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Purpose: To analyze the impact of dynamic changes in inflammation on atherosclerosis in short-duration type 2 diabetes after multifactorial intervention.Methods: In this randomized controlled study, a total of 150 type 2 diabetes patients who had a mean age of 49.8±7.3years, 51% male, with disease duration <1year and without evidence of atherosclerosis were randomized into an intensive intervention group (IG), in which patients received multiple risk factors intervention by the special project team and tried to reach the pre-determined intervention goals, and a conventional group (CG), in which patients received standard diabetes care by the clinic doctor. All patients recieved intervention study for 7 years, then underwent a 3-year observational follow-up study. The primary endpoints were occurrence of subclinical atherosclerosis, defined as the intima-media thickness of the common carotid artery (CC-IMT)≥1.0mm or formation of atherosclerosis plaques, and the occurrence of cardiovascular events.Results: 68 patients in IG and 65 patients in CG completed the 10-year study. The cumulative incidence of subclinical atherosclerosis was 30.7% vs 57.3% (IG vs CG, HR 0.36, 95% CI 0.22-0.60, P<0.0001) and that of cardiovascular events was 12.0% vs 22.7% (IG vs CG, HR 0.46, 95% CI 0.21-0.98, P=0.0516). High sensitivity C-reactive protein (hs-CRP) reduction from baseline to the 10-year follow-up was -1.54mg/L (IG) and -0.67mg/L (CG) with difference (IG minus CG) of -0.87mg/L(95% CI -0.72 to -1.02, P=0.008) and the natural logarithm of serum amyloid A (SAA) reduction was -4.04 (IG) and -1.44 (CG) with difference (IG minus CG) of -2.60 (95% CI -2.30 to -2.90, P=0.002). The decrease in general score of inflammatory markers (combination of hs-CRP and SAA) was independently associated with subclinical atherosclerosis (OR=0.65, P=0.045) and cardiovascular events (OR=0.60, P=0.042).Conclusions: Dynamic changes in inflammation act as an important factor that affects the occurrence of atherosclerosis in type 2 diabetes patients. Multifactorial intensive intervention can reduce systemic low-grade inflammation and delay the occurrence of atherosclerosis in short-duration type 2 diabetes. [ABSTRACT FROM AUTHOR]

As an environmental toxicant, arsenic exposure may cause insulin resistance (IR). Previous studies have shown that pyroptosis plays an important role in the occurrence and development of IR. Although gasdermin D (GSDMD) functions as an executor of pyroptosis, the relationship between GSDMD-mediated pyroptosis and hepatic IR remains unclear. Here, we observed that sodium arsenite (NaAsO 2) activated NOD-like receptors containing pyrin domain 3 (NLRP3) inflammasomes, promoted GSDMD activation, induced pyroptosis and hepatic IR, while GSDMD knockdown attenuated pyroptosis and hepatic IR caused by NaAsO 2. However, GSDMD interference did not affect NLRP3 activation. Ubiquitination modification is widely involved in protein regulation and intracellular signal transduction, and whether it regulates GSDMD and affects its degradation, and exerts effects on arsenic-induced pyroptosis remain unclear. We observed that NaAsO 2 reduced the K48- and K63-linked ubiquitination of GSDMD, thereby inhibiting its degradation through the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway (ALP), causing GSDMD to accumulate and lyse into GSDMD-N, which promoted pyroptosis. In summary, we demonstrated that GSDMD participated in arsenic-induced hepatic IR. Moreover, NaAsO 2 reduced GSDMD ubiquitination and decreased its intracellular degradation, aggravating pyroptosis and hepatic IR. We have revealed the molecular mechanism underpinning arsenic-induced IR, and we provide potential solutions for the prevention and treatment of type 2 diabetes (T2D). [Display omitted] • The reduction of GSDMD would attenuate the arsenic-induced pyroptosis and insulin resistance. • Exposure to NaAsO 2 would reduce the ubiquitination level of GSDMD. • Ubiquitinated GSDMD would be degraded by ubiquitin-proteasome system and autophagy-lysosome pathway. [ABSTRACT FROM AUTHOR]

Glucolipid metabolism disorder in diabetes mellitus (DM) causes human endothelial injury and autophagy dysfunction is an important cause of endothelial dysfunction (ED). Selenoprotein S (SelS) could protect endothelium from oxidative stress, inflammatory responses, and apoptosis. This study assessed the effect of SelS on autophagy in glucolipid metabolic disorders and protection of the resulted vascular endothelial injury. The results showed that high glucose (HG), high oxidized low-density lipoprotein (HL), and HG combined with HL (HGL) could reduce viability of human aortic endothelial cells (HAECs), induce HAECs injury and increase SelS expression in a time-dependent manner. HG, HL, and HGL also initially induced autophagy but later reduced it in HAECs, while activity of the Akt/mTOR signaling was inhibited, especially in HGL culture of HAECs. SelS overexpression reduced the endothelial injury and autophagy and activated the Akt/mTOR signaling in HG, HL and HGL-cultured HAECs, compared to the control. Conversely, knockdown of SelS expression had the opposite effects on HAECs. In conclusion, SelS demonstrated a protective effect on endothelial injury induced by high glucose and/or ox-LDL and the underlying molecular events might be related to its regulation of HAECs autophagy by activating the Akt/mTOR signaling. SelS could be a potential intervention target in prevention and treatment of diabetic vascular complications. • Glucolipid metabolism disorder had a synergistic effect on endothelial injury. • Selenoprotein S could attenuate endothelial injury in HAECs. • Selenoprotein S inhibited human aortic endothelial cell autophagy. • Selenoprotein S regulated autophagy through Akt/mTOR signaling. [ABSTRACT FROM AUTHOR]

Endothelial dysfunction (ED) is a critical and initiating factor in the genesis of diabetic vascular complications whose occurrence and development is closely related to the complex intravascular microenvironment. However, currently, there is no dynamic model simulating the diabetic vascular endothelial microenvironment that can be used to investigate the mechanism underlying multifactor-induced ED. Here, we developed an integrated microfluidic chip as a new methodological platform to study vascular ED. Selenoprotein S (SELENOS) was found to be involved in the defense against oxidative stress-induced vascular endothelial injury in our previous studies. However, the regulatory signaling pathway underlying this process has not been described. With this chip, we demonstrated that multifactor-induced oxidative stress injury in human aortic endothelial cells (HAECs) has a synergistic effects and upregulates SELENOS expression. Subsequently, SELENOS was found to protect HAECs against multifactor-induced oxidative stress injury by regulating the PKCα/PI3K/Akt/eNOS pathway in the diabetic vascular endothelial microenvironment. Based on these data, our diabetic vascular chip provides a promising tool for studying vascular endothelial function, and SELENOS may be a novel target for prevention and treatment of diabetic macrovascular complications. • We constructed a diabetic vascular microfluidic chip to study the roles and mechanism of SELENOS in endothelial injury. • Multifactor-induced oxidative stress injury in HAECs has a synergistic effects and upregulates SELENOS expression. • SELENOS was found to protect HAECs against multifactor-induced oxidative stress injury via the PKCα/PI3K/Akt/eNOS pathway. [ABSTRACT FROM AUTHOR]