Glycaemic variability affects ischaemia-induced angiogenesis in diabetic mice

Abstract

The aim of the present study was to investigate the role of GV (glycaemic variability) in diabetic vascular complications and to explore the molecular pathways modulated by glycaemic 'swings'. We developed a murine model. A total of 30 diabetic mice received once daily basal insulin administration plus two oral boluses of glucose solution (GV group, named 'V') and 30 diabetic mice received once daily basal insulin plus two oral boluses of saline solution (stable hyperglycaemia group, named 'S') for a period of 30 days. Glycaemia was measured eight times daily to detect GV. Finally, postischaemic vascularization, induced by hindlimb ischaemia 30 days after diabetes onset, was evaluated. We found that GV was significantly different between S and V groups, whereas no significant difference in the mean glycaemic values was detected. Laser Doppler perfusion imaging and histological analyses revealed that the ischaemia-induced angiogenesis was significantly impaired in V mice compared with S group, after ischaemic injury. In addition, immunostaining and Western blot analyses revealed that impaired angiogenic response in V mice occurred in association with reduced VEGF (vascular endothelial growth factor) production and decreased eNOS (endothelial nitric oxide synthase) and Akt (also called protein kinase B) phosphorylation. In conclusion, we describe a murine model of GV. GV causes an impairment of ischaemia-induced angiogenesis in diabetes, likely to be independent of changes in average blood glucose levels, and this impaired collateral vessel formation is associated with an alteration of the VEGF pathway.

Glycemic Variability in Diabetes Increases the Severity of Influenza

“…At present, research into the effect of glycemic oscillations on influenza severity is limited by the lack of an appropriate animal model of glycemic variability. Glycemic spikes have been studied in mice through repeated administration of a glucose/ maltose bolus (24)(25)(26)(27). Alternatively, glycemic variability has been modeled using glucose injections in rats fed a high-fat diet (HFD) (28).…”

Association between Omentin-1 and Major Cardiovascular Events After Lower Extremity Endovascular Revascularization in Diabetic Patients: A Prospective Cohort Study

“…Despite similar baseline clinical characteristics-in terms of risk factor control and PAD severity-and the same endovascular approach, some patients do not encounter complications for years while other patients may have complications, even fatal, within a few months [26]. Several potential biomarkers have been proposed, some linked to patient's genetic characteristics [25,[27][28][29], many linked metabolic and in ammatory parameters [19,25,[30][31][32][33]. Among the possible candidates, the pathways linked to adipose tissue represent a promising eld of study.…”

Renal Vascular Disease

“…Furthermore, diabetes -induced renal damage is also amplifi ed by a signifi cantly blunted ECM turnover, largely through reductions of MMP activity [ 121 ]. Hyperglycemia has been shown to play a deleterious role on the function of cell progenitors [ 122 ] and on the VEGF-eNOS pathway, leading to impairment of the angiogenic response [ 123 ]. In the kidney, it has been suggested that hyperglycemia is initially associated with high but ineffective VEGF signaling that translates into a progressive MV dysfunction and damage in early diabetes [ 124 , 125 ].…”

“…Importantly, there is abundant experimental evidence that treatments that blunt fi brosis can also blunt vascular rarefaction, and vice versa [ 108 ]. In this context, targeting infl ammation and the resultant oxidative stress with an agent such as bindarit, which inhibits production of monocyte chemoattractant protein-1, may be a useful therapeutic approach [ 123 ].…”