Global epidemic studies have suggested that coffee consumption is reversely correlated with the incidence of type 2 diabetes mellitus (T2DM), a metabolic disease. The misfolding of human islet amyloid polypeptide (hIAPP) is regarded as one of the causative factors of T2DM. Coffee extracts have three major active components: caffeine, caffeic acid (CA), and chlorogenic acid (CGA). In this study, the effects of these major coffee components, as well as dihydrocaffeic acid (DHCA) (a major metabolite of CGA and CA), on the amyloidogenicity of hIAPP were investigated by thioflavin-T based fluorescence emission, transmission electronic microscopy, circular dichroism, light-induced cross-linking, dynamic light scattering, and MTT-based cell viability assays. The results suggest that all components show varied inhibitory effects on the formation of toxic hIAPP amyloids, in which CA shows the highest potency in delaying the conformational transition of the hIAPP molecule with the most prolonged lag time, whereas caffeine shows the lowest potency. At a 5-fold excess molar ratio of compound to hIAPP, all coffee-derived compounds affect the secondary structures of incubated hIAPP as suggested by the circular dichroism spectra and CDPro deconvolution analysis. Further photoinduced cross-linking based oligomerization and dynamic light scattering studies suggested CA and CGA significantly suppressed the formation of hIAPP oligomers, whereas caffeine showed no significant effect on oligomerization. Cell protection effects were also observed for all three compounds, with the protection efficiency being greatest for CA and least for CGA. These findings suggest that the beneficial effects of coffee consumption on T2DM may be partly due to the ability of the major coffee components and metabolites to inhibit the toxic aggregation of hIAPP.
Excessive nuclear factor-κB (NF-κB) activation mediated by tumor necrosis factor α (TNFα) plays a critical role in inflammation. Here we demonstrate that angiopoietin-like 8 (ANGPTL8) functions as a negative feedback regulator in TNFα-triggered NF-κB activation intracellularly. Inflammatory stimuli induce ANGPTL8 expression, and knockdown or knockout of ANGPTL8 potentiates TNFα-induced NF-κB activation in vitro. Mechanistically, upon TNFα stimulation, ANGPTL8 facilitates the interaction of IKKγ with p62 via forming a complex, thus promoting the selective autophagic degradation of IKKγ. Furthermore, the N-terminal domain mediated self-oligomerization of ANGPTL8 is essential for IKKγ degradation and NF-κB activation. In vivo, circulating ANGPTL8 level is high in patients diagnosed with infectious diseases, and the ANGPTL8/p62-IKKγ axis is responsive to inflammatory stimuli in the liver of LPS-injected mice. Altogether, our study suggests the ANGPTL8/p62-IKKγ axis as a negative feedback loop that regulates NF-κB activation, and extends the role of selective autophagy in fine-tuned inflammatory responses.
The aggregation of human islet amyloid polypeptide (hIAPP) is one of the triggering factors of type 2 diabetes mellitus (T2DM). hIAPP is cosynthesized, costored, and cosecreted with insulin in pancreatic β-cells, and insulin inhibits hIAPP aggregation. In T2DM patients, long-term hyperglycemia causes glycation of near 10% of total insulin. The glycation not only modifies insulin but also cross-links insulin into oligomers. However, the effect of glycated human insulin on hIAPP aggregation is unknown. In this study, four physiologically relevant monosaccharides, methylglyoxal, glucose, fructose, and ribose were used to glycate human insulin and two C-terminus truncated insulin analogues. Glycated insulin monomers or low molecular weight oligomers such as dimers significantly exacerbated the cytotoxicity of hIAPP. Notably, glycation-induced cross-linking of insulin inhibited the aggregation, membrane disruption, and cytotoxicity of hIAPP, which was corroborated by a control study using EGS-induced cross-linking of insulin or lysozyme. Removal of B29 Lys on the C terminus of the insulin B chain not only abolished glycation-induced cross-linking but also attenuated the aggravation effect of glycated insulin on hIAPP cytotoxicity. Taken together, this study reveals a vicious cycle in T2DM, that hyperglycemia-driven insulin glycation exacerbates the cytotoxicity of hIAPP, which accelerates β-cells death and further deteriorates T2DM.
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