Glycemic variability and diabetes retinopathy: A missing link

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Abstract

Daily glucose variability, such as fasting plasma glucose fluctuation or postprandial hyperglycemia, has been proposed as contributors to diabetes-related macrovascular complications. However, its impacts on microvascular complications, such as diabetes retinopathy remain controversial. We reviewed the current evidence of the relationship between glycemic variability and diabetes retinopathy in patients with type 1 or type 2 diabetes. In general, the short-term glycemic fluctuation, either expressed as standard deviation of fasting glucose or mean glucose levels, may contribute to the development or progression of diabetic retinopathy in patients with type 2 diabetes, whereas long-term glycemic fluctuation, reflected by variation of levels of HbA1c, appeared to show a stronger association with diabetes retinopathy both in patients with type 1 and type 2 diabetes. These findings emphasize the need to reduce glycemic variability by various measures in order to reduce development and progression of diabetes retinopathy both in type 1 and type 2 diabetes patients.

Introduction

It is well established that chronic hyperglycemia is one of the major determinants of late diabetic complications and mortality (Balkau et al., 2004, Turner et al., 1996). Recently, daily glucose variability has been proposed as a major contributor to the development of diabetes macrovascular complication. Not only fasting plasma glucose fluctuation (Muggeo et al., 1997, Muggeo et al., 2000), but also marked daily postprandial glucose variability was found to be associated with diabetes-related cardiovascular diseases (Cavalot et al., 2006, Ceriello, 2005, Group, D.S., 2001, Home, 2005). A recent review has highlighted the potential mechanisms of postprandial hyperglycemia in cardiovascular disease (Sheu et al., 2011).

Diabetic retinopathy (DR), a microvascular complication in diabetic populations, is currently the leading cause of blindness among working-aged persons in developed world (Cheung, Mitchell, & Wong, 2010). Many risk factors of DR have been proposed based on epidemiological and laboratory studies. Among them, results from both the Diabetes Control and Complications Trial (DCCT) in patients with type 1 diabetes (Group, T.D.C.a.C.T.R., 1993, Group, T.D.C.a.C.T.R., 1995), and the UK Prospective Diabetes Study (UKPDS) Group (Group, U.P.D.S.U., 1998) in patients with type 2 diabetes all confirmed the close relationship between levels of HbA1C and DR progression. However, the associations between glycemic variability and diabetes microvascular complications have so far attracted relatively little attention and yielded inconsistent findings. Results of an initial analysis in patients with type 1 diabetes from the DCCT showed that, with the same mean HbA1c value, glucose variability might account for the difference in microvascular outcome between intensively and conventionally treated patients (Group, T.D.C.a.C.T.R., 1995). However, a re-analysis of data obtained from the same group showed that HbA1C explained virtually all of the difference in risk of microvascular complications between the intensive and conventional groups while glucose variation only explained a small part of the differences in risk over time (Lachin, Genuth, Nathan, Zinman, & Rutledge, 2008). However, the results of two Japan investigations reported that excessive glucose excursions, especially in the postprandial state, were shown to be associated with both carotid atherosclerosis and diabetic retinopathy in patients with type 2 diabetes (Shichiri et al., 2000, Shiraiwa et al., 2005). Taken together, most studies in the literature show a positive association between glycemic variability and diabetes macrovascular complications, and suggest possible associations between glycemic variability and diabetes microvascular complications, particularly DR (Hirsch and Brownlee, 2005, Lachin et al., 2008). The aim of the present study was to review the evidence of the relationship between glucose variability and DR. We performed a structured literature search using PubMed and Embase according to the PICO (patient, intervention, comparison, and outcome) method (da Costa Santos, de Mattos Pimenta, & Nobre, 2007), which included the relevant literature published online up to June 2014.

Section snippets

Potential mechanisms of glycemic variability on vascular damage

The current hypothesis posits that the relationship between hyperglycemia and vascular complication involves excessive protein glycation and activation of oxidative stress. It was suggested that hyperglycemia could induce an activation of oxidative stress with mitochondrial superoxide overproduction of reactive oxygen species (ROS). This activation leads to a cascade of molecular mechanisms which include enhanced polyol activity, increased formation of advanced glycation end products, and

Type 1 diabetic mellitus

Among type 1 diabetic mellitus patients, glucose variability is especially pronounced due to the lack of basal insulin secretion and intensive insulin therapy (Bolli, Andreoli, & Lucidi, 2011). Emerging studies have found different results on the relationships of retinopathy progression with short-term fluctuations of hypoglycemia and hyperglycemia excursions. Early reports from the DCCT found that intensive glycemic control is a major determinant of the rate of development and progression of

Management of glycemic variability in DM retinopathy

Results from both the DCCT and UKPDS (Barr, 2001, Group, U.P.D.S.U., 1998) revealed that implementation of intensive glycemic control can significantly lower the progression of DM retinopathy compared with conventional treatment, which emphasizes the importance of early and sustained glycemic control. Glycemic variability has been identified as a predictor of cyclic hyperglycemia and hypoglycemia episodes and has been associated with microvascular and macrovascular complications (Holman et al.,

Conclusion

In the present literature review, short-term glycemic fluctuation, may contribute to the development or progression of diabetic retinopathy in type 2 diabetes, whereas long-term glycemic fluctuation, represented by HbA1c, appears to play a more important role in retinopathy in patients with type 1 or type 2 diabetes. Early and sustained glycemic control are crucial to the prevention and delay of retinopathy. Patients with high variations in FPG or HbA1c level should undergo close glycemic

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    Conflict of interest: There are no known conflicts of interest associated with this article and there has been no significant financial support for this work that could have influenced its outcome.

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