The Role of p66Shc in Diabetes: A Comprehensive Review from Bench to Bedside

Abstract

It is well-documented that diabetes is an inflammatory and oxidative disease, with an escalating global burden. Still, there is no definite treatment for diabetes or even prevention of its harmful complications. Therefore, understanding the molecular pathways associated with diabetes might help in finding a solution. p66Shc is a member of Shc family proteins, and it is considered as an oxidative stress sensor and regulator in cells. There are inconsistent data about the role of p66Shc in inducing diabetes, but accumulating evidence supports its role in the pathogenesis of diabetes-related complications, including macro and microangiopathies. There is growing hope that by understanding and targeting molecular pathways involved in this network, prevention of diabetes or its complications would be achievable. This review provides an overview about the role of p66Shc in the development of diabetes and its complications.

Comparative Analysis of Biomarkers in Type 2 Diabetes Patients with and without Comorbidities: Insights into the Role of Hypertension and Cardiovascular Disease

“…In agreement with Ramanjaneya, we observed changes in both Humanin and MOTSc with diabetes progression and correlations with HbA1c and HDL 49 . In addition, p66Shc, which is coded for in the nucleus but also associated with oxidative stress by modulating the mitochondrial electron transport chain 16,75 . However, for the CVD/HT patients C5a, TC, LDL, 8-isoprostane, GSH/GSSG, and MCP-1 became important indicating significant changes in the pathophysiology and associated biomarkers with disease progression and the influence of CVD and HT.…”

Hyperglycemic stress induces oxidative damage of enteric glial cells by triggering redoxosomes/p66SHC activation

“…p66SHC is capable of initiating MAP-kinase signaling and activating the c-fos promoter, distinct from p52Shc and p46Shc [ 29 ]. Accumulating evidence indicated that p66SHC acts as a novel biomarker in determining development and progression of chronic age-related diseases, neoplasms, and metabolic diseases such as diabetes [ 30 ]. Yohei et al have reported that p66SHC-mediated inflammatory cascade leads to oxidative stress and is a causative pathogenic mechanism in diabetes-associated cognitive impairment [ 31 ].…”

The p66Shc Redox Protein and the Emerging Complications of Diabetes

“…Confirming the involvement of p66 Shc in diabetes complications, several drugs, and substances that target p66 Shc or its upstream and downstream molecules have beneficial effects against the complications associated with diabetes (as reviewed in [ 70 ]).…”

“…On the other hand, since the molecular pathways involved in p66 Shc action appear to be different based on the cell type and not yet fully understood, it is necessary to further study and elucidate the intracellular role and the pathway of p66 Shc before using it as a therapeutic target [ 70 ].…”

“…Although p66 Shc ’s involvement in sleep disorders needs to be investigated, p66 Shc ’s correlation with hyperglycemia, inflammatory pathways, impaired glucose metabolism, and oxidative stress is known. Since these mechanisms are shared by T2D and sleep disorders, an involvement of p66 Shc in the pathogenesis of the latter under diabetic conditions is conceivable [ 70 ].…”