The Schizophrenia Risk Gene Tmem108 Regulates Glucose Metabolism Homeostasis

Background: Schizophrenia(SCZ)is a severe psychiatric disease affected by genetic factors and environmental contributors,SCZ affects about 1.0% of the world’s population,with devastating consequences for affected individuals and their families.SCZ is typically present in the young population.The etiology of SCZ is not clear,but there is evidence that genetic factors are the main cause of SCZ.Transmembrane protein 108(Tmem108)is a susceptible gene associated with multiple psychiatric diseases,including SCZ.and premorbid abnormality of glucose metabolism is one of the SCZ characteristics supposed to contribute to the disease’s pathological process.Moreover,Tmem108 mutant mice exhibit SCZ-like behaviors in the measurement of sensorimotor gating.However,it is unknown whether Tmem108 regulates glucose metabolism homeostasis while it involves SCZ pathophysiological process.Results: In this research,We performed relevant behavioral experiments and found that Tmem108 mutant mice exhibited glucose intolerance,insulin resistance,and disturbed metabolic homeostasis.In the metabolic cage experiment,Food and oxygen consumption decreased,and urine production increased,accopanied by weak fatigue resistance in the mutant mice.Simultaneously,we detected the expression of metabolism-related genes in Tmem108 mutant mice,the glucose metabolic pathway was enhanced,and lipid metabolism decreased in the mutant mice,consistent with the elevated respiratory exchange ratio(RER).Furthermore,metformin(Met)is the firstline treatment for Type 2 diabetes mellitus(T2DM).Metformin attenuated plasma glucose levels and improved sensorimotor gating in Tmem108 mutant mice.Conclusions: Abnormal glucose homeostasis emerges from the illness onsetin SCZ,indicating that SCZ patients are at high risk of diabetes mellitus(DM).For many complicated diseases,including SCZ and DM,there is no applicable in clinical genetic marker to early detect them in recent years on SCZ and DM susceptibility genes or loci reported more,but the genes associated with these two diseases is less,its mechanism is unclear.Here,the newly discovered common susceptibility gene Tmem108 for SCZ and DM may be a candidate gene for SCZ and T2 D comorbidity,which provides some theoretical proof for the common biological mechanism of the two diseases.