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

Table 1

Substances which show benefit against diabetes-related complication. Of note, more investigations are needed, and until today, there is not enough evidence to support the actual effect of these agents.

	Substances	Effect and mechanism	Target population	Reference
Cardiovascular	Renin-angiotensin-aldosterone-system (RAAS) inhibitors	Inhibits NADPH-PKC-β–p66Shc axis, so decrease ROS level and cellular apoptosis	—	[20]
	Carvedilol	Reduces ROS level and inflammatory markers	Streptozotocin-induced diabetic rat	[88]
	Adiponectin	Prevents myocardial injury by inhibition of p66Shc	High glucose-treated human cardiac myocytes	[89]
	Pioglitazone	Partially preserves HSPC mobilization by PPAR-γ activation and downregulation of OSM and p66Shc	In diabetic rats and diabetic patients	[92]
	PKC inhibitors like ruboxistaurin and GF109203X	Decrease diabetes-related cardiovascular complication and rescue endothelial vasodilation through reducing NADPH-related ROS production and modulating p66Shc	Diabetic patients	[12, 24]
	C peptide	Inhibits persistent overactivation of p66Shc and p53 after glucose normalization, reduces ONOO(-) and ROS production, decreases endothelial cell apoptosis, and improves vascular injury	In vitro and in vivo in human umbilical vein endothelial cells and diabetic mice	[34, 94]
	Vitamin D receptor agonist	Inhibits PIN1-p66Shc axis and improves vascular dysfunction	Streptozotocin-induced diabetic mice	[95]
Diabetic nephropathy	RAAS inhibitors	Since angiotensin II upregulates p66Shc in proximal tubule cells, RAAS inhibitors can have protective effect	—	[10]
	Probucol	Epigenetically downregulates p66Shc expression and can prevent diabetes-induced renal tubular injury	Streptozotocin-induced diabetic mice and high glucose-treated HK-2 cells	[28, 94]
	Piperazine ferulate (PF)	Can inhibit p66Shc and has protective effect against high glucose-induced mesangial injury	In vitro mesangial cells and in vivo on diabetic mice	[102]
	Enzastaurin	Inhibits PKCβ-p66shc-NADPH oxidase pathway and has protective effect against diabetic nephropathy	Streptozotocin-induced diabetic rats and in vitro on high glucose-treated human renal proximal tubule epithelial cells (HK-2 cells)	[45]
	Rottlerin	A PKCδ inhibitor, thus has inhibitory effect on PKCδ/p66Shc axis	High glucose-treated HK-2 cells	[99]
	Corcumin	Inhibits PKCβII/p66Shc axis and prevents diabetic nephropathy	Streptozotocin-induced diabetic rats	[105]
	Dioscorea zingiberensis	Possibly inhibits p66Shc activity. It shows protective effects against diabetic-induced nephropathy.	High-fat diet/streptozotocin-induced diabetic mice	[106]
	Activated protein C (aPC)	Causes epigenetic changes in p66Shc promoter and suppresses its expression	Rats with diabetic nephropathy	[10, 107].
	Resveratrol	Activates SIRT1, thus suppresses p66Shc and improves mitochondrial function	Glucose-treated mesangial cells and	[10]
Retinopathy	Exendin-4	By inhibition of JNK, protein kinase-β, and p66Shc, it has protective effect against diabetic retinopathy	Adult human retinal pigment epithelial-19 cells	[110]
Wound healing	Ganoderma lucidum polysaccharide (Gl-PS)	Improves diabetic wound healing and increases angiogenesis. p66Shc suppression is one of its mechanisms	STZ-induced diabetic mice	[112]
Erectile dysfunction	Argirein	Inhibiton of p66Shc overactivity	Diabetic rats	[116]