Accumulating evidence indicates the occurrence and development of diabetic complications relates to not only constant high plasma glucose, but also glucose fluctuations which affect various kinds of molecular mechanisms in various target cells and tissues. In this review, we detail reactive oxygen species and their potentially damaging effects upon glucose fluctuations and resultant downstream regulation of protein signaling pathways, including protein kinase C, protein kinase B, nuclear factor-κB, and the mitogen-activated protein kinase signaling pathway. A deeper understanding of glucose-fluctuation-related molecular mechanisms in the development of diabetic complications may enable more potential target therapies in future.

This study aimed to explore the effects of astragaloside IV on metabolic syndrome induced by a high-fructose/high-fat diet in rats. Methods: Rats were randomized into four groups: normal control, metabolic syndrome, metabolic syndrome þ intraperitoneal astragaloside 0.5 mg/kg/day, and metabolic syndrome þ intraperitoneal astragaloside 2.0 mg/kg/day (n¼30 per group) for 14 continuous days. Left ventricular functions were evaluated by hemodynamic and echocardiographic parameters. Results: Metabolic syndrome rats had a thicker interventricular septum and left ventricular posterior wall, accompanied by a higher E/A wave ratio, reduced E 0 wave, increased A 0 wave, decreased E 0 /A 0 wave ratio, and higher E/E 0 wave ratio. Astragaloside decreased insulin and triglyceride levels and improved diastolic dysfunction with no effects on systolic function. A high-fructose/high-fat diet also increased oxidative stress and decreased the myocardial endothelial nitric oxide synthase (NOS) dimer ratio, thus impairing nitric oxide (NO) production and reducing cyclic guanosine monophosphate (cGMP) production. Astragaloside increased NO and cGMP production in the myocardium and improved diastolic function. Conclusions: Astragaloside alleviated oxidative stress and restored NO signaling, thus improving myocardial left ventricular diastolic dysfunction in rats with metabolic syndrome. The underlying mechanisms could be associated with alleviation of oxidative stress and activation of the endothelial NOS/NO/cGMP pathway.

BackgroundGlucose fluctuations may be associated with myocardial fibrosis. This study aimed to investigate the underlying mechanisms of glucose fluctuation-related myocardial fibrosis.MethodsStreptozotocin (STZ)-injected type 1 diabetic rats were randomized to five groups: the controlled blood glucose (CBG) group, uncontrolled blood glucose (UBG) group, fluctuated blood glucose (FBG) group, FBG rats injected with 0.9% sodium chloride (NaCl) (FBG + NaCl) group, and FBG rats injected with MCC950 (FBG + MCC950) group. Eight weeks later, left ventricular function was evaluated by echocardiography and myocardial fibrosis was observed by Masson trichrome staining. The primary neonatal rat cardiac fibroblasts were cultured with different concentrations of glucose in vitro.ResultsThe left ventricular function was impaired and myocardial fibrosis was aggravated most significantly in the FBG group compared with the CBG and UBG groups. The levels of interleukin (IL)-1β, IL-18, transforming growth factor-β1 (TGF-β1), collagen type 1 (collagen I), nuclear factor (NF)-κB, and nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome were significantly increased in the FBG group. In vitro, the inhibition of NF-κB and inflammasome reversed these effects. In vivo, NLRP3 inhibition with MCC950 reversed left ventricular systolic dysfunction and myocardial fibrosis induced by glucose fluctuations.ConclusionGlucose fluctuations promote diabetic myocardial fibrosis by the NF-κB-mediated inflammasome activation.