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?

Abstract

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 HbA1c and avoidance of hypoglycaemia.

Complications of Diabetes and Metrics of Glycemic Management Derived From Continuous Glucose Monitoring

“…A case-control study confirmed the strong association ( r = 0.86) between MAGE and 8-iso-PGF2α urinary excretion rates ( 75 ), while another showed that transient hyperglycemia can induce lasting epigenetic changes in the promotor region of NFκB (a proinflammatory gene) in vitro and in mice ( 73 ). It is also established that high glycemia variability is associated with more frequent episodes of hypoglycemia, which contributes to a range of adverse effects including cardiovascular morbidity and mortality ( 76 ).…”

“…A narrative review by Livingstone et al ( 76 ) explored the glucose variability hypothesis—the notion that glucose variability contributes additional risk of diabetes complications after adjusting for HbA 1c . While they agreed mechanisms for glycemic variability causing complications exist, they concluded that there were insufficient data at the time to substantiate this hypothesis.…”

Carbohydrate Restriction in Type 1 Diabetes: A Realistic Therapy for Improved Glycaemic Control and Athletic Performance?

“…Controlling blood glucose levels after a diagnosis of T1D is a constant challenge, with continuous lifetime risk of both severe hypoglycaemia and severe hyperglycaemia with ketoacidosis [2]. In the long-term, people with T1D are at increased risk of micro- and macrovascular complications due to lifetime exposure to imperfect glucose control [3,4]. The American Diabetes Association (ADA) treatment guidelines suggest a target HbA1c of <7.0% (53 mmol/mol) in adults with T1D (7.5% for youth with T1D) to reduce the risk of long-term diabetes-related complications [5].…”

Lixisenatide in type 1 diabetes: A randomised control trial of the effect of lixisenatide on post‐meal glucose excursions and glucagon in type 1 diabetes patients

“…2 It is generally agreed that reducing glucose excursion after meal improves overall glycaemic control, 3 although recent reviews have cast a doubt on the effect of short glucose variability on long-term diabetes complications. 4 Glucagon levels are physiologically suppressed at high plasma glucose concentrations. In the absence of diabetes and in T2D, glucagon level is found to be higher after oral glucose compared with isoglycaemic intravenous glucose infusion, although more insulin is secreted when glucose is administered by the oral route.…”