DRAK2 suppresses autophagy by phosphorylating ULK1 at Ser56 to diminish pancreatic ß cell function upon overnutrition.

Impeded autophagy can impair pancreatic ß cell function by causing apoptosis, of which DAP-related apoptosis-inducing kinase-2 (DRAK2) is a critical regulator. Here, we identified a marked up-regulation of DRAK2 in pancreatic tissue across humans, macaques, and mice with type 2 diabetes (T2D). Further studies in mice showed that conditional knockout (cKO) of DRAK2 in pancreatic ß cells protected ß cell function against high-fat diet feeding along with sustained autophagy and mitochondrial function. Phosphoproteome analysis in isolated mouse primary islets revealed that DRAK2 directly phosphorylated unc-51-like autophagy activating kinase 1 (ULK1) at Ser56, which was subsequently found to induce ULK1 ubiquitylation and suppress autophagy. ULK1-S56A mutation or pharmacological inhibition of DRAK2 preserved mitochondrial function and insulin secretion against lipotoxicity in mouse primary islets, Min6 cells, or INS-1E cells. In conclusion, these findings together indicate an indispensable role of the DRAK2-ULK1 axis in pancreatic ß cells upon metabolic challenge, which offers a potential target to protect ß cell function in T2D.

Luteolin Protects Pancreatic ß Cells against Apoptosis through Regulation of Autophagy and ROS Clearance.

Diabetes, which is mainly characterized by increased apoptosis and dysfunction of beta (ß) cells, is a metabolic disease caused by impairment of pancreatic islet function. Previous studies have demonstrated that death-associated protein kinase-related apoptosis-inducing kinase-2 (Drak2) is involved in regulating ß cell survival. Since natural products have multiple targets and often are multifunctional, making them promising compounds for the treatment of diabetes, we identified Drak2 inhibitors from a natural product library. Among the identified products, luteolin, a flavonoid, was found to be the most effective compound. In vitro, luteolin effectively alleviated palmitate (PA)-induced apoptosis of ß cells and PA-induced impairment of primary islet function. In vivo, luteolin showed a tendency to lower blood glucose levels. It also alleviated STZ-induced apoptosis of ß cells and metabolic disruption in mice. This function of luteolin partially relied on Drak2 inhibition. Furthermore, luteolin was also found to effectively relieve oxidative stress and promote autophagy in ß cells, possibly improving ß cell function and slowing the progression of diabetes. In conclusion, our findings show the promising effect of Drak2 inhibitors in relieving diabetes and offer a potential therapeutic target for the protection of ß cells. We also reveal some of the underlying mechanisms of luteolin's cytoprotective function.

Acylphloroglucinol derivatives with ATP citrate lyase inhibitory activities from Syzygium oblatum Wall.

Nine undescribed acylphloroglucinol derivatives, oblatones A-I, along with three known ones, were isolated from Syzygium oblatum. Their structures were determined on the basis of extensive spectroscopic analysis, including NMR and MS data interpretation. Oblatones A and B possess an alkylated chromanone scaffold featuring a hemiketal moiety. Oblatones C and D are the first acylphloroglucinol derivatives with an α,ß-unsaturated ketone lipid chain. Some of the isolates showed inhibitory effects on ATP citrate lyase in vitro. The binding mode of oblatone A was predicted by molecular docking.