The Role Of Mitochondria In The Amelioration Of Muscular Lipotoxicity By Early Insulin Initiation

Part 1 Insulin restores UCP3 activity and decreases energy surfeit to alleviate lipotoxicity in skeletal musclePurpose Early insulin regimen ameliorates glucotoxicity but also lipotoxicity in type 2 diabetes;however,the underlying mechanism remains elusive.Here,we investigated the role of mitochondria in lipid regulation by early insulin administration in insulin-resistant skeletal muscle cellsMaterials and Methods Male C57BL/6 mice with 8-weeks of high-fat diet(HFD)were treated with insulin for 3 weeks,and L6 myotubes cultured with 24h-palmitate(PA)were incubated with insulin for another 12hResults Insulin facilitated systemic glucose disposal and attenuated muscular triglyceride accumulation in vivo.Recovered AMP-activated protein kinase(AMPK)phosphorylation,inhibited sterol-regulated element binding protein-1 c and increased carnitine palmitoyltransferase 1B expression were observed after insulin administration.Moreover,increased ATP concentration and cellular energy charge elicited by over-nutrition were suppressed by insulin.Despite maintaining respiratory complexes activities,insulin restored muscular uncoupling protein 3(UCP3)protein expression with the presence of PA in vivo and in vitro.In contrast,knockdown of UCP3 abrogated insulin-induced restoration of AMPK phosphorylation in vitro.Importantly,PA-induced UCP3 decrease could be blocked by the proteasome inhibitor MG 132,and insulin was identified to reduce UCP3 ubiquitination,thereby prohibiting its degradation.Conclusions Our findings,firstly from an energetic view,provided the mechanistic understanding in the promising effect of early insulin initiation on lipotoxicity;that is,insulin,via recovering UCP3 activity,alleviated energy surfeit and potentiated AMPK-mediated lipid homeostasis in skeletal muscle cells with exposure to PA and HFD.Part 2 Comparative efficacy of anti-diabetic agents on nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus:a systematic review and meta-analysis of randomized and non-randomized studiesBackground Nonalcoholic fatty liver disease(NAFLD)has a high prevalence in patients with type 2 diabetes mellitus(T2DM).In this study,we sought to provide a comprehensive assessment regarding the effects of anti-diabetic agents on NAFLD in patients with T2DM.Materials and Methods MEDLINE,EMBASE and the Cochrane Central Register of Controlled Trials were searched for randomized controlled trials(RCTs)with different anti-diabetic agents in T2DM.Observational trials were also recruited to expand our population.Hepatic fat content and liver histology were evaluated as primary outcomes.Pooled estimates were calculated using a fixed effect model.Results One thousand one hundred and ninety-six participants in 19 RCTs and 14 non-randomized studies were included.Evidence from RCTs and observational studies suggested that greater hepatic fat content reduction and improved liver histology were seen in thiazolidinediones for 12-72 weeks;glucagon-like peptide-1 receptor agonists had beneficial effects on hepatic fat content after 26-50 weeks intervention,and insulin/metformin combination with 3-7 months improved hepatic fat content.Initiating metformin or dapagliflozin showed no benefit on hepatic fat content or liver histology in 16-48 weeks.Besides,nateglinide for 18 months was reported in a small sample-size RCT to improve hepatic fat content and liver histology.Sitagliptin therapy of 1 year also provided benefit on nonalcoholic steatohepatitis score in an observational study.Conclusions For T2DM with NAFLD,administrating thiazolidinediones and glucagon-like peptide-1 receptor agonists seems to provide more identified advances in attenuating hepatic fat content.Further RCTs are warranted to assess the efficacy of various hypoglycemic agents on clinical outcomes associated with NAFLD in T2DM.