Novel methodologies for the treatment of type 1 diabetes mellitus using in silico tools

Abstract

Epidemiologic studies reveal that the fight against diabetes is being lost, so to overcome this serious health problem every strategy should be taken seriously. Using in silico data we discuss the therapeutic potential for Diabetes Mellitus type 1 of two possible unstudied strategies; (I) if INSULIN paralog, INSULIN-INSULIN GROWTH FACTOR 2 can be a regulator of glucose in humans, and (II) if extrapancreatic expression of INSULIN and INSULIN- INSULIN GROWTH FACTOR 2 has any relevance in glucose regulation. To address this hypothesis, we access to the collection of protein sequences and gene expression from INSULIN and paralogues in EGB, NCBI and EBI. Phylogenetic and molecular evolutionary analyses were conducted using MEGA software, conserved protein motifs were compared using algorithm MUSCLE and presenting it graphically using CLC Genomics Workbench, transcripts and gene expression from transcriptome and microarray data from different experiments of insulin and paralogues were extracted and graphicaly presented using CIRCOS. Phylogenetic analysis revealed that humans, like most of all mammals, have INSULIN and INSULIN-INSULIN GROWTH FACTOR 2 with the exception of murinae among mammals that share Insulin 1 and Insulin 2. Both Insulin 1 and 2 can regulate glucose since both proteins are highly similar and with a redundant function, as confirmed by in vivo experiments showing that both knockout Insulin 1 or 2 are normoglycemic. Human INSULIN- INSULIN GROWTH FACTOR 2 lacks motif 3 of the INSULIN signature, and part of the predicted protein structure does not present any known domain, making the prediction of a possible function for this gene inconclusive. Extrapancreatic expression of insulin has been observed in diabetic mice with contradictory effects, but available gene expression data in repository data banks also suggests that extrapancreatic expression of insulin occurs in human, mouse and zebrafish under basal condition. Gene expression DataSets demonstrate that extrapancreatic expression of INSULIN occurs under basal condition. Further investigation should be made, to understand if extrapancreatic expression of insulin can have a role in glucose homeostasis, as this could represent a complementary strategy in diabetes treatment.