Glycemic variability and diabetes retinopathy: A missing link
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
References (56)
Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive insulin therapy, by The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. N. Engl. J. Med 342:381–9, 2000
Survey of Ophthalmology
(2001)- et al.
Can glycaemic variability, as calculated from blood glucose self-monitoring, predict the development of complications in type 1 diabetes over a decade?
Diabetes & Metabolism
(2008) - et al.
Diabetic retinopathy
Lancet
(2010) - et al.
Acarbose for prevention of type 2 diabetes mellitus: The STOP-NIDDM randomised trial
Lancet
(2002) - et al.
Fasting plasma glucose variability as a risk factor of retinopathy in type 2 diabetic patients
Journal of Diabetes and its Complications
(2003) - et al.
Should minimal blood glucose variability become the gold standard of glycemic control?
Journal of Diabetes and its Complications
(2005) - et al.
Nateglinide and acarbose for postprandial glucose control after optimizing fasting glucose with insulin glargine in patients with type 2 diabetes
Diabetes Research and Clinical Practice
(2011) - et al.
Postprandial glucose regulation: New data and new implications
Clinical Therapeutics
(2005) - et al.
Risks of diabetic nephropathy with variation in hemoglobin A1c and fasting plasma glucose
American Journal of Medicine
(2013) - et al.
MicroRNA-dependent cross-talk between VEGF and HIF1α in the diabetic retina
Cellular Signalling
(2013)
Glyoxalase I is critical for human retinal capillary pericyte survival under hyperglycemic conditions
Journal of Biological Chemistry
Addressing the burden of type 2 diabetes and cardiovascular disease through the management of postprandial hyperglycaemia: An Asian-Pacific perspective and expert recommendations
Diabetes Research and Clinical Practice
Post-prandial hyperglycemia is an important predictor of the incidence of diabetic microangiopathy in Japanese type 2 diabetic patients
Biochemical and Biophysical Research Communications
The effect of fasting plasma glucose variability on the risk of retinopathy in type 2 diabetic patients: Retrospective long-term follow-up
Diabetes Research and Clinical Practice
The effects of fasting plasma glucose variability and time-dependent glycemic control on the long-term risk of retinopathy in type 2 diabetic patients
Diabetes Research and Clinical Practice
Contribution of postprandial glucose to excess hyperglycaemia in Asian type 2 diabetic patients using continuous glucose monitoring
Diabetes/Metabolism Research and Reviews
Is fasting glucose variability a risk factor for retinopathy in people with type 2 diabetes?
Nutrition, Metabolism, and Cardiovascular Diseases
Standards of medical care in diabetes—2014
Diabetes Care
Prediction of the risk of cardiovascular mortality using a score that includes glucose as a risk factor. The DECODE Study
Diabetologia
Optimizing the replacement of basal insulin in type 1 diabetes mellitus: No longer an elusive goal in the post-NPH era
Diabetes Technology & Therapeutics
Biochemistry and molecular cell biology of diabetic complications
Nature
The pathobiology of diabetic complications: A unifying mechanism
Diabetes
Glycemic variability: A hemoglobin A1c-independent risk factor for diabetic complications
JAMA
Postprandial blood glucose is a stronger predictor of cardiovascular events than fasting blood glucose in type 2 diabetes mellitus, particularly in women: Lessons from the San Luigi Gonzaga Diabetes Study
Journal of Clinical Endocrinology and Metabolism
Postprandial hyperglycemia and diabetes complications: Is it time to treat?
Diabetes
Acarbose treatment and the risk of cardiovascular disease in type 2 diabetic patients: A nationwide seven-year follow-up study
Journal of Diabetes Research
The PICO strategy for the research question construction and evidence search
Revista Latino-Americana de Enfermagem
Glucose tolerance and cardiovascular mortality: Comparison of fasting and 2-hour diagnostic criteria
Archives of Internal Medicine
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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.