ReviewAMPK in microvascular complications of diabetes and the beneficial effects of AMPK activators from plants
Introduction
Diabetes mellitus (DM) is classified as a complex metabolic disorder with derangements in glucose, lipid and protein metabolism that heightens the risk of secondary complications (Forbes and Cooper, 2013). In recent years, AMP-activated protein kinase (AMPK) has emerged as a potential therapeutic target to treat various metabolic disorders including DM (Day et al., 2017). AMPK stands out as a unique and a therapeutic target due to its ability to reprogram the metabolism both at the cellular and whole-body level. AMPK is an evolutionarily conserved serine-threonine kinase that plays a central role in the energy homeostasis via regulating vital metabolic pathways (Garcia and Shaw, 2017). Under low energy stress, increase in the cytosolic AMP to ATP ratio activates AMPK. Upon activation, it counteracts the energy depletion by the stimulating catabolic pathways that generate ATP (fatty acid oxidation and glycolysis) and inhibiting anabolic pathways (fatty acid, triglyceride, and cholesterol synthesis, protein synthesis and transcription) that consume ATP (Herzig and Shaw, 2018). AMPK plays an essential role in regulating critical events in the cell such as autophagy (Kim et al., 2011, Zhang et al., 2016), apoptosis (Eid et al., 2010, Shaw et al., 2004), inflammatory process (Gauthier et al., 2011, He et al., 2015, Mangalam et al., 2016, Sag et al., 2008, Yang et al., 2010) and mitochondrial homeostasis (Dugan et al., 2013, Han et al., 2010, Toyama et al., 2016, Zong et al., 2002). Alterations in these cellular events during diabetes and down-regulation of AMPK activity play a crucial role in the pathogenesis of diabetic complications. In this review, we have discussed the recently available evidence on how AMPK downregulation is associated with diabetic nephropathy, diabetic retinopathy, and diabetic neuropathy. Since AMPK is an important therapeutic target in diabetes, the role and the available mechanisms of action by a few plant-derived bioactive compounds and bioactive-rich extracts in alleviating the secondary complications of diabetes is listed.
Section snippets
AMPK structure and activation
Functional AMPK is a heterotrimer consisting of a catalytic subunit (α), and two regulatory subunits (β and γ). Each subunit exists in various isoforms (α 1, α 2, β 1, β 2, γ 1, γ 2, γ 3), which are encoded by separate genes and thus give rise to a large variety of heterotrimer combinations (Herzig and Shaw, 2018). The exact role of these different subunit compositions is mainly unknown. According to the recently reported work, different subunit composition of AMPK affects its activity,
AMPK and microvascular complications of diabetes mellitus
Chronic high glucose during diabetes damages blood vessels and leads to long-term vascular complications. Damage to small blood vessels leads to nephropathy (kidney disease), retinopathy (eye disease), and neuropathy (neuronal damage) generally called as “microvascular complications.” and they cause significant morbidity and mortality in diabetic individuals (Forbes and Cooper, 2013). Current accumulating evidence signifies the role of AMPK in the pathophysiology of chronic microvascular
AMPK activators of dietary origin and their beneficial effects on secondary complications of diabetes
Non-pharmacological approaches including diet and nutrition are important factors in treating various diseases/disorders including diabetes and its complications. As discussed earlier, AMPK is an attractive target to treat diabetes and its complications. Various pharmacological AMPK activators are shown to be effective in mitigating diabetes and its complications. Current understanding of natural AMPK activators in mitigating secondary complications of diabetes is limited. Few bioactive
Conclusion and future perspective
Our present knowledge of the role of AMPK in the pathogenesis of various diabetic microvascular complications is insufficient. However, the current state of understanding of AMPK suggests that it plays a critical role in the pathogenesis of multiple complications associated with diabetes. Many of the plant-derived AMPK activators show beneficial effects in mitigating diabetic microvascular complications both in vitro and in vivo. Based on the studies, a repertoire of AMPK activators can be
Acknowledgments
The authors thank the CSIR- CFTRI for funding, and Srikanth C.B. thanks CSIR for the award of senior research fellowship.
Conflict of interest
The authors like to state that there is no conflict of interest associated with this manuscript.
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