The Pathogenesis of Diabetes Mellitus by Oxidative Stress and Inflammation: Its Inhibition by Berberine

Abstract

A substantial knowledge on the pathogenesis of diabetes mellitus (DM) by oxidative stress and inflammation is available. Berberine is a biologically active botanical that can combat oxidative stress and inflammation and thus ameliorate DM, especially type 2 DM. This article describes the potential of berberine against oxidative stress and inflammation with special emphasis on its mechanistic aspects. In diabetic animal studies, the modified levels of proinflammatory cytokines and oxidative stress markers were observed after administering berberine. In renal, fat, hepatic, pancreatic and several others tissues, berberine-mediated suppression of oxidative stress and inflammation was noted. Berberine acted against oxidative stress and inflammation through a very complex mechanism consisting of several kinases and signaling pathways involving various factors, including NF-κB (nuclear factor-κB) and AMPK (AMP-activated protein kinases). Moreover, MAPKs (mitogen-activated protein kinases) and Nrf2 (nuclear factor erythroid-2 related factor 2) also have mechanistic involvement in oxidative stress and inflammation. In spite of above advancements, the mechanistic aspects of the inhibitory role of berberine against oxidative stress and inflammation in diabetes mellitus still necessitate additional molecular studies. These studies will be useful to examine the new prospects of natural moieties against DM.

Keywords: cytokines; diabetes mellitus; inflammation; oxidative stress; pathogenesis; signaling pathways.

Figure 1

Chemical structure of berberine (Dong et al., 2012).

Figure 2

Schematic illustration of the protein networks of berberine and its interacting entities, acquired from STITCH database (accessed in March, 2017). Thicker lines represent the stronger linkages. Gray and green lines show the protein-protein interaction. [AKT1, v-akt murine thymoma viral oncogene homolog 1; CASP3, caspase 3; MAPK1, mitogen-activated protein kinase 1; TP53, tumor protein p53; LDLR, low density lipoprotein receptor; PCSK9, proprotein convertase subtilisin/kexin type 9; DPP4, dipeptidyl-peptidase 4; CCND1, cyclin D1; ATP5G2, ATP synthase; HMOX1, heme oxygenase (decycling) 1; HPR, haptoglobin-related protein; HP, Haptoglobin; STAT3, signal transducer and activator of transcription 3; PTGS2, prostaglandin-endoperoxide synthase 2; SLC2A4, solute carrier family 2 (facilitated glucose transporter), member 4; STK11, serine/threonine kinase 11; ADIPOQ, Adiponectin; CTSB, cathepsin B; ITGAM, integrin, alpha M; MMP9, matrix metallopeptidase 9; JUN, jun proto-oncogene; PTGER4, prostaglandin E receptor 4; UCP2, uncoupling protein 2; INSR, insulin receptor; CYP2D6, cytochrome P450 enzyme; GCG, glucagon; DAXX, death-domain associated protein; CASP12, caspase 12 (gene/pseudogene); ALDH7A1, aldehyde dehydrogenase 7 family, member A1; MAU2, MAU2 chromatid cohesion factor homolog; TLR4, toll-like receptor 4; PLAU, plasminogen activator, urokinase; PTPN1, protein tyrosine phosphatase, non-receptor type 1; BECN1, beclin 1, autophagy related; SRC, v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (avian); FN1, fibronectin 1; GATA2, GATA binding protein 2; IL17A, interleukin 17A; LPL, lipoprotein lipase; AIFM1, apoptosis-inducing factor, mitochondrion-associated, 1; NODAL, nodal homolog; AKR1B1, aldo-keto reductase family 1, member B1 (aldose reductase); EGFR, epidermal growth factor receptor; VMP1, vacuole membrane protein 1; SLC6A4, solute carrier family 6 (neurotransmitter transporter, serotonin), member 4; NRF1, nuclear respiratory factor 1; PON1, paraoxonase 1; KCNQ1, potassium voltage-gated channel, KQT-like subfamily, member 1; and NME1, NME/NM23 nucleoside diphosphate kinase 1].

Figure 3

Mechanistic aspects of the antioxidant and anti-inflammatory action of berberine. It can be divided into three parts: Firstly, the downregulated NADPH oxidase expression and upregulated UCP and SOD could be involved in the berberine-induced suppression of oxidative stress that is likely controlled by the SIRT1/FOXO or AMPK pathways. Secondly, the antioxidant and anti-inflammatory action of berberine involves the activation of Nrf2 pathway, which further depends on the activated P38, AMPK and P13K/Akt signaling pathways. Finally, the inflammation is inhibited by berberine through the suppressed MAPK, Rho GTPase, NF-κB, and AP-1 pathways. The molecules and the pathways involved in the antioxidant activity of berberine are shown by the squared boxes/lines, while double squared boxes/dotted lines represent molecular species and pathways engaged in the anti-inflammatory activity. Additionally, the molecules and pathways shared by both antioxidant and anti-inflammatory activities of berberine are indicated by the encircled boxes. The pathways and the mechanisms that necessitate further investigations are shown by the curved bold lines. Berberine could terminate the malicious association between oxidative stress and inflammation.