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Hyperglycaemia link to corneal damage

2nd November 2023

A new population-based study, reported in a recent issue of Diabetologia, uses confocal microscopy to show that dysfunctional glucose metabolism is linked to corneal neurodegeneration. The findings suggest that nerve damage may start well before the onset of type 2 diabetes and early tight control of glycaemia may help protect from both corneal damage and diabetic neuropathy. Dr Susan Aldridge reports. 

The damage inflicted by hyperglycaemia may start long before the onset of type 2 diabetes. The authors of this paper have previously shown links between adverse glucose metabolism and various measures of neurodegeneration, for example. Chronic hyperglycaemia also leads to the formation of advanced glycaemic end-products (AGEs), which initiate neurodegeneration. Since AGEs have intrinsic fluorescence, they can be measured non-invasively as skin autofluorescence (SAF). The authors have shown that AGEs assessed as SAF are associated with lower retinal nerve fibre layer thickness. 

Current methods for monitoring central and peripheral nervous system activity are costly and time consuming and therefore not suitable for routine and large-scale use. There is a need for a sensitive and practical method for detecting early hyperglycaemia-mediated neurodegeneration. 

Therefore, Sara Mokhtar and Frank van der Heide from Maastricht University and colleagues have looked at how hyperglycaemia affects morphological changes in small nerve fibres, using confocal microscopy to assess corneal nerve degeneration. Confocal microscopy has the advantage of being an in-vivo, non-invasive and sensitive method for assessing neurodegeneration. 

Previous research has suggested that hyperglycaemia does affect the corneal nerve fibres and that these changes can also be an early indicator of diabetic neuropathy, which could allow timely diagnosis and intervention. However, these studies had a number of limitations – they were not population-based, did not control for lifestyle and cardiovascular risk factors and did not investigate the link between glycaemia and corneal nerve fibre damage in detail. This new study used data from a large and well-characterised population-based cohort study – the Maastricht Study – to look at whether a more adverse glucose metabolism status and higher measures of glycaemia are associated with neurodegeneration using corneal confocal microscopy to obtain various measures of corneal nerve fibre damage. 

The Maastricht Study

The Maastricht Study is an observational prospective population-based study that includes many people with type 2 diabetes. Its main focus is on the aetiology, pathophysiology, complications and comorbidities of type 2 diabetes. This current study comprised 3471 participants, of whom 729 had type 2 diabetes and 509 had prediabetes. The researchers took measures of glucose metabolism status and glycaemia, including SAF. Using confocal microscopy, they also measured corneal nerve bifurcation density, corneal nerve density, corneal nerve length and corneal nerve fractal dimension. 

Together, these measures give a detailed picture of the state of the corneal nerve and were combined and analysed to give a composite Z-score. Statistical analysis accounted for a number of potential confounding factors, such as age, sex, hypertension, smoking and so on, which might contribute to hyperglycaemia and corneal neurodegeneration.  

Hyperglycaemia and the corneal nerve

Overall, participants with a lower composite Z-score for corneal nerve fibre measures were older and had an adverse cardiovascular risk profile. Those with type 2 diabetes and prediabetes also had lower Z-scores. When it came to specific measures of glycaemia, higher measures of fasting plasma glucose, 2-h post-load glucose, HbA1c, SAF and duration of diabetes were all associated with a lower Z-score. In general, directionally similar associations were noted for the individual corneal nerve fibre measures that contribute to the composite Z-score. Moreover, these associations were linear across glucose metabolism categories, which implies that glycaemia-associated corneal nerve damage starts well before the onset of type 2 diabetes. 

This is the first large population-based study to investigate glycaemia-associated corneal nerve damage across glucose metabolism categories with adjustment for a large number of previous potential confounding factors. This is also the first study to show a linear association between fasting plasma glucose, 2-h post-load glucose, SAF and duration of diabetes with corneal nerve measures.

These new findings are in line with the ‘ticking clock hypothesis’, which states that glycaemia-induced microvascular and neuronal deterioration is a continuous process, starting long before the onset of type 2 diabetes, gradually worsening through prediabetes and as type 2 diabetes progresses. They are comparable to previous findings on retinal nerve fibre layer thickness, brain structural abnormalities, peripheral nerve function and heart rate variability – all measures of neurodegeneration and/or neural dysfunction. 

Additionally, this study shows that AGEs are involved in the pathophysiology of corneal neurodegeneration. SAF, which reflects the accumulation of AGEs in the skin, was significantly associated with lower composite Z-score for corneal nerve measures. And this was the case even after adjusting for fasting plasma glucose, 2-h post-load glucose or HbA1c. 

Implications for clinical practice

This study suggests that early glycaemic control is essential for the prevention of neurodegeneration, both in the cornea and maybe elsewhere. Glycaemia-associated morphological changes in the corneal nerves seems to be a process that starts well before the onset of type 2 diabetes. Whether early intervention to reduce hyperglycaemia can prevent this requires further study. 

Also, corneal neurodegeneration may be a biomarker for diabetic neuropathy. Therefore, measuring corneal nerve fibres could be a relatively inexpensive way of detecting the early stages of neuropathy. The authors say that their findings suggest that corneal degeneration starts before the development of clinical sensory neuropathy, so can be seen as an early warning sign. In conclusion, corneal confocal microscopy could be used to detect neurodegeneration and neuropathy at the very earliest stages of type 2 diabetes pathophysiology. 

To read this paper, go to: Mokhtar SBA, van der Heide FCT, Oyaert KAM, van der Kallen CJH, Berendschot TTJM, Scarpa F, Colonna A, de Galan BE, van Greevenbroek MMJ, Dagnelie PC, Schalkwijk CG, Nuijts RMMA, Schaper NC, Kroon AA, Schream MT, Webers CAB, Stehouwer CDA. (Pre)diabetes and a higher level of glycaemia measures are continuously associated with corneal degeneration assessed by corneal confocal microscopy: the Maastricht Study. Diabetologia 17 August 2023

To learn more, enrol on the EASD e-Learning courses ‘Management of hyperglycaemia in type 2 diabetes’ and ‘Diabetic foot disease’.

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.