish SO - BMC Complement Med Ther. 2023 Jul 24;23(1):264. doi: 10.1186/s12906-023-04033-5.