Targeting AMPK signaling pathway by natural products for treatment of diabetes mellitus and its complications

Abstract

Diabetes affects a large population of the world. Lifestyle, obesity, dietary habits, and genetic factors contribute to this metabolic disease. A target pathway to control diabetes is the 5′‐adenosine monophosphate‐activated protein kinase (AMPK) signaling pathway. AMPK is a heterotrimeric protein with α, β, and γ subunits. In several studies, AMPK activation enhanced glucose uptake into cells and inhibited intracellular glucose production. Impairment of AMPK activity is present in diabetes, according to some studies. Drugs used in the treatment of diabetes, such as metformin, are also known to act through regulation of AMPK. Thus, drugs that activate and regulate AMPK are potential candidates for the treatment of diabetes. In addition, many patients encounter important adverse effects, like hypoglycemia, while using allopathic drugs. As a result, the investigation of plant‐derived natural drugs that lack adverse side effects and treat diabetes is necessary. Natural products like berberine, quercetin, resveratrol, and so forth have shown significant potential in regulating and activating the AMPK pathway which can lead to manage diabetes mellitus and its complications.

<p>Emerging Roles and Therapeutic Interventions of Aerobic Glycolysis in Glioma</p>

“…26 Conversely, a higher glycolytic index along with activated procedures of lipid and protein synthesis was induced by HKII overexpression. 27 Nie et al 28 also reported that the elevated HKII contributed to an increase in glucose uptake and lactate production in glioma cells with IDH1R 132 H mutation. Further in vitro experiments illustrated that HKII was significantly upregulated in gliomas and related to proliferation, invasion, apoptosis, and angiogenesis.…”

“…129 The AMPK, expressed extensively in all eukaryotic cells, comprises of a catalytic subunit (α) and two regulatory subunits (β and γ). 130,132 According to different inputs, outputs, functions, and sub-cellular localizations, a total of 12 potential AMPK complexes were assembled by various isoforms of each subunit. 133 Moreover, the α subunit, phosphorylated at Thr-172, translocates a phosphate group from ATP to the Ser/ Thr sites, known as a biomarker for AMPK signaling.…”

“…133 Moreover, the α subunit, phosphorylated at Thr-172, translocates a phosphate group from ATP to the Ser/ Thr sites, known as a biomarker for AMPK signaling. 132 The γ subunit serves as an allosteric activator, while the β subunit provides a structural bridge between α and γ subunits. 134,136 Therefore, upon binding to γ-subunit, AMPK would be elevated via the allosteric activation of AMP, which could also be precisely modulated by upstream kinases.…”

Protective Mechanisms of Quercetin Against Myocardial Ischemia Reperfusion Injury

“…However, the AMPK signaling is impaired in diabetes. Despite that certain drugs like metformin can regulate the activity of AMPK, they also have some adverse effects like hypoglycemia (Joshi et al, 2019). On the other hand, it showed that Que can activate AMPK signaling and improve insulin resistance in skeletal muscle cells and stimulate insulin secretion (Eitah et al, 2019).…”

Resveratrol and Resveratrol-Aspirin Hybrid Compounds as Potent Intestinal Anti-Inflammatory and Anti-Tumor Drugs

“…Resveratrol is a naturally occurring phytoalexin present in grapes, peanuts, and other plants [6]. Having a simple structure and low molecular weight, resveratrol can target key proteins such as cyclooxygenase (COX) enzymes, AMPK [1,7], and NFκB, factors strongly associated with inflammation and carcinogenesis [8]. In addition, resveratrol can also regulate other targets such as Phosphoinositide 3-kinases (PI3)-kinases, Sirt1, DNA methyltransferases [9], and others.…”