Study The Mechanism Of Menin Phosphorylation Mediated Pancreatic Beta Cell Function Regulation By GLP-1/PKA Signaling

Diabetes is a metabolic disease characterized by high blood glucose.Diabetes-induced hyperglycemia is mainly caused by defects in insulin secretion,insulin resistance,or both.Diabetic patients have long-term high blood glucose levels,which cause chronic damage to various tissues and lead to death due to multiple organ failure.Type 2 diabetes is an acquired type of diabetes.Long-term hyperglycemia causes proliferation of islet cells,exorbitant insulin secretion,and eventually damage to beta cells,resulting in reduced insulin secretion or insulin receptor resistance.Glucagon-like peptide-1(GLP-1)is a hormone secreted by endocrine cells at the end of the small intestine.In human,it is a peptide consisting of 29 amino acids with the function of promoting insulin secretion and pancreatic beta cells proliferation.Exendin-4 is a GLP-1 receptor agonist,which is reported to promote insulin secretion and lower blood glucose.It has become an important clinical drug for the treatment of type 2 diabetes.The short half-life of Exendin-4 is less than GLP-1,therefore,in our study,Exendin-4 was used to substitute GLP-1,and the GLP-1 pathway was activated to study the downstream mechanism.Menin,encoded by the Men1(multiple endocrine neoplasia type 1,Men1 in mice)gene whose loss-of-function mutations lead to inherited MEN1 syndrome,regulates cellular homeostasis of various endocrine organs by controlling gene transcription.Numerous studies have shown that menin is a pro-diabetic factor and ablation of Men1 leads to ameliorated diabetes in multiple rodent models.However,molecular mechanisms underlying how menin is involved in diabetes are not well understood.Menin also inhibits the development of endocrine tumors,by interacting with different proteins and altering their biological functions.The expression of Men1 gene can be regulated by phosphorylation and histone methylation modification.Menin and GLP-1 pathways play important but opposite roles in islet beta cells,with menin inhibiting and GLP-1 promoting beta cell function.In the current study,fewer people have reported how the GLP-1 pathway inhibits the function of menin.Our study shows that PKA(protein kinase A)which is affected by intracellular levels of c AMP(cyclic AMP)downstream of the GLP-1 pathway,interacts with menin.The GLP-1 pathway phosphorylates menin at Ser487 residue via PKA,and the inhibitory effect of menin on insulin expression is attenuated after phosphorylation of menin.Menin interacts with SUV39H1(suppressor variegation 3-9 homolog protein 1)and HDAC1(histone deacetylases 1)at the Ins1 gene locus to inhibit Ins1 transcription.Although phosphorylation of menin at Ser487 does not affect menin,SUV39H1,and HDAC1 interaction,it attenuates the transcriptional inhibition of Ins1 gene by menin.