The Mitigation Effect And Mechanism Of Akkermansia Muciniphila Subtype On Hyperglycemia And Insulin Resistance Induced By Olanzapine In Mice

Background and ObjectivesAtypical antipsychotic olanzapine is widely used to treat mental illness such as schizophrenia and bipolar disorders.Olanzapine has severe metabolic side effects,including increased food intake,weight gain,fatty liver,dyslipidemia,and hyperglycemia.These factors ultimately lead to an increased risk of type 2 diabetes and cardiovascular disease,which are the leading causes of death in schizophrenia.And there are reports that patients with obesity signs can aggravate the side effects of olaczapine.The humau intestinal flora is composed of about 1013 to 1014 of bacteria.They live in the gastrointestinal tract and symbiotic with the host.Akkermansia muciniphila(A.muciniphila/Akk)is a mammalian anaerobic bacteri-um that can be cultured in vitro.Many studies have found that the abundance of A.muciniphila is reduced in models of obesity and type 2 diabetes.And in animal experiments,it has been found that intragastric treatment of A.muciniphila in mice can reduce obesity caused by high-fat diets and improve metabolic disorders,including hyperglycemia,insulin resistance and hyperlipidemia.Our team’s research demonstrated that the Akkermansia muciniphila subtype(A.muciniphilasub)significantly reduced weight gain and improved spatial memory in mice on high-fat diet.Therefore,the purpose of this study was to investigate whether hyperglycemia and insulin resistance caused by olanzapine are related to diet,and to explore whether A.muciniphilasub can improve the side effects ofolanzapine,especially hyperglycemia and insulin resistance.Methodssixty 5-week-old female C57BL/6 mice were maintained in a 12:12h light-dark cycle,with one week adaptation period.After adaptation,30 mice were randomly converted to high-fat diet(HFD)for 8 weeks,the remaining 30 only maintained a normal chow diet(NCD).After 8 weeks,an oral glucose tolerance test(OGTT)was performed on 60 mice to assess the difference in glucose metabolism between NCD and HFD.Thereafter,all mice were orally administered with olanzapine(5mg/kg/d)or vehicle in the morning and PBS or A.muciniphilasub solution in the afternoon for 16 weeks.So for the HFD group,it is divided into three groups,including VEH-PBS,OLZ-PBS and OLZ-Akk.The NCD group is also divided into the above three groups.The body weight and food intake of the mice were measured weekly.After 16 weeks of treatment,the mice were fasted overnight and euthanized by cervical dislocation after intraperitoneal injection of sodium pentobarbital.Collect mouse tissues(blood,liver,fat,colon)for subsequent experiments.ResultsAfter olanzapine gavage,mice on both the normal chow diet and high fat diet developed hyperglycemia and insulin resistance.A.muciniphilasub treatment significantly reduced hyperglycemia and insulin resistance.A.muciniphilasub reduces the weight gain caused by olanzapine by increasing the activity of mice.At the same time,A.muciniphilasub repaired the intestinal barrier damage in mi-ce,further reduced the inflammatory mediators interleukin-6(IL-6),tumor necrosis factor-α(TNF-α)and CD68,and reduced the expression of insulin resistance-related proteins adipose triglyceride lipase(ATGL)and protein tyrosine phosphatase 1B(PTP1B).The expression of Glucose-6-phosphatase(G6Pase)and phosphoenolpyruvate carboxykinase(PEPCK),the key enzymes of gluconeogenesis,was significantly reduced after A.muciniphilasub treatment,which improved the development of hyperglycemia and insulin resistance in mice.ConclusionAfter olanzapine gavage,mice on both the normal chow diet and high fat diet developed hyperglycemia and insulin resistance.A.muciniphilasub treatment significantly reduced hyperglycemia and insulin resistance.A.muciniphiasub reduces the weight gain caused by olanzapine by increasing the activity of mice.At the same time,A.muciniphilasub repaired the intestinal barrier damage in mice,further reduced the inflammatory mediators IL-6,TNF-α and CD68,and reduced the expression of insulin resistance-related proteins ATGL and PTP1B.More directly,the expression of G6Pase and PEPCK,the key enzymes of gluconeogenesis,was greatly reduced after A.muciniphilasub treatment,which improved the development of hyperglycemia and insulin resistance in mice.