Impact of Astaxanthin on Diabetes Pathogenesis and Chronic Complications

Abstract

Oxidative stress (OS) plays a pivotal role in diabetes mellitus (DM) onset, progression, and chronic complications. Hyperglycemia-induced reactive oxygen species (ROS) have been shown to reduce insulin secretion from pancreatic β-cells, to impair insulin sensitivity and signaling in insulin-responsive tissues, and to alter endothelial cells function in both type 1 and type 2 DM. As a powerful antioxidant without side effects, astaxanthin (ASX), a xanthophyll carotenoid, has been suggested to contribute to the prevention and treatment of DM-associated pathologies. ASX reduces inflammation, OS, and apoptosis by regulating different OS pathways though the exact mechanism remains elusive. Based on several studies conducted on type 1 and type 2 DM animal models, orally or parenterally administrated ASX improves insulin resistance and insulin secretion; reduces hyperglycemia; and exerts protective effects against retinopathy, nephropathy, and neuropathy. However, more experimental support is needed to define conditions for its use. Moreover, its efficacy in diabetic patients is poorly explored. In the present review, we aimed to identify the up-to-date biological effects and underlying mechanisms of ASX on the ROS-induced DM-associated metabolic disorders and subsequent complications. The development of an in-depth research to better understand the biological mechanisms involved and to identify the most effective ASX dosage and route of administration is deemed necessary.

Keywords: ROS; antioxidant; astaxanthin; diabetes complication; diabetes mellitus; diabetic nephropathy; diabetic neuropathy; diabetic retinopathy; hyperglycemia; insulin resistance; oxidative stress.

Figure 1

Schematic representation of molecular pathways implied in the protective potential of astaxanthin (ASX): Due to its membrane penetrance, ASX has both intra- and extracellular reactive oxygen species (ROS) scavenging actions. Moreover, in the phospholipid membrane, the ASX polyene chain participates in the reduction of lipid peroxidation. Through the regulation of different pathways, ASX reduces inflammation, oxidative stress, and apoptosis. Red arrows indicate inhibitory action, and green arrows show enhancement action.

Figure 2

Beneficial effects of astaxanthin at different developmental stages of diabetes mellitus (DM) and its complications.

Figure 3

Schematic representation of different pathways suggested for the protective effect of astaxanthin on diabetic retinopathy (DR) via its ROS scavenging potential and reduced oxidative stress induced by the enhanced antioxidant and the downstream pathways activated in hyperglycemic states: In parallel, ASX inhibits inflammation through the nuclear factor-kappa (NF-κB) pathway, microvascular damages through vascular endothelial growth factor (VEGF) production, and finally apoptosis through the regulation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/protein kinase B PI3K/Akt pathways. The grey arrow indicates different pathways implied in the development of the pathology, the red arrow indicates the inhibitory/regulatory effect, while the green ones represent a stimulatory effect.

Figure 4

Schematic representation of different pathways suggested for the protective effect of astaxanthin (ASX) on diabetic nephropathy (DN): Through its ROS scavenging and antioxidant potential, ASX reduces oxidative stress and the downstream pathways activated in the development of the disease. In addition, ASX directly inhibits NF-κB translocation and transforming growth factor beta (TGF-β) production as well as reduces inflammation and fibrosis, which are strongly implied in DN. The grey arrow indicates different pathways implied in the DN development, the red arrow indicates an inhibitory/regulatory effect, while the green ones indicate a stimulatory effect.

Figure 5

Schematic representation of different pathways suggested for the protective effect of astaxanthin (ASX) on diabetic neuropathy: Through its ROS scavenging potential and the enhancement of antioxidant activities, ASX reduces oxidative stress and the downstream pathways activated in the development of DM-induced neuronal abnormalities. In addition, ASX directly inhibits inflammation through NF-κB, microvascular damages through VEGF production, and finally apoptosis through the regulation of MAPK and PI3K/Akt pathways. The grey arrow indicates different pathways implied in the development of DM-induced neuronal abnormalities, the red arrow indicates an inhibitory/regulatory effect, while the green ones indicate a stimulatory effect.

Figure 6

Schematic representation of different pathways suggested for the protective effect of astaxanthin (ASX) on diabetic cardiovascular complications in the literature: through its ROS scavenging potential and the enhancement of antioxidant activities, ASX reduces oxidative stress and the downstream pathways activated in the development of the pathology. In addition, ASX directly inhibits inflammation through NF-κB pathway. Thrombosis and vasoconstriction reduction are also associated with oxidative stress regulation. Moreover, ASX lowers oxidized low-density lipoprotein (oxLDL), enhances endothelial nitric oxide synthase (eNOS), and reduces vasoconstriction. The grey arrow indicates different pathways implied in the development of DM-induced neuronal abnormalities, the red arrow indicates an inhibitory/regulatory effect, while the green ones indicate a stimulatory effect.