The Role of Insulin Receptor Isoforms in Diabetes and Its Metabolic and Vascular Complications

Abstract

The insulin receptor (IR) presents by alternative splicing two isoforms: IRA and IRB. The differential physiological and pathological role of both isoforms is not completely known, and it is determinant the different binding affinity for insulin-like growth factor. IRB is more abundant in adult tissues and it exerts mainly the metabolic actions of insulin, whereas IRA is mainly expressed in fetal and prenatal period and exerts mitogenic actions. However, the change in the expression profile of both IR isoforms and its dysregulation are associated with the development of different pathologies, such as cancer, insulin resistance, diabetes, obesity, and atherosclerosis. In some of them, there is a significant increase of IRA/IRB ratio conferring a proliferative and migratory advantage to different cell types and favouring IGF-II actions with a sustained detriment in the metabolic effects of insulin. This review discussed specifically the role of IR isoforms as well as IGF-IR in diabetes and its associated complications as obesity and atherosclerosis. Future research with new IR modulators might be considered as possible targets to improve the treatment of diabetes and its associated complications.

Diabetes pharmacotherapy and effects on the musculoskeletal system

“…Insulin signals primarily through the insulin receptor, a hetero‐tetramer made up of two extracellular α‐subunits and two transmembrane β‐subunits, which is present on most cell‐types . Insulin‐mediated signaling can occur through phosphorylation of insulin receptor substrate (IRS)‐1 and IRS‐2 and subsequent activation of phosphatidylinositol (PI) 3‐kinase or by activation of the mitogen‐activated protein/ERK kinase pathway . Insulin can mediate various cellular events including glucose uptake and promotion of mitogenesis …”

Alternative mRNA Splicing in the Pathogenesis of Obesity

“…They demonstrated that the expression of adipose IR-B is negatively correlated with fasting insulin levels [ 42 , 43 ]. Although conflicting data was reported by other group [ 44 ] and the role of insulin receptor isoforms in noninsulin-dependent diabetes mellitus remained elusive, the studies raised the possibility of cellular metabolic status alters the ratio of splice variants. As splicing enhancer and silencer elements are responsible for the alternatively spliced insulin receptor intron 10 and exon 11 [ 45 ], several splicing factors (namely hnRNPA1, SF3A, and SFRS7) are proposed to have regulatory role in the exon inclusion of insulin receptor [ 42 ].…”

Changes in Splicing Machinery Components Influence, Precede, and Early Predict the Development of Type 2 Diabetes: From the CORDIOPREV Study

“…In particular, this study demonstrated that the expression of some splicing machinery components is altered in control individuals during the postprandial phase, which is consistent with previous results demonstrating a regulatory response of specific splicing variants to the postprandial environment [ 26 , 27 ]. Therefore, these data suggest that the changes observed in the splicing machinery during the postprandial phase may be responsible for the regulation of the expression of particular splicing variants under these conditions [ [12] , [19] , [28] ], which could be essential to the appropriate response of the organism to metabolic challenges and disturbances. Moreover, our results also demonstrate for the first time that the response of key splicing machinery components to metabolic insults is altered in individuals who will develop T2DM (Incident-T2DM patients), but especially in those developing T2DM during the first two years of follow-up.…”

“…Therefore, since postprandial alterations are closely related to the phenotypic flexibility, which is strongly linked to T2DM development [ 9 ], our data primarily demonstrate that the alteration in the splicing machinery precedes the instauration of T2DM, thereby suggesting its putative implication as a driving force in the development of this pathology. Based on all the information mentioned above, it is tempting to propose that the splicing machinery could be acting as a biosensor of the whole body metabolism to adapt cell gene expression to the pathophysiological conditions, and that its dysregulation could lead to an unbalance in the landscape of splicing variants present in a given cell at a given moment [ 12 , 28 , 29 ], which may be associated to the instauration of T2DM [ 10 , 30 ]. This idea is further supported by two pieces of evidence presented herein.…”