Glucose variability and diabetes complications: Risk factor or biomarker? Can we disentangle the "Gordian Knot"?

« Variability in glucose homoeostasis » is a better description than « glycaemic variability » as it encompasses two categories of dysglycaemic disorders: i) the short-term daily glucose fluctuations and ii) long-term weekly, monthly or quarterly changes in either HbA1c, fasting or postprandial plasma glucose. Presently, the relationship between the "variability in glucose homoeostasis" and diabetes complications has never been fully clarified because studies are either observational or limited to retrospective analysis of trials not primarily designed to address this issue. Despite the absence of definitive evidence from randomized controlled trials (RCTs), it is most likely that acute and long-term glucose homoeostasis "cycling", akin to weight and blood pressure "cycling" in obese and hypertensive individuals, are additional risk factors for diabetes complications in the presence of sustained ambient hyperglycaemia. As hypoglycaemic events are strongly associated with short- and long-term glucose variability, two relevant messages can be formulated. Firstly, due consideration should be given to avoid within-day glucose fluctuations in excess of 36% (coefficient of variation) at least for minimizing the inconvenience and dangers associated with hypoglycaemia. Secondly, it seems appropriate to consider that variability in glucose homoeostasis is not only associated with cardiovascular events but is also a causative risk factor via hypoglycaemic episodes as intermediary step. Untangling the" Gordian Knot", to provide confirmation about the impact of variability in glucose homoeostasis and diabetes complications remains a daunting prospect.