Glycemic Variability Promotes Both Local Invasion and Metastatic Colonization by Pancreatic Ductal Adenocarcinoma

Background & Aims: Although nearly half of pancreatic ductal adenocarcinoma (PDAC) patients have diabetes mellitus with episodes of hyperglycemia, its tumor microenvironment is hypoglycemic. Thus, it is crucial for PDAC cells to develop adaptive mechanisms dealing with oscillating glucose levels. So far, the biological impact of such glycemic variability on PDAC biology remains unknown. Methods: Murine PDAC cells were cultured in low- and high-glucose medium to investigate the molecular, biochemical, and metabolic influence of glycemic variability on tumor behavior. A set of in vivo functional assays including orthotopic implantation and portal and tail vein injection were used. Results were further confirmed on tissues from PDAC patients. Results: Glycemic variability has no significant effect on PDAC cell proliferation. Hypoglycemia is associated with local invasion and angiogenesis, whereas hyperglycemia promotes metastatic colonization. Increased metastatic colonization under hyperglycemia is due to increased expression of runt related transcription factor 3 (Runx3), which further activates expression of collagen, type VI, alpha 1 (Col6a1), forming a glycemic pro-metastatic pathway. Through epigenetic machinery, retinoic acid receptor beta (Rarb) expression fluctuates according to glycemic variability, acting as a critical sensor relaying the glycemic signal to Runx3/Col6a1. Moreover, the signal axis of Rarb/Runx3/Col6a1 is pharmaceutically accessible to a widely used antidiabetic substance, metformin, and Rar modulator. Finally, PDAC tissues from patients with diabetes show an increased expression of COL6A1. Conclusions: Glycemic variability promotes both local invasion and metastatic colonization of PDAC. A pro-metastatic signal axis Rarb/Runx3/Col6a1 whose activity is controlled by glycemic variability is identified. The therapeutic relevance of this pathway needs to be explored in PDAC patients, especially in those with diabetes

A randomised trial of a pre-synaptic stimulator of DA(2)-dopaminergic and alpha(2)-adrenergic receptors on morbidity and mortality in patients with heart failure

Background: By pre-synaptic stimulation of DA2-dopaminergic and α2-adrenergic receptors, nolomirole inhibits norepinephrine secretion from sympathetic nerve endings. We performed a clinical study with nolomirole in patients with heart failure (HF). Methods: The study was designed as a multicentre, double blind, parallel group trial of 5 mg b.i.d. of nolomirole (n=501) versus placebo (n=499) in patients with severe left ventricular systolic dysfunction, recently in New York Heart Association (NYHA) class III/IV. The primary endpoint was time to all cause death or hospitalisation for HF, whichever came first. The study was event driven and required 420 primary events. The study was completed as scheduled. Results: Mean age of patients was 70 years, and 73% were male. Heart rate and blood pressure were not different in the two treatment groups. There were no changes in blood pressure. There were 233 primary events in the nolomirole group versus 208 in the placebo group (p=0.1). There were 142/145 deaths and 369/374 all cause hospitalisations in the nolomirole/placebo groups. There were no differences in walking distance, quality of life or NYHA class. Conclusion: A dose of 5 mg b.i.d. of nolomirole was not beneficial (or harmful) in patients with heart failure