How tightly controlled do fluctuations in blood glucose levels need to be to reduce the risk of developing complications in people with Type 1 diabetes?

In 2011, the James Lind Alliance published a 'top 10' list of priorities for Type 1 diabetes research based on a structured consultation process. Whether reducing fluctuations in blood glucose can prevent long-term microvascular and macrovascular complications was one of these. In this narrative review, 8 years on, we have assessed the updated evidence for the assertion that increased glucose variability plays an independent and clinically important role in the complications of Type 1 diabetes, over and above mean blood glucose and the effects of hypoglycaemia: the 'glucose variability hypothesis'. Although studies in cultured cells and ex vivo vessels have been suggestive, most studies in Type 1 diabetes have been small and/or cross-sectional, and based on 'finger-prick' glucose measurements that capture glucose variability only in waking hours and are affected by missing data. A recent analysis of the Diabetes Control and Complications Trial that formally imputed missing data found no independent effect of short-term glucose variability on long-term complications. Few other high-quality longitudinal studies have directly addressed the glucose variability hypothesis in Type 1 diabetes. We conclude that there is little substantial evidence to date to support this hypothesis in Type 1 diabetes, although increasing use of continuous glucose monitoring provides an opportunity to test it more definitively. In the meantime, we recommend that control of glycaemia in Type 1 diabetes should continue to focus on the sustained achievement of target HbA and avoidance of hypoglycaemia.